286‒Journal club with Andrew Huberman: light exposure on mental health & an immunotherapy for cancer

1. 0:00 – 9:13

   0:00:11-Relationship between light exposure, circadian rhythms, & mental health

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the "Drive" podcast. I'm your host, Peter Attia. Andrew, great to have you here for Journal Club number two. I'm already confident this is gonna become a regular for us.

   2. AHAndrew Huberman0:17

      I'm excited. I really enjoy this because I get to pick papers I'm really excited about. I get to hear papers that you're excited about, and we get to, um, sharpen our skills at reading and sharing data, and people listening can do that as well.

   3. PAPeter Attia0:33

      So last time I went first, so, uh, I think I'm gonna put you on the hot seat first and have, uh, have you go first, and I'll follow you.

   4. AHAndrew Huberman0:40

      Okay. Well, I'm really excited about this paper, um, for a number of reasons. First of all, it, at least by my read, is a very powerful paper in the sense that it examined light exposure behavior as well as dark exposure behavior, and that's gonna be an important point in more than eighty-five thousand people as part of this, um, cohort in the UK. Um, I'll just mention a couple of things to give people background, and I'll keep this relatively brief. First of all, there's a long-standing interest in the relationship between light and mental health and physical health, and we can throw up some very well agreed upon bullet points. First of all, there is such a thing as seasonal affective disorder. It doesn't just impact people living at really northern locations. But basically, there's a correlation between day length and mood and mental health, such that for many people, not all, but for many people, when days are longer in the spring and summer, they feel better. They report fewer depressive symptoms. And conversely, when days are shorter, significantly more people report feeling lower mood and affect, okay? So there's a long-standing treatment for seasonal affective disorder, which is to give people exposure to very bright light, especially in the morning. The way that that's normally accomplished is with these SAD lamps, seasonal affective disorder lamps, and those lamps are basically bright, meaning more than ten thousand lux lights that they place on their kitchen counter or at their table in the morning or in their office, so they're getting a lot of bright light. That has proven to be fairly effective for the treatment of seasonal affective disorder. What's less understood is how light exposure in the middle of the night can negatively impact mood and health. And so where we're, we are headed with this is that there seems to be, based on the conclusions of this new study, a powerful and independent role of both daytime light exposure and nighttime dark exposure for mental health. Now, a couple of other key points. The biological mechanisms for all this are really well established. There's a set of cells in the neural retina, which aligns the back of your eye. They're sometimes called intrinsically photosensitive retinal ganglion cells or sometimes called melanopsin retinal ganglion cells. We'll talk about those in a bit of detail in a moment. It's well known that those cells are the ones that respond to two different types of light input. Not one, but two different types of light input, and send information to the hypothalamus, where your master circadian clock resides. And then your master circadian clock sends out secretory signals, so peptides, hormones, but also neural signals to the brain and body and say, "Hey, now it's daytime. Now it's nighttime. Be awake. Be asleep." But it goes way beyond that. These melanopsin intrinsically photosensitive retinal ganglion cells we know also project to areas of the brain like the habenula, which can trigger negative affect, negative mood. They can trigger the release of dopamine or the suppression of dopamine, the release of serotonin, the suppression of do- of serotonin. And so they're not just cells for setting your circadian clock. They also have a direct line, literally one synapse away, into the structures of the brain that we know powerfully control mood. So, so the mechanistic basis for all this is there. So there's just a couple of other key points to understand for people to really be able to digest the data in this paper fully. There are basically two types of stimuli that these cells respond to. One is br- very bright light, as we just talked about. That's why getting a lot of daytime sunlight is correlated with elevated mood. That's why looking at a ten thousand lux artificial lamp can offset seasonal affective disorder.

   5. PAPeter Attia4:37

      By the way, just a couple questions on that. Um, how many lux does the sun provide on a sunny day at noon?

   6. AHAndrew Huberman4:44

      Okay, great question. So if you're out in the sun with no cloud cover or minimal cloud cover in the middle of the day at noon, chances are it's over a hundred thousand lux. Ch- on a really bright day, could be three hundred thousand lux, okay? Most indoor environments, even though they might seem very bright-- I like to think of your, your kind of like, uh, department store with the bright lights. Believe it or not, that's probably only closer to six thousand lux maximum and probably more like four thousand lux. Most brightly lit indoor environments are not that bright when it comes down to total photon energy. Now, h-here's the interesting thing. On a cloudy day, when you're outside, it can be as bright as or an average of a hundred thousand lux, but it won't seem that bright because you don't, quote-unquote, "see the sun." But it's also because when there's cloud cover, a lot of those long wavelengths of light, such as orange and red light, aren't coming through. However, and this is so important, the circadian clock, the suprachiasmatic nucleus, it sums photons. It's a photon summing system. So basically, if you're outside in eight thousand lux, very overcast UK winter day, and you're walking around hopefully without sunglasses, because sunglasses are going to filter a lot of those photons out, your circadian clock is summing the photons. So it's an integration mechanism. It's not triggered in a moment. And actually, the, the experiments of recording from these cells first done by David Berson at Brown were, you know, historic in the field of visual neuroscience when shown br- bright light on these intrinsically photosensitive cells. You could crank up the intensity of the light and the neurons would ramp up their membrane potential and then start spiking, firing action potentials, long trains of action potentials that have been shown to go on for hours. And so that's the signal that's propagating into the whole brain and body. Okay, so the, the important thing to understand is this is not a quick switch. That's why I suggest on non-cloudy days, we'll call them, that people get ten minutes or so of sunlight in their eyes in the early part of the day, another ten minimum in the later part of the day, as much sunlight in their eyes as they safely can throughout the day. But since you're a physician, I should just, um, and you had a guest on talking about this recently. When the sun is low in the sky, low solar angle sunlight, that's really the key time for reasons we'll talk about in a moment. And when the sun is low in the sky, you run very, very little risk of inducing cataract by looking in the general direction of the sun. You should still blink as needed to protect the eyes. It's when the sun is overhead and there's all those photons coming in quickly in one-- in a short period of time that you do have to be concerned about cataract and, um, macular degeneration if you're getting too much daytime sunlight. So the idea is sunglasses in the middle of the day are fine, but you really should avoid using them in the early and later part of the day unless you're driving into the sun and you need-- you know, for safety reasons.

   7. PAPeter Attia7:58

      Another question, Andrew.

   8. AHAndrew Huberman7:59

      Yeah.

   9. PAPeter Attia7:59

      If, if a person is indoors, but they have large windows, so they're s- they're getting tons of sunlight into their space, they don't even need ambient indoor light. How much of the photons are making it through the glass, and how does that compare to this effect?

   10. AHAndrew Huberman8:16

       Yeah. In general, unless the light is coming directly through the window, most of the relevant wavelengths are filtered out.

   11. PAPeter Attia8:24

       In other words, if you can't see the sun through the window, even if sufficient light is being provided, that's insufficient to trigger this phenomenon?

   12. AHAndrew Huberman8:32

       That's right. However, if you have, um, you know, windows on your roof, which some people do, skylights, that makes the situation much, much better. In fact, the neurons that-- in the eye that signal to the circadian clock and these mood centers in the brain reside mainly in the bottom two-thirds of the neural retina and are responsible for looking up, basically. They're gathering light from above. These cells are also very low resolution, so s- think of them as big pixels. Uh, they're not interested in patterns and edges and movement. They're interested in how much ambient light there happens to be. Now, keep in mind that this mechanism is perhaps the most well-conserved mechanism in cellular organisms.

2. 9:13 – 15:25

   Importance of low solar angle sunlight

   1. AHAndrew Huberman9:13

      So they're-- And I'll use that as a way to frame up the four types of light that one needs to see every twenty-four hours for optimal health. And, and when I say optimal health, I really mean mental health and physical health, but we're going to talk about mental health mainly today in this paper. There's an absolutely beautiful evolutionary story whereby single-cell organisms all the way to humans, dogs, rabbits, and everything in between have at least two cone opsins, one that responds to short wavelength light, AKA blue light, and another one that responds to longer wavelength light, orange and red. So your dogs have this, we have this, and it's a comparison mechanism in these cells of the eye, these neurons of the eye. They compare contrast between blues and orange, or sometimes blues and reds and pinks, which are also all long wavelength light. There are two times of day when the sky is enriched with blues, oranges, pinks, and reds, and that's low solar angle sunlight at sunrise and in the evening. These cells are uniquely available to trigger the existence of those wavelengths of light early in the day and in the evening, not in the middle of the day. So these cells have these two cone photopigments, and they say, how much blue light is there? How much red light is there, or orange light? And the subtraction between those two triggers the signal for them to fire the signal off to the cir- circadian clock of the brain. And that's why I say look at low solar angle sunlight early in the day. What that does is it-- what we call it is phase advances the clock. This can get a little technical, and we don't want to get too technical here, but think about pushing your kid on a swing. The period of that swing, the duration of that swing is a little bit longer than twelve hours, okay? So when you stand closer to the kid, so he's-- your kid swings back and you give it an, a push, you're shortening the period, right? You're not allowing the swing to come all the way up. That's what happens when you look at morning sunlight. You're advancing your circadian clock. Translated to English or non-nerd speak, you're making it such that you will want to go to bed a little bit earlier and wake up a little bit earlier the next day. In the evening, when you view low solar angle sunlight, so in the aft- the afternoon setting sun or evening setting sun, you do the exact opposite. You're phase delaying the clock. It's the equivalent of your kid being at the very top of the s- of the arc. And so it's gone, you know, maybe twelve and a half hour, uh, twelve-- let's say twelve and a half hours is the duration of that swing, and you run up and you push them from behind and give them a little more push. That's the equivalent of making yourself stay up a little later and wake up a little later. These two signals average so that y- your clock stays stable. You don't drift, meaning you're not waking up earlier every single day or going to sleep later every single day. This is why it's important to view low solar angle sunlight in the morning and again in the evening as often as possible. And it's done by that readout of those two photopigments. Now, midday sun which contains its bright light, but you see it as white light, contains all of those wavelengths at equal intensity. So the middle of the day is the so-called circadian dead zone. In the middle of the day, bright light triggers the activation of the, of the other opsin, the melanopsin, which increases mood, increases feelings of wellbeing, has some other consequences, but you can't shift your circadian clock by viewing the sun in the middle of the day because it's in the circadian dead zone. It's the equivalent of pushing your kid on the swing when they're at the bottom of the arc. You can get a little bit more, but not much, and in biological terms, you get nothing. So this is why looking at sunlight in the middle of the day is great, but it's not gonna help anchor your sleep-wake cycle. And if you think about it, this is incredible, right? Every organism, from single cells to us, has this mechanism to know when the sun is rising and when the sun is setting, and it's a color comparison mechanism, which tells us that actually color vision evolved first not for pattern vision, not for seeing beautiful sunsets and recognizing that's beautiful or paintings or things of that sort, but rather for setting the circadian clock.

   2. PAPeter Attia13:31

      Now, what if you only do one of these, Andrew? So what if you've got constant exposure to low morning light, but [clears throat] your job prevents you from doing the same in the evening or vice versa?

   3. AHAndrew Huberman13:42

      Yeah, a great question. Better to get the morning light because if, if you have to pick between low solar angle light early or later in the day. And keep in mind, if you miss a day, no big deal. It's a slow integrative mechanism averaging across the previous two or three days. But if you miss a day, you'll wanna get twice as much light in your eyes that next morning. The reason it's better to do in the morning as opposed to the evening, although both would be to do-- uh, best would be to do both, excuse me, is that most people are getting some artificial light exposure in the evening anyway. And here's the diabolical thing. Your retina is very insensitive to light early in the day. You need a lot of photons to trigger this mechanism early in the day. As the day goes on, retinal sensitivity increases, and it takes very little light to shift your circadian clock late in the day. Keep in mind also that if you do see afternoon and evening sunlight, there's a beautiful study published in Scien- uh, Science Reports, uh-- yes, Science Reports two years ago showing that that can partially offset the negative effects of artificial light exposure at night. I think of this as your Netflix inoculation. And the amount of melatonin suppression from nighttime light exposure is halved by viewing evening setting sun. Now, keep in mind you don't need to see the sun cross the horizon. It can just be when it's low solar angle. So you're looking for those yellow-blue or blue-pink, blue-red contrasts. And on cloudy days, believe it or not, they're still there, just you don't perceive as much of it coming through. So there really-- So that's three things that we should all strive to do. View low solar angle sunlight early in the day, view solar angle sunlight later in the day, and get as much bright light in our eyes as we safely can, ideally from sunlight, throughout the day.

3. 15:25 – 17:51

   Lightbulb technology that simulates low solar angle sunlight

   1. AHAndrew Huberman15:25

      And if you can't do that, g- perhaps invest in one of these, uh, SAD lights, although they can be a bit expensive. Uh, there are a couple companies that are starting to design sunrise simulators and evening simulators that are actually good, that actually work. Um, but right now, my read is that aside from one company out there, which by the way I have no relationship to, it's called the Tuo light, T-U-O, and that light bulb was developed by the biologists at the University of Washington who basically discovered these color opponent mechanisms. Um, those lights are not particularly expensive, but they're, um, th-they do seem to work. In fact, they, they're-- The study that is emerging, again, unpublished data, seems to indicate that if you look at it for more than five or six minutes, it can induce a mild euphoria. That's how powerful this contrast is. And what they did there in that light, I'll just tell you the mechanism, is they figured out that when most people look at low solar angle sunlight in the morning, they're getting 19 reversals of blue-orange per second. So when you look at this light, it looks like a, a barely flashing, uh, white light, but it's reversals of orange and blue, orange and, um, and, you know, red and blue, and it's happening very fast.

   2. PAPeter Attia16:36

      And so what does the, what does the person looking at it perceive?

   3. AHAndrew Huberman16:39

      Um, well, I've used one of these. Um, it just looks like a, a flickering light. And of course, there's the, always the potential of a placebo effect, but-

   4. PAPeter Attia16:46

      Well, that's what I was gonna say. Is there a way to control for that by having something that looks the same to the user-

   5. AHAndrew Huberman16:53

      Yeah

   6. PAPeter Attia16:53

      ... but of course is not producing the same photo effect?

   7. AHAndrew Huberman16:56

      Yeah. Well, they've done that with the 10,000 lux SAD lamps, and you would-- and which most people use to try and induce sunrise simulation in their home. But keep in ri- in mind that sunrise is-- gives you this comparison of short and long wavelength light. Just a bright 10,000 lux light triggers one of the opsins that, that-- but it won't set your circadian clock. So most of the SAD lamps that are out there are activating only one of the mechanisms in these cells that's relevant and not the one that's most relevant. So I'm excited about what Tuo is doing. I think that, um, and again, I have no relation to them except that I know the biologists who did the work that, that provide the mechanistic logic for the, that engineering. I still think, um, we're in the, like, the really, like, early days of this stuff. What should be done is to have this stuff built into your laptop, right? It should be built into your phone, and hopefully it will be.

4. 17:51 – 20:22

   Significance of darkness & the need for direct light exposure to the eyes

   1. AHAndrew Huberman17:51

      Now, I mentioned this color contrast thing in sunrise and sunset. I mentioned the bright light throughout the day. But there's a fourth light stimulus that turns out to be really important, and this will, will provide the segue into the paper. Turns out that dark exposure at night, independent of light exposure during the day, is important for mental health outcomes. Now, most people think dark exposure, how do I think about that? Well, it is dark, yes.

   2. PAPeter Attia18:16

      Absence of light exposure?

   3. AHAndrew Huberman18:17

      It's the absence of light, but what this paper really drives home is that people who make it a point to get dark exposure at night, AKA the absence of light at night, actually benefit even if they're not getting enough sunlight during the day. And this is especially true for people with certain mental health issues. So I don't think we can overstate the value of of accurately timed light exposure to the eyes in the context of mental health. I think, you know, there's so much data by now. I will say, however, that some people seem more resilient to these light effects than others, meaning some people, you know, also don't suffer from jet lag too much. Some people can stay up late, get a lot of bright light exposure in the middle of the night, and during the day, they've got their sunglasses on all day, and they're in a great mood all the time. Other people are more susceptible to these sorts of things, and we don't know whether or not genetic polymorphisms underlie that. I personally am very sensitive to sunlight in the sense that if I don't get enough sunlight, I don't feel well after a couple of days. Um, but I'm less sensitive to light exposure at night, for instance. But I think it is perhaps, this is a big statement, but is perhaps the most fundamental environmental stimulus for levels of arousal and alertness, which correlate with all sorts of, you know, neuromodulator and hormone outputs. And, um, so it-- none of this should come as any surprise. I will mention one last thing. There was a study published, gosh, over ten years ago now from Chuck Czeisler's lab at Harvard Medical School. It was a phenomenal lab exploring circadian human health behavior. He's just considered a l- huh, no pun, a luminary in the field. But there wasn't a study that was in error where they had published in Science Magazine that light shone behind the knee could shift circadian rhythms, and that paper was retracted. Um, and a lot of people don't know that it was retracted. Light exposure to the eyes is what's relevant here. And as far as we know, the color of one's eyes, like darkness or lightness of one's eyes, bears no relevance on their sensitivity to these types of mechanisms and on and on. Yeah.

   4. PAPeter Attia20:21

      So, so

5. 20:22 – 23:57

   Tips regarding optimizing light exposure & effects on circadian rhythm

   1. PAPeter Attia20:22

      one question, one comment. The question again is going back to the morning, evening light. And I spend a lot of time looking at those types of skies, for example, just 'cause of m- the nature of my hobbies.

   2. AHAndrew Huberman20:32

      Great.

   3. PAPeter Attia20:32

      Right? 'Cause I'm always doing archery in the morning and rucking in the afternoon, so it's not uncommon that I'm seeing both of those. How relevant is it that the sun be above the horizon? So for example, um, it begins to get light about in thirty minutes before sunrise.

   4. AHAndrew Huberman20:49

      Mm-hmm.

   5. PAPeter Attia20:49

      And then, you know, right at-- So if sunrise is at seven thirty, first light is seven, and then, you know, sort of seven fifteen to seven, uh, thirty is actually quite bright. I mean, you can see anything and everything, and the same is true at sunset. So does, does that thirty minutes pre or when sun is beneath the horizon constitute part of that ten minutes?

   6. AHAndrew Huberman21:10

      It does. I mean, in an ideal circumstance, you'd get outside and see the sunrise every day, and you'd see the sunset every day, even on cloudy days. Some people, like myself, wake up before the sun comes up, in which ca-- and I get this question all the time. Well, in the absence of powers to make the sunrise faster, which I'm not aware anyone has, certainly not me, I think the best thing to do is simply to turn on as many bright lights as you can indoors to trigger that melanopsin mechanism if you want to be awake. If you want to stay asleep or sleepy, then keep them dim, and then get outside once the sun is starting to come out. Some people wake up after the sun has risen, right? In which case, get what you can. And some people wake up ten AM or noon, in which case you can still get the bright light exposure, but you won't shift your circadian clock. Now, in the evening, especially in the winter months, it's important to look west and try and get some sunlight in your eyes in the evening. If you've ever gone into the clinic, for instance, at two o'clock in the afternoon after lunch, you know, and then in the winter, and then come out and it's dark when you walk into your car, it's a kind of eerie feeling. That sort of eerie feeling may correlate with the fact that y-you missed a signal. Your, your brain is trying to orient your brain and body in time, and that's what all of this is, right? It's trying to orient in time. And again, some people are more susceptible to that than others. Some people might like that, um, feeling of, oh, I went in when it was bright and I come out when it's dark. But the vast majority of people feel better when they're getting this morning and evening sunlight exposure. And this is especially important in kids. All right? This is one of the things that, you know, this paper points out, and there are good data, that people are spending approximately ninety percent of their time indoors nowadays. N-- daytime time indoors. And those indoor environments are simply not bright enough. You think, oh, there's all these bright lights, and some people are putting blue blockers on in the middle of the day, which is the worst thing you could possibly do. If you're gonna wear blue blockers, and I don't think they're necessary, but if you're going to wear them, you'd want to wear them at night. And in the evening, you don't need to wear blue blockers. You just simply should dim the lights and ideally have lights that are set a little bit lower in your environment, which the Scandinavians have been doing for a long time. So, you know, kill the overhead lights. And don't obsess about bright light exposure in the middle of the night. In fact, for a long time, I and some other people were saying, oh, you know, even just a brief flash of light in the middle of the night can, you know, quash your melatonin. That's true. But the other time in which you're in this quote unquote circadian dead zone is in the middle of the night. You can't shift your circadian clock in the middle of the night. But, you know, all of this gets down to interweaving rhythms of light sensitivity, temperature, hormone output, cortisol. It-- I mean, there's a whole landscape of circadian biology.

6. 23:57 – 33:31

   Andrew presents a paper which suggests avoiding light at night & seeking light during the day is associated with better mental health

   1. AHAndrew Huberman23:57

      This paper, um, which was published in a new journal I'm really excited about called Nature Mental Health, this journal was just launched recently, um, is entitled Day and Night Light Exposure Are Associated with Psychiatric Disorders: An Objective Light Study in More Than Eighty-Five Thousand People. Now, I have to say that I think the title of this paper is terrible. Sorry, folks at Nature Mental Health. Because if one just read the title, it sounds like day and night light exposure are associated with psychiatric disorders, right [chuckles] If this were, if this were a newspaper headline, you'd be like, "Oh my goodness. Well, what are you supposed to do?" Right? But that's not the conclusion. The conclusion is that getting a lot of sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health. And in a number of ways. Now, I'm not one to bring up a- another paper unannounced, but I will say that this paper built off a previous study entitled "Time Spent in Outdoor Light is Associated with Mood, Sleep, and Circadian Rhythm-Related Outcomes," and that was a cross-sectional longitudinal study in 400,000 biobank participants. So this UK Biobank is an incredibly valuable resource, and there are now multiple studies establishing that one's pattern of light exposure is extremely important. Now, the previous study in 400,000 participants basically nailed home the idea that the more time you spend outdoors, the better your, is your mood, the better is your sleep, the better is the rhythmicity of your sleep-wake cycles, and on and on. Something that I think, even though people will say, "We've known that for thousands of years," needed scientific substantiation. This new study essentially looked at the relative contributions of daytime light exposure and nighttime dark exposure, and they did that on a background of it looking pr- in particular at people who had major depressive disorder, generalized anxiety, PTSD, bipolar disorder. H- here's the, the basic takeaway, and I'll, I'll quote them here, and then I'll g- I'll tell you my interpretation. The... Here I'm quoting, "Avoiding night at light and seeking light during the day," I love that word seeking, "may be a simple and effective non-pharmacologic means for broadly improving mental health." So that's a pretty bold statement, right? And I love that they say seeking because it implies that people aren't reflexively getting the light exposure that they need, that this needs to be a practice m- much like Zone 2 cardio or resistance training. Okay, so what, so what do they do in this study? So basically, they gathered up 100,000 people or so. It eventually was pared down to about 86,000 participants 'cause some just didn't qualify or didn't report their data back. They equipped them with accelerometers on their wrist, and those wrist devices also could measure ambient light. Now, that's not a perfect tool 'cause what you'd love to do is measure ambient light at the level of the eyes. By the way, will somebody design an eyeglass frame that changes color when you've gotten sufficient light from sunlight during the day, and then ch- and then at night is a different color, and then if you're getting too much light exposure will go to a different color frame? This has to be possible so that you don't have to wonder if you got enough light during the day. And of course, if it's at the level of the eyes, then you know that's what's landing at the eyes.

   2. PAPeter Attia27:18

      Yeah, and it's la-- I mean, that's what I was gonna ask you about that. Uh, uh, do these wrist-based devices potentially get covered by clothing in some-

   3. AHAndrew Huberman27:25

      Yep. Turned over

   4. PAPeter Attia27:25

      ... like, you, you have your sleeves down.

   5. AHAndrew Huberman27:26

      Yeah.

   6. PAPeter Attia27:27

      I have my sleeves up.

   7. AHAndrew Huberman27:27

      Yeah. They had it on the outside of the sleeve, but they asked that people just keep it on their dominant hand. It's not perfect, but in some ways it's kind of nice that it's not perfect. We could turn that disadvantage into an advantage by thinking, you know, when the person is out and about, they're not often looking right at the sun, you know, if you're talking to a colleague under an overhang, for instance. So it's, it's not perfect.

   8. PAPeter Attia27:49

      It's directionally-

   9. AHAndrew Huberman27:50

      It's directionally right.

   10. PAPeter Attia27:51

       Yeah.

   11. AHAndrew Huberman27:51

       Okay. And then they had two hypotheses, two primary hypotheses. One, that greater light exposure in the day is associated with lower risk for psychiatric disorders, and two, second hypothesis, greater light exposure at night is associated with higher risk for psychiatric disorders and poorer mood. This is oh so relevant for the way we live now, people on screens and tablets in the middle of the night. Okay. Then they collected information about how much light exposure people were getting, as well as their sleep and their activity and so on. I should mention this was done in males and females. It was a slightly older cohort than one is used to seeing, people in their 50s and 60s. They had psychiatric diagnosis information. And then they divided people into essentially two groups, but they had a lower, so a Q1 and a Q2, a lower quartile. That meant people that were getting less daytime light as opposed to the third and fourth quartile, more daytime light. They also had a nighttime light exposure evaluation, and they had people w- in the low Q1 and Q2, so these people are getting less nighttime light versus Q3, Q4, more nighttime light. Nicely, they also looked at sleep duration, and they looked at photoperiod, meaning how long the days were for those individuals, how active they were. What, 10 hours a day? 14 hours a day? Because the more active you are, the more opportunity for light exposure you have during the day or night, for instance. Okay. So it... They had, I would say, fairly complete datasets. Then, and I'm just gonna kind of to- hit the top contour of what they did in each-

   12. PAPeter Attia29:26

       And sorry, sleep duration, sleep efficiency, et cetera-

   13. AHAndrew Huberman29:29

       Yeah

   14. PAPeter Attia29:29

       ... was determined off the accelerometer?

   15. AHAndrew Huberman29:31

       That's right, as well as self-report. Yeah. Not, not ideal, right? You'd love to- for people to be wearing a Whoop band or, or, or a ring or something of that sort, but this was initiated some time ago, so, um, they either didn't have access to that technology or for whatever reason didn't select it. Then what they did is they got-- They have information on who has major depressive disorder, who has PTSD, generalized anxiety, bipolar, psychosis, et cetera, and then they ran three models. And you can tell me what you think about the power of these models, but you know, as somebody who thinks about the mechanistic aspect of all of this a lot, but not somebody who's ever run this type of study, I'd be really curious. Model one examined the unadjusted association between day and nighttime light exposure and psychiatric outcomes. So just basically asking, is there a relationship between how much light you get a- during the day and how much light you get at night, and how bad your, or your depression is or anxiety is, et cetera? Looking at, you know, just a standard ratio of the probability that you have a certain symptom or set of symptoms versus you don't, given a certain amount of light exposure. Model two adjusted for the age of the person, their sex and ethnicity And photo period. So they looked at, you know, how long the days were in that given person's region of the world. And then model three also-

   16. PAPeter Attia31:00

       All these people were all in the UK or were they around the world?

   17. AHAndrew Huberman31:02

       They were all in the UK.

   18. PAPeter Attia31:02

       Okay. All right.

   19. AHAndrew Huberman31:03

       As far as I know. And then model three adjusted for employment, so employed versus unemployed, which if you think about it, is pretty important. Like, you say, well, an unemployed person has a lot more time to control these variables, but an employed person who's doing shift work does not, right? And they, they incorporated information about employed versus unemployed physical activity, which turns out to be very important, and then things like shift work, et cetera. And so these-- What, what we can say very safely is that the outcomes with each of these models, the results were very similar. So we don't want to discard the differences between those models entirely. But in my read is in every figure of the paper, it doesn't seem like w- model one, two, or three differ from one another in terms of total outcome.

   20. PAPeter Attia31:51

       Yeah. It-- That's an unusual aspect of this paper. So, so these adjustments are very standard, right?

   21. AHAndrew Huberman31:57

       Okay.

   22. PAPeter Attia31:57

       So that's-- this is a, a classic, uh, tool that's used in most epidemiology, um, because you don't have randomization. So once randomization is out the window, you know, you, you're-- Like, so for example, the paper I'm gonna present is based on an RCT. There will be no models. It's just here are the data.

   23. AHAndrew Huberman32:13

       Right.

   24. PAPeter Attia32:13

       And so you-

   25. AHAndrew Huberman32:13

       Yeah, here they're asking people what, what do you do? Report back to us. We're gonna measure your light exposure. But no one was assigned to any groups or swapped.

   26. PAPeter Attia32:20

       That's right.

   27. AHAndrew Huberman32:20

       There, there-- The, the c- whatever con-- quote-unquote controls are there, uh, they're really not there. It's just comparisons between groups.

   28. PAPeter Attia32:28

       So what is interesting to me, uh, is that as it's exactly as you said, and we'll make all these figures available in addition to the papers. But, um, I mean, they're-- it's very unusual that there's no difference between the unadjusted and the adjusted models. And as you say, there's probably two places out of, you know, 30 when you look at all the different quartile comparisons where you might creep from-

   29. AHAndrew Huberman32:57

       Mm-hmm

   30. PAPeter Attia32:57

       ... you know, statistically significant just out of it or just into it.
7. 33:31 – 46:18

   Negative impact of increasing nighttime light exposure & the positive effects of daytime light exposure

   1. AHAndrew Huberman33:31

      I'm very curious what that question is, but I'll ho- I'll ho- I'll suppress my curiosity for the moment. You know, so if we look at figure two of this paper, and I realize a lot of people are listening and, and they're not able to look at this, although we have posted the figures on the YouTube versions of this, uh, just wanna make clear what's going on just for those that are listening. Essentially what they're looking at is what they call the odds ratio, which is the probability of something happening in one group versus-- divided by the probability of something happening in another group. I guess, uh, would a, by way of example, would be, you know, if you were gonna look at the odds ratio of, you know, the probability of somebody getting lung cancer if they smoke versus probability of somebody getting lung cancer if they don't smoke.

   2. PAPeter Attia34:12

      So odds ratios and hazard ratios are often confused. They're very similar, and odds ratios generally refer to a lifetime exposure, whereas a hazard ratio is, um, defined over a specific period of time. But the math is still effectively the same. And, uh, using the example you gave, if you took the odds ratio of, um, you know, death, so let's talk all-cause mortality for a smoker versus a non-smoker, and the answer were one point seven eight, I'm making that up, but that's directionally correct. One point seven eight as an odds ratio means there's a seventy-eight percent chance greater of the outcome of interest, in this case death by any cause, in the affected group, which would be the smokers. So a odds ratio of two is a hundred percent, an odds ratio of three is two hundred percent. So the math is take the number, subtract one, and that's the percent.

   3. AHAndrew Huberman35:03

      You know, figure two of this paper is w- one of the key take homes. They essentially look at the odds ratio of people who are in the-- L- let's say that-- Let's just look at the nighttime light exposure.

   4. PAPeter Attia35:16

      And just remind me, Andrew, 'cause and, and everybody else watching.

   5. AHAndrew Huberman35:19

      Mm-hmm.

   6. PAPeter Attia35:19

      The-- every one of these is showing second, third, fourth as your X-axis.

   7. AHAndrew Huberman35:23

      Right.

   8. PAPeter Attia35:24

      Meaning they're all being compared to the first quartile.

   9. AHAndrew Huberman35:27

      That's right.

   10. PAPeter Attia35:27

       And the first quartile is lowest light exposure or highest light exposure?

   11. AHAndrew Huberman35:32

       That's right. Lowest.

   12. PAPeter Attia35:33

       Okay.

   13. AHAndrew Huberman35:33

       Well, or well, we have to, um, nighttime-

   14. PAPeter Attia35:35

       We should differentiate between day and night.

   15. AHAndrew Huberman35:36

       That's right. That's right.

   16. PAPeter Attia35:36

       Okay, so re- restate it, um-

   17. AHAndrew Huberman35:38

       Sure. So, uh, if we look at, you know, what is your risk of a psychiatric challenge, broadly speaking, well, panel A is, is major depressive disorder. If you are in the second quartile, third quartile, or fourth quartile of nighttime light exposure.

   18. PAPeter Attia35:55

       Yep.

   19. AHAndrew Huberman35:55

       So second being the least amount of nighttime light exposure, third being more nighttime light exposure, and fourth the most nighttime light exposure relative to the first quartile.

   20. PAPeter Attia36:06

       This is just a stupid thing, like if I were doing this figure, if you were doing this in a lecture-

   21. AHAndrew Huberman36:11

       Yep

   22. PAPeter Attia36:11

       ... you know what you would do to make it so easy? You would draw arrows on it that say increasing light exposure at night.

   23. AHAndrew Huberman36:17

       Right. Yep.

   24. PAPeter Attia36:17

       Decreasing light exposure in the day.

   25. AHAndrew Huberman36:19

       Yep.

   26. PAPeter Attia36:19

       It's the same information. It just makes it easier for the reader to understand.

   27. AHAndrew Huberman36:22

       Absolutely. And, and I-

   28. PAPeter Attia36:23

       But that's-- But, and maybe the teaching point I think is for people when they review articles, like don't be afraid to do that and just kind of like-

   29. AHAndrew Huberman36:31

       Oh, I've got to scribble all over this

   30. PAPeter Attia36:32

       ... wait, what is this? Yeah, yeah, exactly.
8. 46:18 – 50:45

   Statistical analysis: the importance of focusing not only on statistical significance but also clinical relevance, power analysis, error bar range, & more

   1. PAPeter Attia46:18

      I like about a study like this is that it puts the error bars so easy to see on the data. And why is that interesting? Well, um, there's, there's, um, there's a, there's a belief that bigger is always better in sample size. And we often talk about that through the lens of power analysis, right? So how many subjects do we need to, um, to, to reach a, a conclusion that is powered to, you know, this level? [lips smack] And that's, that's true, but what I don't think gets discussed as often is the opposite of that, which is, what if you overpower a study? In other words, what if the power analysis says to be, uh, to, to have a level of power at ninety percent, you need a thousand subjects. And you say, "Great, we're gonna do ten thousand subjects." Well, you're clearly powered for it, but you might be overpowered, and people might say, "Well, why would that be a bad thing?" It could be a bad thing because it means you are very likely to reach statistical significance in things that might not be actually significant. And so one thing about this study that is just a quick back, like, kind of a quick and dirty way to tell that it's probably not overpowered is that you have varying lengths of error bars. And what that tells me is that... And again, this is not, like, a formal statistical analysis. It's just kind of like a back of the envelope statistical analysis. If you look, for example, at self-harm in the top quartile, you actually have pretty big error bars. In fact, all the self-harm have sort of slightly bigger error bars. And yet when you look at, for example, the depression, even though the error bars aren't all the same size, they're tighter. In fact, when you look at the relationship between depression and daytime light, the error bars are really, really small. So [lips smack] that just gives me confidence that there is variability in this, which paradoxically you kind of want to see 'cause it tells me that this wasn't just done... You know, there was-- I think you said eight thousand subjects were in this, and I realized-

   2. AHAndrew Huberman48:16

      Eight- eighty-- More than eight. Eighty-six thousand.

   3. PAPeter Attia48:18

      Eighty-six thousand.

   4. AHAndrew Huberman48:19

      Yeah.

   5. PAPeter Attia48:19

      Sorry.

   6. AHAndrew Huberman48:19

      Eighty-six thousand.

   7. PAPeter Attia48:19

      Yeah, you realize that it wasn't that, oh, this should have been done with a tenth of that or a half of that.

   8. AHAndrew Huberman48:24

      Mm-hmm.

   9. PAPeter Attia48:24

      And we're picking up, um, signal that is statistically relevant, but clinically irrelevant.

   10. AHAndrew Huberman48:30

       Mm-hmm. Yeah, thanks for, for that point that I didn't pay attention to that. Um, I mean, I paid attention to the error bars, but I didn't know that. Um, so thank you. I'm learning, too. And I, I suppose for people that are listening, we can just give them a sense of what the error bar ranges are. For self-harm, you know, they're running at, you know, as much as twenty percent either side of the, the mean, the average. And for major depression, it looks like it's more like, let's say, eight to ten percent.

   11. PAPeter Attia48:57

       If, if that. Yeah.

   12. AHAndrew Huberman48:58

       If that.

   13. PAPeter Attia48:58

       Yeah, yeah.

   14. AHAndrew Huberman48:58

       Maybe more like five, right? So, um, yeah, I see what you're saying. So when you get a, a, a very large sample size, you're gonna have some outliers in there, and you can mask those outliers just by having so many data points, right?

   15. PAPeter Attia49:15

       Yeah, because these error bars directly tell you whether or not you're statistically significant. So n- what's really nice about this type of graph, and you see these in, uh, there's gonna be a graph in my paper where you see the same analysis Um, they're always drawing the 95% confidence interval on the, on the data point. And if the 95% confidence interval does not touch the y- the line of unity, which in this case is the, the, the, the odds ratio of 1.0 or the X-axis, then you know it's statistically significant to the confidence interval they've defined, which is almost assuredly 95%. Sometimes they'll make it tighter at 99. And so that's why you can just look right at these and go, oh, look, you know, in depression, the second quartile didn't reach statistical significance 'cause the error bars are touching the line, just as the case for the second and third quartile for self-harm. But when you look at the fourth quartile, you can see that the lower tip of the error bars isn't anywhere near unity, and so we know without having to look up the P value that it's, uh, smaller than either .05 or .1, however they've defined it. And it's really amazing when you see these, you know, overpowered studies, which are easier to do epidemiologically, where, you know, the P value ends up being microscopic. Y- you know, they can, they can drive their P values down to anything low because sample size can be infinite. But y- you know, you can see that it's just, like, the, the error bar is just skimming above the, uh, the, the unity line, but it's so, so, so tight.

9. 50:45 – 56:53

   Takeaways from the study of daytime & nighttime light exposure

   1. AHAndrew Huberman50:45

      One thing that I hope people are taking away from this study is that imagine you're somebody who has a very sensitive circadian mood system. Well, that would mean you need less daytime light exposure to feel good or less bad, but it also means that you might need very little light at night in order to negatively impact your mood systems. And in fact, they make this argument in the discussion as an interesting point that I think is worth mentioning. What-- Because here what I, again, what I like about this study is that they've separated day and nighttime light exposure.

   2. PAPeter Attia51:26

      Yeah.

   3. AHAndrew Huberman51:26

      Turns out that many of the drugs that are used to treat bipolar disorder reduce the sens- are, are effective, perhaps in part because they reduce the sensitivity of the light-sensing circadian apparati. Now, that's interesting, right? I- if y- if you think about this, okay, so these are drugs that can ameliorate some of the symptoms of bipolar, perhaps in part by reducing the extent to which nighttime light exposure can relieve bipolar symptoms. C- excuse me, can exacerbate bipolar symptoms. Conversely, there's evidence that people who take certain antidepressants may suppress the ability for daytime light-

   4. PAPeter Attia52:05

      Hmm

   5. AHAndrew Huberman52:05

      ... to positively impact the mood systems of the brain. Now, of course, we don't want people halting their medication on the basis of that statement alone. Please don't. You know, talk to your psychiatrist. But if we know one thing for sure, it's that if you want a significant outcome and a paper as a scientist, give a drug, any drug, and look at the amount of rapid eye movement sleep or their circadian cycle. Pretty much any drug alters the circadian rhythm, for better or worse. But if we start to think about which medications might adjust our overall sensitivity to light, sometimes this could be a good thing. You think less sensitivity to light. Well, for people who have bipolar disorder, the amount of daytime light exposure isn't that important for their overall mood regulation, but the amount of nighttime light exposure really is. In other words, darkness for eight hours every night should be viewed, in my opinion, as a treatment for bipolar disorder. Not the only treatment, but it's also clear that we should all be avoiding really bright, extensive really bright nighttime light exposure. I mean, if, if anything, you know, my takeaway from this study is that darkness at night is the fourth key light stimulus. Now, o- a couple of things. Very bright moonlight, very bright candlelight is probably only like, gosh, three to 50 lux.

   6. PAPeter Attia53:30

      What?

   7. AHAndrew Huberman53:30

      When you go outside on a br- b- brightly lit full moon night, I, I encourage people to download this free app, I have no relationship to it, called Light Meter, and y- it gives you a pretty good read of what the lux are in that environment. By the way, a lot of people don't realize this. They think you just tap the button, and then it tells you how many lux. You hold it down. It's kind of fun. You can scan around the room and see how many lux are on average coming from that location or outside. Go out on a really bright moonlit night.

   8. PAPeter Attia53:55

      I mean, we, we should have a f- full moon tonight.

   9. AHAndrew Huberman53:58

      Yeah.

   10. PAPeter Attia53:58

       I don't know if it-

   11. AHAndrew Huberman53:58

       Let's do it.

   12. PAPeter Attia53:59

       Yeah.

   13. AHAndrew Huberman53:59

       Y- you're not gonna get above 100 lux.

   14. PAPeter Attia54:01

       That's incredible.

   15. AHAndrew Huberman54:02

       You're sitting at a candlelight dinner with your spouse or with friends, and it's clearly bright enough to see them. Put that lux meter right up, not too close to the flame, 50 to 200 lux.

   16. PAPeter Attia54:14

       I, I had, I mean, I had, I had-

   17. AHAndrew Huberman54:15

       Maybe 400 lux

   18. PAPeter Attia54:15

       ... an interesting experience a couple of months ago on an elk hunt where it was a full moon, which actually makes the hunting not so great, but it was the first time I've ever noticed my shadow in relation to the moon. Uh, that's how bright it seemed the light was. But-

   19. AHAndrew Huberman54:32

       This is Halloween appropriate.

   20. PAPeter Attia54:33

       Yeah, yeah.

   21. AHAndrew Huberman54:33

       Since we're coming up, we're g-

   22. PAPeter Attia54:34

       Yeah

   23. AHAndrew Huberman54:34

       ... we're recording this close to Halloween.

   24. PAPeter Attia54:36

       So, so-

   25. AHAndrew Huberman54:36

       Yeah, it's remarkable

   26. PAPeter Attia54:37

       ... super interesting to think it could be that dim.

   27. AHAndrew Huberman54:39

       Campfire, you know-

   28. PAPeter Attia54:41

       Yeah

   29. AHAndrew Huberman54:41

       ... and firelight, you think, okay, gathering around a campfire. Well, then, okay, you know, everyone's circadian rhythm must have been disrupted for ages before the development of e- of electric- electricity. No. No, th- th- those campfires are extremely bright, but they're, they're, they're not, they're not that bright compared to a very densely overcast day.

   30. PAPeter Attia54:59

       And what is your phone if you don't use any sort of, uh, light mitigating, uh, tech on it?
10. 56:53 – 1:08:30

    The practicalities of minimizing light exposure & screen time at night, sleep trackers, & challenge of modern, indoor lifestyles

    1. PAPeter Attia56:53

       about Rick?

    2. AHAndrew Huberman56:53

       Yeah, of course. Of course.

    3. PAPeter Attia56:55

       You know this story, but just the, uh, just in case Rick's listening, he'll appreciate this. You know, when Rick was, uh, here staying last summer, um, he's up in our guest house, and he came down after the first night, and he was like, "Unacceptable." You know what I'm talking about, right?

    4. AHAndrew Huberman57:09

       Yeah, unacceptable accommodations.

    5. PAPeter Attia57:11

       What did he do?

    6. AHAndrew Huberman57:12

       He removed all the lighting that existed in that room and replaced it with red light bulbs, which I later used when I stayed here and then later stole when I left. [laughs] The teenage me, I took them. I took them. That's why Derek, when he stayed here, or Lane or anyone else who stayed here, Conti or anyone else didn't have those. I took them. I love them.

    7. PAPeter Attia57:33

       So funny. Jill is like, "You know Rick changed every light in the guest house to red?"

    8. AHAndrew Huberman57:38

       Yeah.

    9. PAPeter Attia57:38

       I'm like, "Yeah. I'm... No, I didn't know that, but I'm not surprised."

    10. AHAndrew Huberman57:41

        Yeah. Well, in his place, he has mostly either no lighting or red lighting, so during the day, he just goes by ambient light, um, and then red light in the evening and, or candlelight, and it, it's great. And, you know, people hear red lights, and they think they have to buy these expensive red light units, but that's not what we're talking about. The... You can literally buy red party lights or just a red bulb. Some people say, "Well, can I just use a red film or can I put a T-shirt over the lamp?" I worry about people putting T-shirts over lamps-

    11. PAPeter Attia58:07

        Yeah, that starts to get bad

    12. AHAndrew Huberman58:07

        ... because of the fire hazard.

    13. PAPeter Attia58:09

        Yeah.

    14. AHAndrew Huberman58:09

        Um, but I'll be honest, I dim the lights in my home at night. Um, when I travel, sometimes I will bring one of the, the stolen from Rick Rubin red lights.

    15. PAPeter Attia58:18

        The red, the Rick Rubin stash. He- here's something where I've, I've sort of softened my tune. So I used to be kind of a hard liner, no blue light in the evening guy. Um, you know, had the, you know, everything was red light at night as far as my phone, using f.lux on the computer, you know, whatever it was. Um, I suspect that that matters somewhat, but I think what matters more is the stimulation that may come from those things. And what I've come to realize, at least in me, which means it probably is true in others as well, and at least some others, is that what I'm doing on my phone matters more than how bright my phone is. In other words, if I've got the best blue light filter in the world on my phone, but I'm doom scrolling social media and getting lit up on email, that's way worse for me than if I've got my phone on maximum light and I'm, like, watching YouTube videos of F1 cars and driving around having fun. Like-

    16. AHAndrew Huberman59:23

        Yeah. Oh

    17. PAPeter Attia59:23

        ... it's a totally different experience.

    18. AHAndrew Huberman59:25

        Yeah.

    19. PAPeter Attia59:25

        So, so, so the context matters and, um, I think, I think for that reason I, I would want people to be mindful of the whole picture. Um, you know, going to bed under a period of, you know, intense duress brought on by something, uh, y- you know, that's an equally dangerous component to all of this that's, that's distinct from what we're talking about.

    20. AHAndrew Huberman59:45

        Yeah.

    21. PAPeter Attia59:46

        But, but, you know, you just wanna... I'd like... I want people to be able to think of this in the context of everything.

    22. AHAndrew Huberman59:49

        Yeah. I... It's a really important point. Uh, you know, one thing I'll say is that if you're going to stay up past your normal bedtime, if you're gonna get a lot of light in your eyes, I would hope that it would be for fun reasons and for reasons you enjoy. You should definitely spend some nights out. You should definitely do some all-nighters studying if you really [chuckles] you know, if you... If it's gonna help you get the grade, that's permanent, right? I'd certainly have done all-nighters studying and grant writing for years. Um, you know, there are going to be the inevitable all-nighters due to, God forbid, a hos- trip to the hospital, or you heard something on the news that really amped you up, or you just simply can't sleep. That stuff is gonna happen. So I think the goal should be to minimize light exposure at night. And I think what you just said is especially true because we don't know... For instance, people talk about the negative impact of social media. Is it the fact that people are looking at this little box for so many hours per day? Is it all the things they're not doing?

    23. PAPeter Attia1:00:41

        Yeah.

    24. AHAndrew Huberman1:00:42

        Is it what they're looking at per se? All of those things interact and are really important. I... We know based on studies from the Stanford Sleep Lab that if you wake up in the middle of the night, looking at what time it is can be very disruptive to your ability to fall back asleep and to your sense the next day. It's just a placebo effect, but it's a powerful one, of how tired you are the next day. Y- they've done this where they wake people up in the middle of the night, and then they say it's, you know, 4:00 AM versus 2:00 AM versus 6:00 AM, and people's perceived levels of energy during the day in some ways correlate with what they think, how much sleep they think they got. Likewise, and this is one of the concerns, potential concerns with sleep trackers.

    25. PAPeter Attia1:01:22

        Yep.

    26. AHAndrew Huberman1:01:23

        Ali Krummen talked about this when she came on our podcast. You know, if people see a poor sleep score, they often feel worse than if they see a good sleep score. Now, of course, physiology matters. You can't lie to yourself and say you, you know, got a great night's sleep simply by virtue of a sleep score. But I worry more about the, the false Well, I won't-- If it's a false negative that we don't want to put valence on this. Seeing a bad sleep score and then deciding that you're gonna have a terrible day, it... You know, I think a bad sleep score is an indication that you might need to dial some things in a bit better. S- getting a great sleep score is an indication that you might be doing a number of things right and start looking at these things as averages. Wouldn't you, would you agree?

    27. PAPeter Attia1:02:00

        Yeah, completely. I, I, I, I don't think it's that different from CGM, right? Like, I think that CGM is an amazing tool to provide insight, and you pretty much know the insights after a relatively short period of time. Thirty days, maybe at the outside ninety for, for a really per- for a person with a very complicated life. Um, and you know all you need to know about how the inputs affect the output. Thereafter, if you choose to use it, it's a behavioral tool. In other words, you're using this to build in a Hawthorne effect. I think the same is largely true with sleep trackers. Um, most people have this profound sense of learning when they first encounter one of these things. And, and it's, again, you've heard it all a hundred times. "Oh my God, I can't believe what alcohol does to my sleep."

    28. AHAndrew Huberman1:02:42

        Right. Or caloric trackers.

    29. PAPeter Attia1:02:43

        Exactly.

    30. AHAndrew Huberman1:02:44

        Like I think, uh, Layne Norton's app Carbon, I have no financial relationship to it. I use it or-- and it's taught me, wow, like I consume a lot of calories in the form of certain things at certain times of day, and there's just a lot of good learning in that.
11. 1:08:30 – 1:16:29

    Potential limitations of the light exposure study, reverse causality, & the complex interplay of variables in epidemiological studies

    1. PAPeter Attia1:08:30

       that a potential limitation of this study in that it didn't have a sensor that could pick up the full spectrum of light?

    2. AHAndrew Huberman1:08:37

       Potentially, especially since they're-- w- you know, we don't think of humans as UV, uh, capable. Like, we can't perceive UV light. Um, like a, a ground squirrel, for instance, can... has UV sensors in its eyes. Turns out, you know why they use this? It's crazy. They actually-- You know, when the ground squirrels sit up on their haunches, they're actually signaling one another. They rub urine on their belly, and it reflects UV. Um, the, the New York Times, for some reason, has been running a series of papers, uh, or articles rather, about, uh, naturally occurring fluorescence at night in all sorts of species. Scorpions and, uh, monotremes like the platypus. No one really knows the reason for these odd, odd wavelength of light emissions for, for all these animals. But, you know, we view things in the blue, violet, and up to red and, you know, uh, we're not pit vipers. We can't see far red. But we can see lower than 470 nanometers, and we can see higher than, uh, 700-- 650.

    3. PAPeter Attia1:09:34

       I- is there a technology reason why they had such a narrow band in these sensors? Is it not possible that they could have used a wrist sensor that was wider?

    4. AHAndrew Huberman1:09:42

       This study was initiated in 2013. The tech was probably far worse than it is now. Again, I would love for somebody to design an eyeglass where it's measuring how many photons you're getting across the day. I'm not a big fan of having everything be app-ified, so I would love it if it, the frame would just shift color across the morning. Like, you go outside on a cloudy day, you know, you wear these glasses and, um... And by the way, it's fine to wear eyeglasses or contacts for sunlight viewing for setting your circadian rhythm. Um, people always say, "Well, why is that okay and a window's not?" Well, corrective lenses are actually focusing the light onto your retina. The windows and, and windshields are scattering the light and filtering it.

    5. PAPeter Attia1:10:21

       And how much are sunglasses filtering this out?

    6. AHAndrew Huberman1:10:24

       Way too much. We can safely say way too much, probably causing a tenfold decrement in the total lux count that's landing on your retina. But of course, I g- you know, sunglasses are important driving in the su- into sun and, um, and some people have very sensitive eyes. I can't sit at a cafe with a bright, brightly reflective table in the afternoon. I just, I just squint like crazy. I can't do it. My dad, who's, you know, darker eyed and, you know, he's South, South American descent, he, um, you know, he can just sit there just fine. My mom, who's got light eyes like me and, you know, we're like, ah, it's really tough. We just have a terrible time. Um, you know, people differ in their light sensitivity.

    7. PAPeter Attia1:11:04

       So there's one other macro question I have here, and it's not answerable because without randomization, we can't know it. But it's the question of how much reverse causality can exist in these observations. So again, these observations, um, demonstrate very tight correlations, very strong associations, especially in the five areas that we highlighted. Um, but it's possible that part of what we're seeing, um, is reverse causality brought on by both the treatments, which you've already kind of alluded to, and also the condition itself.

    8. AHAndrew Huberman1:11:44

       Do you want to explain reverse causality for people? And maybe could you mention, um, for those that missed, uh, the Hawthorne effect, just 'cause you-

    9. PAPeter Attia1:11:50

       Yes

    10. AHAndrew Huberman1:11:51

        Yeah.

    11. PAPeter Attia1:11:51

        Yeah. The, the Hawthorne effect, uh, is, is a, is an effect that is named after, uh, an, uh, you know, an observation of what took place in a factory where they were actually studying worker productivity with light of, of all things. Um, but it-- what it, what it refers to is the idea that people will change their behavior when they are observed. So if, um, if I said, "Well, I really want to know what a day in the life is like for Andrew Huberman, I'm gonna follow him around for a day," it's very unlikely that his behavior that day will be exactly as it was if I wasn't there. And so the reason-

    12. AHAndrew Huberman1:12:26

        Which is why you probably will never see a day in the life of Andrew Huberman. [laughs] Although it's pretty, it's pretty scripted unless I'm traveling. It's a, it's a, you know, it's morning sunlight, hydration, and, you know, some cardio or weight training, and then a lot of time reading papers. It'd be the most boring video in the world 'cause it'd be mostly me reading and underlining things.

    13. PAPeter Attia1:12:44

        But it's why, um, gamifying things can be beneficial, right? It's why a CGM can, can be beneficial because it's sort of like somebody's watching you, and you're gonna modify what you eat in response to it, or why tracking can really be an effective way to reduce input because you, there's a sense of being monitored by doing that, especially if someone literally monitors it. In other words, you can set up an accountability partner where your health coach or someone is actually seeing the data. So that's what it is. Now, as far as reverse causality, when you look at variables, so, um, l- let's just pick a, a common one that's unrelated to this. So there, there's an association that more diet soda consumption is associated with greater obesity. It's a bit paradoxical, right? Um-

    14. AHAndrew Huberman1:13:34

        Is that true?

    15. PAPeter Attia1:13:35

        It is. Yeah. It's, it's been demonstrated in many series that the, the, the greater the consumption of diet soda, the greater the prevalence of obesity. And that has been postulated by some to suggest that non-nutritive sweeteners, such as aspartame or sucralose or things like that, are actually part of what's causing obesity. Um- And while there are probably some arguments you could make around the impact that those things might have on the gut microbiome, and maybe there's some way and that's happening, it's also equally likely, if not probably more likely, that there's reverse causality there, that a person who is obese is therefore contemplating how much they're eating or thinking, "Hey, what's an easy way that I can reduce calories? How about instead of drinking a Coke, I drink a Diet Coke?" And so there, the causality which you would impute to mean the drink is causing the obesity, it might be no, the obesity is causing the choice of drink. So here the question is, um, how much of the effect we're seeing is a result of the condition that's being studied, right? How much of the disruption in both day and night ex-- uh, light exposure is the result of the depression? It's dysregulating the sleep. Maybe they're sleeping more during the day and more awake at night because of depression. Again, these are... You can't know this. This is where epidemiology never allows us to determine this, and sadly, these questions can only be answered through either direct randomization or Mendelian randomization. Which by the way, I was going to also ask you, do you know if anyone has examined this from a Mendelian standpoint? That would be, that would be very interesting because I have to believe... Well, it would be interesting. I don't know enough about the biology to know what SNPs would be studiable, but that would be interesting.

    16. AHAndrew Huberman1:15:27

        What Peter is saying is, you know, if you knew something about the genomes of these people, um, you would be in a great position to perhaps even link up light susceptibility genes or light, light sensitivity-

    17. PAPeter Attia1:15:41

        Right

    18. AHAndrew Huberman1:15:41

        ... genes with genes for, you know, pathways involved in major depression, bipolar. I mean, get-getting to this issue of reverse causality, I mean, uh, I think it's very straightforward to imagine that the person who's experiencing a manic episode is gonna be up for two weeks at a time, um, sadly, and getting a lot of nighttime light exposure, you know? Now, dark-- nighttime dark exposure as a treatment for bipolar is something that people are starting to talk about. So making sure that even if those people are awake, that they're at least blue blocking at night, um, reducing their online activities. But people with severe manic episodes have a hard time regulating their own behavior, of course.

    19. PAPeter Attia1:16:19

        And it's not one or the other. Like, I don't want the question to come across to the listener that it has to be one or the other. It's only A can cause B or B can cause A. No,

12. 1:16:29 – 1:21:23

    A tangent on diet soda & sugar substitutes as an example of reverse causality

    1. PAPeter Attia1:16:29

       it's actually a lot of times these things feed off each other. Going back to the soda example, I actually think there's a bit of both, right? I, I actually think there's a real clear, um, body habitus dictates beverage choice. But I also am starting to think that, um, in susceptible individuals, non-nutritive sweeteners will alter the gut biome, and that alters metabolism.

    2. AHAndrew Huberman1:16:51

       What about just hunger? I, I remember Layne telling me, and I, I've seen at least one of the studies that, you know, water is probably better for us than diet soda, but that for some people, diet soda is a great tool for reducing caloric intake. I, I also know some individuals, not me, who drink diet soda. I dr- I drink diet soda from time to time, mainly stevia-sweetened sodas. But, but what I'm referring to here are people besides myself who drink diet soda, and it seems to stimulate their appetite. There's something about the, the sen- the perception of sweet as driving hunger, whereas not eating, uh, or drinking anything with calor- with any sweetness doesn't seem to. This is one of the things I, I wonder, um, if it impacts why some people like intermittent fasting. Because for some people, you know, just even the, the perception... I wonder if the perception of sweetness or the s- even just the smell of food we know can stimulate appetite. So you can imagine the, the perception of sweetness in the mouth, even if there's no calories there. Um, I don't think it necessarily makes people hypoglycemic, but p-perhaps it makes them think about, "Mm, like sweet means food." For instance, for years, I loved the combination of a Diet Coke and a slice of pizza whenever I was in New York, ideally two slices of pizza. So now every time I have a Diet Coke, which isn't that often, but I like Diet Coke, especially with a little bit of lemon in it, I just think about a slice of cheese or mushroom or pepperoni pizza. It's like I want it. I crave it more. So there's a paired association there that I think is real. And we know based on Dana Small's lab at Yale, that there's this paired association between the, uh, sweetness from sucralose and that there's an insulin response. They actually had to cease the study in kids because they were, they were becoming pre-diabetic, you know, which unfortunately meant the study was never published. Have you talked to Dana on this podcast?

    3. PAPeter Attia1:18:43

       No. We, we wrote a premium newsletter on this, um, several months ago. It, it's gotta be like, I don't know, ten to twenty thousand words on all things related to sugar substitutes.

    4. AHAndrew Huberman1:18:56

       Okay. I'll read that.

    5. PAPeter Attia1:18:57

       So-

    6. AHAndrew Huberman1:18:57

       I need to read that.

    7. PAPeter Attia1:18:57

       So yeah.

    8. AHAndrew Huberman1:18:58

       I'm behind.

    9. PAPeter Attia1:18:58

       Folks who are interested in this topic, um, I would refer them to the premium newsletter on sugar substitutes. I think it was our September edition. Um, the short of it is the data are a little bit noisy, um, but, but there is indeed some, some sweeteners in some studies do, do result in that phenomenon you described, the cephalic insulin response. Um, and I came away from the research that went into that, which was a Herculean effort, um, on the part of the team, uh, a little bit more confused [chuckles] than when I went in, but, um, being even more cautious around artificial sweeteners than I was going in.

    10. AHAndrew Huberman1:19:38

        Yeah. So-

    11. PAPeter Attia1:19:39

        And not for the reasons that I don't necessarily... Uh, I, I don't, I didn't find any evidence that these things are cancer causing, right? So that's the headline stuff people worry about.

    12. AHAndrew Huberman1:19:48

        Yeah.

    13. PAPeter Attia1:19:48

        Oh, aspartame causes-

    14. AHAndrew Huberman1:19:48

        You have to do just, like, like ten grams of it.

    15. PAPeter Attia1:19:50

        Yeah, yeah, yeah.

    16. AHAndrew Huberman1:19:50

        Something crazy like that.

    17. PAPeter Attia1:19:51

        The, the, the... I came away more confident that from a s- from a long-term safety perspective in terms of meta-- i-in terms of, you know, cancer and catastrophic outcomes like that, that wasn't the issue. But I came away much more cautious around these things can really be mucking around with both your brain chemistry and your gut chemistry, which can pertain to your metabolism. And mer- therefore my takeaway was buyer beware, use limited amounts only. The one, by the way, that still emerged to me as a reasonable one, it's the only one that I use and I've talked about it a lot, is xylitol. Xylitol is the... Uh, pardon me, I shouldn't say that. Xylitol for chewing, so for gum, um, and allulose as an additive. So those were the-

    18. AHAndrew Huberman1:20:37

        Safer, you're saying?

    19. PAPeter Attia1:20:38

        Yes. Those were, those are basically the only two I will consume.

    20. AHAndrew Huberman1:20:42

        Yeah. I'll, I'll drink a Diet Coke every now and again if I'm on a plane or something.

    21. PAPeter Attia1:20:45

        Yeah, yeah.

    22. AHAndrew Huberman1:20:45

        You know this law that got passed a few years ago that you couldn't bring liquids in, in, of your own into the airport and onto the plane? Like what a great-

    23. PAPeter Attia1:20:52

        A few years ago. [chuckles]

    24. AHAndrew Huberman1:20:53

        What, what a great scheme, what a great scheme to get people to buy overpriced fluids in the airport. Like I, I mean, there are more important issues in the world, but like this one really gets me. Um, but yeah, I'd, I use a little bit... I drink things with a little bit of stevia in it, the occasional, um, Diet Coke. Um, and I, I generally avoid sucralose. I don't like the way it tastes. Monk fruit's too sweet. But yeah, we could, we could-- maybe we'll do a, a podcast on that in the future. Okay. So I think we can wrap this

13. 1:21:23 – 1:29:59

    Opinions on the causality vs. correlation of light exposure to mental health, the damage of circadian disruption, & the interpretation of observational data

    1. AHAndrew Huberman1:21:23

       paper, 'cause I really-

    2. PAPeter Attia1:21:24

       Well, but tell me what you think about that point, Andrew. Like how, I mean, y- you know, you, you know more about this stuff than I do. But if, if you had to just lay on your judgment, right? So, so if it were, if it were 100 to zero, you would say the light is 100% causal in the effects we're seeing. If it were zero to 100, you'd say nope, the behavior is 100% causal of the exposure to light. Where do you... Again, you can't know it.

    3. AHAndrew Huberman1:21:55

       Yeah.

    4. PAPeter Attia1:21:55

       But what does your intuition tell you?

    5. AHAndrew Huberman1:21:56

       Okay. There's my intuition, and then there's my recognition of my own bias. Um, because, you know, I started working on these circadian pathways originating in the eye back in year, in '98 as a graduate student at Berkeley. The, the cells, these melanopsin intrinsically sensitive retinal ganglion cells were discovered in the early 2000s by a guy named Iggy Provencio, Dave Berson, Samer Hattar, Sachin Pant, and others. But that, and it was like one of the most important discoveries in all of biology, clearly. Um, so I've been very excited about these systems. But if I set that aside, so, um, bias disclosure made, I think 65 to 75% of the effects are likely due to light directly. Now, it's impossible to tease those apart, as you mentioned, but to play devil's advocate against myself, you know, you could imagine that the depressed individual is laying around indoors with the curtains drawn. They didn't sleep well the night before, which gives you a photosensitivity that isn't pleasant. Like it sucks to have bright light in your eyes first thing in the morning if you, especially if, especially if you didn't sleep well. And then they're, you know, making their coffee in a dimly lit, what they think is brightly lit environment, and then they're, you know, looking at their phone and the, the state of the world sucks and their state of their internal landscape is rough. And they're, maybe they're dealing with a pain or, or, you know, an injury or something, and their likelihood of getting outside is, is low. And when they do get outside, they're gonna shuffle and not, you know. So I could see how the behaviors could really limit the amount of, of light exposure. And then evening rolls around, they've been tired all day, and a common symptom of depression, you fall asleep and then 2:00 or 3:00 in the morning they're wide awake. What are you gonna do at 2:00 or 3:00 when you're wide awake? Sit in the dark? No. You're gonna get online. You're gonna listen to things. You might have, I'm not recommending this, but an alcoholic drink in order to try and fall asleep. I mean, this is the pattern. And so, you know, shaking up that pattern is really what, what so much of my public health work these days is about, and trying to get people onto a more natural daylight, night, uh, night dark rhythm. Uh, but yeah, it's impossible to tease apart. We do know this, and this is, uh, really serious. We know that in almost every instance, ev- almost every psychopathology report of suicide, in the weeks, but especially in the days preceding suicide, that person's circadian rhythms looked almost inverted from their normal patterns. And that's true of non-bipolar individuals as well. You know, circadian disruption and disruption in psychiatric health are inextricable. Conversely, positive mood and affect and s- and circadian behavior seem very correlated. I mean, I think, um, it's clear that if you want to become an early riser, get light in your eyes and get activity in your body early in the day. You, you built, you entrain to those rhythms so that you start to anticipate that morning workout. You start to anticipate the morning sunlight. Just one, um, more scientific point. We know that when you view bright l- bright sunlight in the morning or just sunlight that's illuminating your environment, as you said, you don't even have to see the sun itself, that there's a 55, zero, percent increase in the amplitude of the morning cortisol spike, which is a good thing.

    6. PAPeter Attia1:25:18

       Right. That's where you want it.

    7. AHAndrew Huberman1:25:19

       Be- because it's inversely re- the amplitude of the morning cortisol spike is inversely related to the amplitude of the evening cortisol spike, and high evening cortisol is associated with middle of the night waking, and on and on. So, um, you know, I'm very bullish on these mechanisms. I also love that they're so deeply woven into our evolutionary history, you know, that we share with single cell organisms. It's so wild. Um, but of course there's going to be a bidirectionality there, and it's, it's impossible to see where one thing starts and the other one stops.

    8. PAPeter Attia1:25:51

       I mean, here's my take, Andrew. First of all, I, I actually, with far less authority than you, um, agree with your assessment and might even be a little bit more bullish, might even put it at 80/20. And, and here I'll, I'll give you my explanations which, uh, stem more from my fastidious battles with epidemiology in general, right? Like, because so much of the world that I live in still has to rely on epidemiologic data, and so how do you make sense of it? And the truth of it is most of it is really pretty bad. Um, but I, I tend to find myself looking at the Austin Bradford Hill criteria all the time. And for folks who don't know, um, he was a statistician who basically proposed a set of criteria, um, believe there are eight of them, and I can't believe I don't know every one of them off by heart. I certainly used to. Um, but the more of these criteria that are, that are met within your correlations, the more likelihood, uh, you will find causality. So when I think of your data here, the data in this paper, I'll tell you what makes these correlations seem to have causality within them in the direction that's being proposed. [lips smack] Um, look at the dose effect. So dose effect matters, and this is done in quartiles, and that's a very elegant thing. If they just did it as on/off, it would be harder.

    9. AHAndrew Huberman1:27:14

       High low.

    10. PAPeter Attia1:27:15

        That's right. But the fact that they did it in quartiles allows you to see that every example in figure two, I don't believe there is an exception to this.

    11. AHAndrew Huberman1:27:22

        No, and I think also in the, in the other figure-

    12. PAPeter Attia1:27:24

        There's on- there's only one exception to what I'm about to say, sorry, two out of, like, God knows how many. They're all monotonically increasing and decreasing. In other words, the dose effect is always present. [lips smack] Another thing is biologic plausibility. You've s- spoken at length about that today. So in other words, sometimes you have to look at epidemiology and ask, "Is there a biologic explanation?" And here there is. You've added another one, which is evolutionary conservation to the biologic plausibility. Then you can talk about animal models or experiments in humans over short durations that generally support these findings. And, and so those are just a couple of the, the Bradford Hill criteria that, that lead to, um, you know, my belief that, yeah, there's reverse causality here, but, um, it's not the full explanation and that more of the explanation is probably the direction that's being proposed. Um, and if that's true, 'cause then at the end of the day, like, what's the purpose of the discussion? The purpose of the discussion is if you are under the influence of any of these psychiatric conditions, in addition to the treatments you're doing now, what else can you do? And to me, the takeaway is follow these light behaviors. I mean, it's, it's, it's a, it's a relatively low lift-

    13. AHAndrew Huberman1:28:40

        Yeah

    14. PAPeter Attia1:28:40

        ... when you consider some of the other things, like I'm over here asking people to do zone two for three hours a week and VO2 max workouts and all this other stuff, and, like, I think all those things matter for mental health as much as physical health, but this strikes me as on the spectrum of low asks. If it shows-- if it's only even 30% causality, 70% reverse causality, like I'll take those. I, I, I would still instate that.

    15. AHAndrew Huberman1:29:06

        Yeah. And it's, you know, it's taking your coffee on the balcony. It's-- And people will often say, "Well, how do you do this with kids?" The kids should be doing it, too, right? You know, it means popping your sunglasses off. It means getting out for just a few minutes. And the fact that it's additive, that these, you know, these photon me- uh, mechanis- photon counting mechanisms, they sum, is great. And look, y- this paper also says, and I should have stated this earlier, if you missed your daytime light ration, get your nighttime dark ration. They are independent and additive. So that's, I mean, that's really something. Um, but of course, ideally you get both. But I appreciate your take on it and, um, [lips smack] you know, and thanks for, for your, uh, expertise in parsing epidemiology. I look at fewer studies of that, of that sort, but I learned from you and, um, that's one of the reasons I love doing these journal clubs is I learn. So

14. 1:29:59 – 1:41:46

    Primer on the immune system

    1. AHAndrew Huberman1:29:59

       along those lines, uh, tell us about the paper you selected. I'm really eager to learn more.

    2. PAPeter Attia1:30:05

       Well, I, I wanted to pick a paper that was, you know, kind of interesting as a paper and, and this, this paper I think is, um, interesting in that it is kind of the landmark study of a class of drugs. But in the same way that you kind of picked a paper that I think has a much broader overarching, um, imp- importance, the reason I picked this paper, which is, um, from The New England Journal of Medicine, it's about 10 years old, no correction, 13 years old, [lips smack] is because it is kind of the landmark study in a class of drugs that I believe are the most relevant class of drugs we've seen so far in cancer therapy. And even though the net effect of these drugs has only served to reduce mortality by maybe 8% to 10%, which is not a huge amount, um, it's the manner in which they've done it that gives me great hope for the future, even if it's through other means. So, [lips smack] um, I'll take a step back before we go into the paper for, again, just the context and background. Um, so the human immune system is kind of a remarkable thing. Uh, it, it's, it's hard when you're sort of trying to imagine what's the most amazing part of the human system, and maybe it's my bias as well, because just as you spent, you know, your time in the, in the light system and the, and the photosensing system, I spent my time in the immunology world. But it is remarkable to me how our immune system's evolved. And they have this really brutal task, which is how can they be tuned to detect any foreign pathogen that is harmful without knowing a priori what that could be, while at the same-- So in other words, how can you tune a system to be so aggressive that it can eradicate any virus or bacteria billions of years into the future without knowing what it's going to be, but at the same time, it has to be so forgiving of the self that it doesn't turn around and attack the self? It's remarkable. And of course, we can always think of the exceptions. There are things called autoimmune conditions, so clearly the system fails, and the immune system turns around and attacks the self. If you see a person with vitiligo, I have a little bit of vitiligo on my back, a couple of spots, clearly the immune system is attacking something there and destroying some of the pigment.

    3. AHAndrew Huberman1:32:39

       I didn't realize vitiligo was autoimmune.

    4. PAPeter Attia1:32:41

       Yeah. Um, if, you know-- So there are lots of, you know, more serious autoimmune conditions, of course, you know, somebody that has lupus or, you know, where the immune system can be attacking the kidney, the immune system can be attacking anywhere. Autoimmune conditions can be deadly, but fortunately, they are very rare, and for the most part, this immune system works remarkably well. So how does it work, and why is it that cancer seems to evade it virtually all of the time? This is the question. Now, let's first of all talk about how it works, and then when I tell you how it works, you'll say, "That sounds amazing. Clearly, it should be able to destroy cancer." Um, I'm gonna simplify it by only talking about one system, which is how T cells recognize and get activated, how T cells recognize antigens. So we have something called, uh, an antigen. So an antigen is an antibody-generating peptide. So it's a, it's a, it's a protein, almost always a protein. They can be carbohydrates, but they're almost always proteins, and they're very, very small peptides. Like, we're talking as little as nine amino acids, maybe up to 20 amino acids, so teeny, tiny little peptides. But it's amazing that in such a short peptide, the body can recognize if that's Andrew or not Andrew. I mean, when, again, think, think about, like, we talk about proteins in kilodaltons, right? We're talking about proteins in terms of thousands of amino acids that make up every protein in your body. And yet, if it samples a protein and sees that, hey, this little nine, 10, 15 peptide amino acid is not part of you, I know it's bad, and therefore, I'm going to generate an immune response to it. So we have what are called antigen-presenting cells. You have cells that go around sampling peptides, and they will, on these things called MHC class receptors, bring the peptide up to the surface and serve it up to the T cell. There are two types of these. There's MHC class one and MHC class two. I only bring them-

    5. AHAndrew Huberman1:34:54

       So this is major histocompatibility-

    6. PAPeter Attia1:34:55

       Compatibility

    7. AHAndrew Huberman1:34:56

       ... complex.

    8. PAPeter Attia1:34:57

       That's correct. And, um, we refer to them that way because they det- they-- because of the context in which they were discovered, which was for organ rejection. So not surprisingly, when you need to put a kidney into another person, if that kidney is deemed foreign, it will not last long, and the early days of organ transplantation were rife with immediate rejections. And by, not, not im-- I mean, the immediates are the ABO incompatibilities, but, you know, the, the sort of next layer of incompatibility was MHC incompatibility, which would lead to, you know, within, within weeks, the organ is gone, as opposed to within hours. So you have these two classes of MHC. You have class one and class two. Class one is what we call endogenous. So this is basically what happens when a protein or an antigen is coming from inside the cell. So let's consider the flu. So if you get the flu, the influenza virus infects the respiratory epithelium of your, uh, you know, your larynx, and that virus, as, you know, folks listening might remember from our days of talking about COVID, viruses can't replicate on their own. What they do is they hijack the replication, um, machinery of the host, and they use that either to insert their RNA or DNA to replicate. And in the process, proteins are being made. Well, those proteins are the proteins of the virus, not of us. So some of those peptides get launched onto these MH class, MHC class one, uh, glove, basically. The glove comes up to the surface, and a T cell comes along, and in the case of MHC class one, it's a CD8 T cell. These are what are called the killer T cells, right? And so this cell comes along, and with its T cell receptor, the T cell receptor meets the MHC class one receptor with the antigen in it, and if that's a lock, it realizes that's my target, and it begins to replicate and proliferate and target those, and that creates the immune response. And by the way, that's how it works when you vaccinate somebody. You're basically pre-building that thing up.

    9. AHAndrew Huberman1:37:09

       So would this fall under the adaptive immune response or the innate immune response?

    10. PAPeter Attia1:37:14

        No, this is adaptive, yep. Innate is just the pure antibody response in the, on the B cell side. I won't get into that for, for the, for the purpose of this discussion. The other example is MHC class two, and that's also part of the adaptive system or the innate system, which, uh, is more what we call the, um, exogenous form. So these are peptides that are usually coming from outside the cell. So we're gonna focus more on the MHC class one, because this is peptides that come from inside the cell. Okay, so just keep in the back of your mind, if a foreign protein gets presented from inside a cell to outside a cell, the T cells recognize that, and they will mount a foreign response. And by the way, that's why we basically can beat any virus. Like, if you consider how many viruses are around us, the fact that we almost never die from a viral infection is a remarkable achievement of how well this immune system works. And by-

    11. AHAndrew Huberman1:38:09

        We're constantly combating these viruses.

    12. PAPeter Attia1:38:11

        Constantly, and by the way, we don't really have very effective antiviral agents. It's not like antibiotics. Like, we have antibiotics up the wazoo. I mean, we're way better at fighting viruses than bacteria

    13. AHAndrew Huberman1:38:23

        Can I just ask one question? I've always wondered about this. To what extent is our ability to ward off viruses on a day-to-day basis as an adult r- reliant on us having been exposed to that virus during development? Like, like as I walk around today, maybe I'll be exposed to 100,000 different viruses. Would you say that half of those I have already got antibodies to because I ex- I was exposed to them at some prior portion of my life?

    14. PAPeter Attia1:38:47

        Yeah, hard, hard one to quantify

    15. AHAndrew Huberman1:38:48

        Or, or, and, and the other ones I'm just building up antibodies. Like I was on a, I was on a plane last night, someone was coughing, so I was hiding. And I had COVID a little while ago, so I wasn't too worried about that, and I feel great today, but, you know, I just assume that on that plane, I'm in a swamp of viruses no matter what, and that most of them I've already been exposed to since I was a little kid. So I've got all the antibodies, and they're just fighting it back, binding up those viruses and, and, and destroying them.

    16. PAPeter Attia1:39:18

        Yeah, I think it's part that, and I also think it's part of them that our body can destroy without mounting much of an immune response, so therefore your immune system is doing the work and it's, yet it's not mounting a systemic inflammatory response that you're not sensing

    17. AHAndrew Huberman1:39:30

        So, so is it also a physical trapping in, you know, in my nasal epithelium? It's a virus-

    18. PAPeter Attia1:39:34

        Yeah, yeah. So, so yeah. Let, like there, you have huge barriers, right? So the skin, you know, the hairs in your nose, all of these things are huge barriers, but assuming that still a bunch of them are getting in, at least the respiratory ones. That's the other thing to keep in mind, right? There are certain viruses that are totally useless floating around the air, right? There are certain viruses, you know, the viruses that most people are really afraid of, you know, hep C, hep B, HIV, well, you know, if they're sitting on a table or floating around the air, they're of no threat to you. They have to be s- you know, sort of transmitted through the barrier. Um, but again, some of these viruses you're gonna defeat without an enormous response, and then some of them, you know, like why is influenza, quote unquote, such a bad virus, whereas the common respiratory cold kind of sidelines you for a day? It's the immune response that you're feeling. The worse-- The bigger the immune response to the virus, the more you're feeling that. You feel your immune system going crazy, right? You, you know, the interleukins that are spiking, y- the third spacing that occurs to get more and more of the immune cells there, the spike of your temperature as your body basically tries to cook the virus. All of that stuff is your body doing its-

    19. AHAndrew Huberman1:40:43

        The fatigue.

    20. PAPeter Attia1:40:43

        Yeah. Yeah.

    21. AHAndrew Huberman1:40:44

        Yeah. Yeah

    22. PAPeter Attia1:40:44

        You're being drained and all this happening. So, um, one more point I'll mention just by, just to close the loop on the autoimmunity, um, how is it that we learn not to attack ourselves? That's something called thymic selection that occurs in infancy. So y- you and I have a no good for nothing, tiny little thymus that would be-- It's almost impossible to see these things. You know, when we used to operate on people, y- you know, y- y- the thymus is barely visible in an adult, in a healthy adult, outside of thymic tumors. But as a chi-- In a child, the thymus is quite large, and the purpose of the thymus is to educate T cells and basically show the T cells what self is, and any T cell that doesn't immediately recognize it gets killed. So it's a, it's a really clever system where we basically teach you to recognize self ver- at a very early age, and if you can't do that, you're weeded out. And then the, the thymus involutes thereafter because it's sort of served its purpose. Okay,

15. 1:41:46 – 1:57:45

    Background on cancer: causes, how it evades the immune system, & the logic behind immune checkpoint inhibitor therapy

    1. PAPeter Attia1:41:46

       now let's talk about cancer. So what do we know about cancer? So we know that, again, you know, cancer is a genetic disease in the sense that every cancer has genetic mutations. Um, most of those mutations are somatic, which means most of those mutations are m- mutations that occur during the course of our life. They're not germline mutations

    2. AHAndrew Huberman1:42:08

       The germline being the, uh, eggs and sperm, right?

    3. PAPeter Attia1:42:12

       Right.

    4. AHAndrew Huberman1:42:12

       So it's all other cells. And I love that you pointed out that, you know, there can be gene- that cancer can be genetic but isn't necessarily inherited, right?

    5. PAPeter Attia1:42:22

       In fact, it's rarely inherited

    6. AHAndrew Huberman1:42:22

       Peop- people hear genetic and they think inherited, right?

    7. PAPeter Attia1:42:24

       Yes.

    8. AHAndrew Huberman1:42:25

       But, um, inherited is always genetic to some extent, but, um, genetic isn't always inherited.

    9. PAPeter Attia1:42:30

       Yeah. So there are a handful of cancers that are, uh, derived from inherited mutations. So Lynch syndrome is an example of that. Uh, hereditary polyposis is an example of that, where you have a gene that gets passed through the germline, and that gene codes for a protein, like all genes do, and it's either you have too much of a gene or too little of a gene. So it's either a gene that promotes cancer or, and you have too much of that, or it's a gene that prevents cancer, and you have too little of it or a dysfunctional version of it, right? So BRCA is an example of that. BRCA is hereditary. BRCA codes for a protein, and the, the women and men, but mostly the women that we think about who have a BRCA mutation, that al- in some cases almost guarantees breast cancer, it's because of a defective copy. So it's like they don't get the protein that they need to protect them from breast cancer. So what do we know? Well, we know that, and this is probably one of the most remarkable things I've ever learned, and it still blows my mind every time. Um, well, actually, before I get to that point, I wanna make, I wanna make another point. Okay, so, so you might think, so cancer, we, we, you know, our cells become cancerous, but they're clearly hijacked because they have these mutations, and as a result of these mutations, they make proteins that allow cancers to behave differently. And cancers behave differently from non-cancers in two very critical ways. The first way is that they do not respond to cell cycle signaling. So if you cut your skin, it heals. But how does it know to heal just right and not to keep growing and growing and growing and growing and growing? Well, it knows that because there are cell cycle signals that tell it time to grow, time to stop If, believe it or not, this is an extreme example, if you donated to me half of your liver, which I know you would-

    10. AHAndrew Huberman1:44:31

        Absolutely

    11. PAPeter Attia1:44:31

        ... um

    12. AHAndrew Huberman1:44:32

        I'd, I'd give you more than half of my liver

    13. PAPeter Attia1:44:34

        Well, you'd only need to give me half

    14. AHAndrew Huberman1:44:35

        If it, if it meant that we could keep doing these journal clubs, right?

    15. PAPeter Attia1:44:37

        Yeah, yeah, yeah. Um, within months, you would regenerate a full liver.

    16. AHAndrew Huberman1:44:41

        That's so wild.

    17. PAPeter Attia1:44:42

        Isn't that amazing?

    18. AHAndrew Huberman1:44:43

        That's so wild. It's like a salamander. You cut off a salamander limb, and please don't do that experiment 'cause other people are doing it anyway, and it grows back.

    19. PAPeter Attia1:44:50

        Yeah.

    20. AHAndrew Huberman1:44:50

        It's a stem cell-

    21. PAPeter Attia1:44:50

        And it knows how much to grow back.

    22. AHAndrew Huberman1:44:52

        It's so wild.

    23. PAPeter Attia1:44:53

        So, so when a cell is perfectly functioning, it knows how much to grow and, and it's simple. Cancer loses that ability. That is one of the hallmarks of cancer. It just keeps growing. It doesn't grow faster, by the way. That's a misnomer. People think cancers grow faster than non-cancers. There's no real evidence that that's the case. They just don't stop growing. The second property of cancer is the capacity to leave the site of origin, go someplace else, and take up residence.

    24. AHAndrew Huberman1:45:20

        So that's metastasis.

    25. PAPeter Attia1:45:21

        That's the metastasis component. So if you think about it for a minute, a cell that never stops replicating and has the capacity to up and leave and move and take up residence is clearly different from the cell itself, right? So if I have a cell of colonic epithelium, the cell that lines the inside of my colon, it's clearly got a set of proteins in it, but if all of a sudden that thing can grow, grow, grow, grow, grow, not stop, not stop, not, not listen to the signal, and then somehow wind its way into the liver and just keep growing and growing and growing, it must have different proteins. So the question then becomes, why does cancer even exist? How has our immune system not figured out a way to just silence this and eradicate it the way it does to virtually every virus you encounter? And to me, this is one of the most interesting questions in all of biology, and it really comes down to how clever cancer is, unfortunately, how evolutionarily clever it is. It basically does a lot of things to trick the immune system. So it has its own secretory factors that tamp down the immune system. It grows in an environment because of its nature. So one of the things that's long understood about cancer is it's heavily glycolytic, and when something is heavily glycolytic, it's going glucose to pyruvate to lactate nonstop. There are lots of reasons for that. Um, I, I think there's more than one. Uh, the war-

    26. AHAndrew Huberman1:46:51

        What does that afford it? Does that, a mi-

    27. PAPeter Attia1:46:52

        Well, so it's interesting

    28. AHAndrew Huberman1:46:53

        Does that, does that afford it a migratory potential?

    29. PAPeter Attia1:46:55

        No, so it's super interesting. So, so that's the effect, what I just described is called the Warburg effect, and when Warburg proposed this, uh, which God, was probably in the 1920s, it was before World War I, before World War II, um, he proposed it bec- he thought the mitochondria of cancer cells were defective. So he proposed that the, you know, cancer cells' mitochondria don't work, hence they have to undergo glycolysis. They can't undergo, uh, aerobic, um, uh, metabolism. Um, we now know that that's not the case. So we now know that the, the, the Warburg effect, or the Warburg effect, if I'll refer to him correctly by his name, um, almost assuredly does not have to do with defective mitochondria. Others have proposed several mechanisms. I think there's probably more than one thing going on. So, so, so a paper that came out in 2009, very influential paper, um, by a guy named Matt Vander Heiden and, um, Craig Thompson and, uh, Lou Cantley proposed that the reason that cancer cells do the Warburg effect is that they're not optimizing for energy. They're optimizing for cellular building blocks. And if you do the mass balance, it completely makes sense. Like dividing cells need building blocks more than energy, and glycolysis, while very inefficient for generating ATP, is much more efficient at generating substrate to make more cells. But another proposed mechanism is exactly at this one. Glycolysis lowers the surrounding pH because of lactate. Lactate attracts hydrogen, pH goes down, and guess what that does to the immune system? Detracts the immune system. So it's also a way to hide from the immune system.

    30. AHAndrew Huberman1:48:32

        So there's a, like a pH cloaking.
16. 1:57:45 – 2:08:14

    Peter presents a paper on immune checkpoint inhibitor therapy in cancer patients

    1. PAPeter Attia1:57:45

       [clears throat] this study, um, sought to compare the effect of anti-CTLA-4 to a placebo, and the placebo in this case was not a real placebo. It was a peptide vaccine called GP100, um, to ask the question, in patients with metastatic melanoma, what would be the impact on median survival and overall survival? [lips smack] So, um, let's talk a little bit about the paper. So again, one of the funny things about this is, um, I used to read these papers a lot, Andrew. These, these used to be, these used to be my bread and butter papers, so I, I mean, I, you know, be, you know, reading these like I'm, you know, it's my hobby. And, and I don't read them that much anymore, so it was kind of amazing how long it took me to remind myself of stuff I used to remember. But you do have to kind of go back and read the methods and figure out who were the patients in this? What was the eligibility criteria? Why did they do it this way? And of course, it all kind of came back to me, but, um, it, it took a minute. So, so the first thing is these are all patients who, um, had progressed through every standard therapy. So these are patients for whom there were no other options. Um, these patients either had very advanced stage three melanoma, which means it was local regional melanoma, but it couldn't be resected. So an example of that would be, um, a cancer that was, you know, completely engulfing, like where let's say the primary site was the cheek, and it had completely grown into all of the surrounding soft tissue. It hadn't spread anywhere, but it was, you know, f- all the lymph nodes of the neck, um, and, and I've seen patients like this, and it's, you know, it's just completely disfiguring. Um, and they'd already been through the standard chemotherapy, and nothing was working, and the thing was growing. And then it was mostly made up of patients with stage four cancer. Now, melanoma has a very funny staging system. So in cancer, we typically talk about something called the TNM staging system. It is the standard way that cancers are staged. T refers to the tumor size, N refers to the lymph node status, and M refers to the presence or absence of metastases. And for most cancers, it is a very simple system. It is, you know, T is typically a number one, two, sometimes up to three and four. N is typically zero, one or two, and M is zero or one. Either there's no mets or there are mets. So for example, in colorectal cancer, um, the T staging determines the depth in the colon wall that it went. N is did it go to mets, and I think in colon, I may be a little rusty on this, I think colon has N zero, one, or two, depending on how many lymph nodes. And then M zero, did it go to anything beyond that, like to the liver, lung, et cetera, or not? Melanoma's a bit more complicated. It has M zero, meaning no mets, but it also has M1A, M1B, M1C, and M1D, and within each of those, it has a threshold for high and low lactate dehydrogenase, or LDH. So it's both a staging based on imaging and biochemical, and the reason for that is LDH level is such a strong prognostic indicator of survival, in addition to M staging. Uh, higher LDH levels tend to reflect more acidity, which we talked about why that's problematic, tends to reflect faster growing tumors, higher turnover, higher metabolic activity. M1A, let me see if I can remember this. M1As are cancers that have metastasized to, um, surrounding soft tissue or soft tissue anywhere in the body, so anywhere else on the skin. And you might think, well, that's kind of crazy, like, how does that happen? And it's really bizarre. You can have a patient who had a melanoma that showed up in one part of their body, and then they have metastases on other parts of their skin. M1B is, uh, and I always get B and C confused. I think B is the lung. So M1B is to the lung, M1C is to any internal organ, so liver, et cetera, and M1D is to the CNS. And as those numbers increase, as those letters increase, the prognosis gets lower and lower and lower. So one of the first things I always look at when I look at a paper like this is tell me about the patient population. Like, what, what was the, um, you know, what was the breakdown of patients? And in table one, so that's, again, in clinical papers like this, table one is always, always, always baseline characteristics. Um, oh, I should mention one other thing, Andrew. This was done as a three-to-one-to-one randomization So again, in the simplest form, a study would have two groups, right? You would have, um, we're gonna just have a treatment group and a placebo group. But in this arm, you had three groups, with one of them being the placebo. The placebo got just GP100, which is just a cancer vaccine. By the way, this is a cancer vaccine that never showed any efficacy. So it was a cancer vaccine that had been tested both with interleukin-2 directly and, um, as an adjuvant for patients who had metastatic melanoma res- or had, sorry, not metastatic melanoma, who had melanoma resected, who were tumor-free, and then given the vaccine as adjuvants to see did that have an effect on outcomes, and it didn't. So it's kind of a known placebo. So you had that group. Then you had the anti-CTLA-4 group, and then you had anti-CTLA-4 plus GP100 as-

    2. AHAndrew Huberman2:03:35

       Yeah, what's the rationale-

    3. PAPeter Attia2:03:37

       For the three to one to one? It's basically it increases statistical power, right? So, you know, this total study was a little under 700 people. They put 400 in the anti-CTLA-4 plus GP100 group and then, you know, a little over 130 in each of the other two groups. So you're always gonna be able to make these two comparisons, right? What you can check by doing this is, is there any effective GP100 in this setting, which had never been done before. So again, GP100 is a known protein expressed by melanoma, and all of these people were haplotyped to make sure that their immune system would recognize it. And the question was, would giving people anti-CTLA-4, i.e. taking the brakes off their immune system, with or without GP100 make a difference? So kind of going through this, you can see it sort of skews about 60% to 40% male to female. They talk about something called the ECOG performance status. That refers to how healthy a patient is coming in. So ECOG zero is no limitations whatsoever, which is kind of amazing when you really consider something. I think this speaks to just how devastating this disease is. Um, these are patients who all have, like, six months to live, right? You know, a year max. And yet look at this, 58% to 60% of them have no limitation on their quality of life at this very moment. That's going to change dramatically, um, you know, absent a cure here. And then ECOG one has some limitation, and you can see that ECOG one plus ECOG zero is basically 98% of the population. You can see the staging there. So again, very, very few of these patients are the M0 category. M0s are people who have stage III disease that is so aggressive it can't be resected. That's about 1%. But the majority of these people are the M1as, M1bs, M1cs. So these are people with very aggressive cancers. You can also see that about 10% to 15% of these people also have CNS metastases, again, the poorest prognosis of the poor. And then you can see the, uh, about 40% of them have the LDH level above cutoff. All of this is to say we're talking about a group of patients who have, um, you know, a very high likelihood of not surviving m-more than, you know, a year. It would be very, you know, unlikely that, that many of these patients would survive more than a year. So, so ba- basically, more than 70% of these people have visceral metastases, uh, a third have high LDH, and 10, more than 10% have brain mets. They've also all progressed through standard therapy. So, um-

    4. AHAndrew Huberman2:06:27

       Radiation, chemo.

    5. PAPeter Attia2:06:28

       Y- yeah, and the chemo for, for, for melanoma can be, you know, kind of a, a toxic chemo that, that really just doesn't really do anything.

    6. AHAndrew Huberman2:06:38

       So is it commonplace to use a treatment that failed in clinical trials as a placebo in these sorts of studies?

    7. PAPeter Attia2:06:47

       Yeah, it's interesting. I, I think you're referring obviously to the GP100, and I think the thinking was, okay, it hasn't been effective in other treatments, for example, when combined with IL-2 or as an adjuvant, but never before has it been tried with a checkpoint inhibitor, which is the technical term for this type of drug. Um, I think there was also some belief that it would be easier to enroll patients. I don't think they stated this, but that's often the case. It would be easier to enroll patients if they would know that even in the placebo arm, they're still getting an active agent.

    8. AHAndrew Huberman2:07:26

       Got it. And I suppose there's always the possibility that the combination of the, uh, failed drug with a new drug would work, and then so you're increasing the probability for novel discovery.

    9. PAPeter Attia2:07:37

       For sure. And again, if you go back to the randomization of three to one to one, it's really only one-fifth or 20% of the participants that would get just the GP100. So in other words, you're basically telling people when they come into this study, there's an 80% chance you're going to get anti-CTLA-4. That's a much better set of odds than, you know, your typical study where you're gonna be 50% likely to get the, uh, agent of interest.

    10. AHAndrew Huberman2:08:06

        Right, and people who are literally dying of cancer, they, they w- they don't wanna be in the control group.

    11. PAPeter Attia2:08:12

        Right. That's right.

17. 2:08:14 – 2:25:51

    Unpacking the results of the checkpoint inhibitor trial

    1. PAPeter Attia2:08:15

       So the primary outcome for this study actually changed in the study. Now, they have to get permission to do that.

    2. AHAndrew Huberman2:08:22

       Mm-hmm.

    3. PAPeter Attia2:08:23

       Um, but the, so the original primary endpoint was the best overall response rate. So I have to explain how response rates are measured. This is, this is a bit complicated. Remember, all of these patients by definition have measurable, visible cancer. By visible, either on the surface of their body, but more likely on an MRI or CT scan. So all of these patients had to be scanned head to toe within 12 weeks of enrollment. Um, again, there's another thing I should point out here, which I know you understand, but it's always worth reminding people. When a study like this takes place, it usually takes place over many years. And so it's not the case that all 700 of these patients were enrolled on the same day and finished, you know, we finished observing them on the same day. No, no, no. This took place for a very long period of time. This took place across tens of centers. Uh, I can't remember if this was just globally or across the world. It might've been across the world. Um, and so every center really needs to adhere to a very strict protocol. And you have a central organization that is running this. So you have a drug company, I think this is Bristol Myers Squibb, that makes the drug. They provide the drug. And then you have a CRO or clinical research organization that d- that is basically managing the trial. And the trial is being done at cancer centers all over the world or all over the country. And, you know, enrollment, I think, began in 2008 for this. No, no, I think it completed in 2008. It probably started in about 2004, 2005. And therefore, you had to kind of have real clear protocols around this. So a complete response is the easier of these to understand. A complete response is everything vanishes completely. That's very rare in cancer therapy. So instead, what we kind of look for is a partial response. A partial response, and there's really different ways to define this. There are different criteria, but this is the most common way you define a partial response. A partial response is at least a 50% reduction by diameter, because remember, in this type of imaging, you're looking at 2D versus 3D. So if you're looking at a lung lesion and it's this big, it ha-- you know, if it's two centimeters long, it has to go to at least one centimeter in diameter. So it's a 50% reduction at least of every single lesion with no new lesions appearing and no lesions growing. So it's very strict criteria, right? Again, CR means everything vanishes. PR means at least a 50% by diameter, which by the way, is a much bigger diameter, much bigger reduction in terms of tumor volume when you consider the linear versus the third power relationship of length and volume of every single lesion with nothing new appearing, regardless of how small and no lesion growing. So that's a PR. So you basically have no response, progression, right? We talk about those together, and then partial response and complete response. So initially, the, the authors of this study were going to ch- the primary endpoint of this was going to be the best overall response rate. So what was the proportion of patients that hit PR? What was the proportion that hit a CR? Um, that's very common in this type of paper where the outcomes are typically so dire. Um, however, uh, oh, I think I said, I think I said that the study was, um, I, I don't remember when the study ended, but the amendment was made to change the primary endpoint to overall survival, um, at, at some point during the study. So, and by the way, that tends to be the metric everybody cares most about. So the overall survival for metastatic melanoma is zero, um, with the exception of people who respond to interleukin-2, high dose interleukin-2, and that will boost the overall survival rate to somewhere between eight and 10%. Very, very low. These patients, many of whom had already taken and progressed through interleukin-2. Let me refresh my memory on what percentage of those patients. About a quarter of these patients had already taken high dose interleukin-2, and by definition, the fact that they're in this study means they had already progressed through that. That treatment had failed. Just reiterate, um, just kind of the state these patients are in. So now let's look at figure one. So again, I'll describe it because I realize many people are just listening to us. All of this will be available both in the video, and then we'll link to the paper. So figure one is a, a figure that probably looks really familiar to people who look at, you know, any data that deal with survival. It's called a Kaplan-Meier survival curve. So on the x-axis for this curve is time, and time here is shown in months. And on the y-axis is the overall survival. At the very top, 100%, at the bottom, 0%. And it has three graphs or three curves that are superimposed on one another for each of the three groups. Again, the control group, which is the GP100, the, um, anti-CTLA-4 group by itself, and the anti-CTLA-4 plus GP100. And one of the characteristics of a Kaplan-Meier curve is by definition, they have to be decreasing in a monotonic fashion because it's cumulative overall survival. That just means it can't, like, come down and go back up. Nobody comes back to life. So once a person dies, they are censored from the study, and the curve drops and drops and drops. And you can see that they kind of highlight, and I actually think it makes the graph a little harder to read when they, when they put some of those marks on there. But what really becomes clear when you look at this is that there's a, a key, th- there's a clear distinction between the curve for the placebo group, the GP100 group, and the other two, the two treatment groups. Now, you'll note at the very end that the two treatment groups appear to separate a little bit. I'll talk about that in a second. So when I look at these, Andrew, I-- the first thing I always turn my attention to, I can't resist, I have to look at the right-hand side of the graph 'Cause what is that really telling me, right? The tail of this is showing me the true overall survival, and I want to sort of figure out what is going on. So in the GP100 group, which is the placebo group, it is kind of amazing to think that there is still one person who is alive at 44 months. It's, it's amazing. I mean, it's both sobering and amazing that, like, one person made it to 44 months. Um, the next thing I ask myself is, well, how long did half of the people make it? That's called median survival, and to do that, you go up to the Y-axis, and you draw a little line from the 50 over, and then you bring that down. A- and, and that's, you know, that's, that's, that's awfully low. That's about... Yeah, in fact, the table will tell us exactly what that is, 'cause I think it's really hard to eyeball that stuff. So let's go to... So there's always a table that will accompany these things, and let's pull up that table. I've got this paper spread out over so many things. That's adverse events. Where's our survival table here?

    4. AHAndrew Huberman2:15:56

       Figure two, subgroup analysis of overall survival.

    5. PAPeter Attia2:16:04

       It would probably be helpful if I stapled these things together 'cause it would be easier.

    6. AHAndrew Huberman2:16:07

       Well, this is always a trade-off. Actually, for, uh, since this is a journal club episode, I, I will say that stapling helps, but it also prevents one from separating things out and writing in the margins.

    7. PAPeter Attia2:16:17

       Yeah.

    8. AHAndrew Huberman2:16:17

       So I like these little mini clips.

    9. PAPeter Attia2:16:19

       Yeah.

    10. AHAndrew Huberman2:16:19

        No financial relationship to the mini clips either.

    11. PAPeter Attia2:16:22

        [laughs]

    12. AHAndrew Huberman2:16:22

        Um, just have to state that 'cause I always get if you don't say that, people go, "Oh, you must have a stake in these mini clips."

    13. PAPeter Attia2:16:28

        [laughs]

    14. AHAndrew Huberman2:16:28

        I like these little mini clips. In fact, I'm such a nerd, I always have one of these, uh, Pilot V5, V7s in my poc- on my pocket or my hip, and then my pockets are always filled with, um, with these little mini clips, and, um, but then again, I have a friend who's a musician, and he's, and he's always raining guitar picks. So, you know, it's an... As far as occupational hazards go of being a nerd-

    15. PAPeter Attia2:16:49

        No, I l-

    16. AHAndrew Huberman2:16:49

        These mini clips are, are pr-

    17. PAPeter Attia2:16:50

        I'm, I'm a big fan of the mini clips as well.

    18. AHAndrew Huberman2:16:52

        Yeah, I know. Yeah.

    19. PAPeter Attia2:16:52

        But I, I, I, I went without it today. All right. So thank you. Yes, table two. All right. So, so let's look at table two while looking at the Kaplan-Meier curve 'cause now this allows us to see a couple things. By the way, remember how I said there's, like, that one person who kind of is still alive in the treatment group? Well, you can tell that he's not a complete responder. He or she is not a complete responder because, um, under evaluation of therapy in table two, it says best overall response, and it says complete responders, zero. So there were zero complete responders in the placebo. There were two partial responders. Again, a partial responder is, um, some lesions got smaller, some got bigger. Stable disease is it didn't really change that much, and progressive disease is obviously it, it, it went beyond. Not eval-

    20. AHAndrew Huberman2:17:45

        Wait, and when you say a partial response, like lesions got smaller, are they literally just tracing the, the circumference of one of these, you know, skin lesions and saying-

    21. PAPeter Attia2:17:55

        Yep

    22. AHAndrew Huberman2:17:55

        ... okay, it got bigger, smaller?

    23. PAPeter Attia2:17:56

        Yeah, we'd, you'd literally, we'd had rulers in clinic.

    24. AHAndrew Huberman2:17:58

        Like, like just morphology.

    25. PAPeter Attia2:17:59

        Yep, yep.

    26. AHAndrew Huberman2:17:59

        Gosh, it feels-

    27. PAPeter Attia2:18:00

        Um, but-

    28. AHAndrew Huberman2:18:00

        This feels so crude in terms of like m- like, I mean, it makes total sense, but, like, in terms of, like, modern medicine. Oh, like your lesion grew from like three millimeters to six millimeters.

    29. PAPeter Attia2:18:09

        Yeah.

    30. AHAndrew Huberman2:18:09

        And the... I mean, you're literally, like, drawing little boundaries around little blotches on the skin.
18. 2:25:51 – 2:30:35

    Noteworthy observations, including the differing results between males & females

    1. PAPeter Attia2:25:51

       So what is exciting about this drug, although it's, this paper is not the one that shows it. The reason I chose this paper, Andrew, is because it was the first approval. A second drug came along that is an anti-PD-1 drug. That drug is called Keytruda. That drug turned out to be even better and had, has even a greater response rate, both in terms of median survival and overall survival. But this was the landmark paper. I also have a slight bias here w- and I'll disclose in a moment why. Um, but I, but I think it, it just talks about very interesting biology. So let's talk about a couple things that stuck, stuck out to me in this paper. Um, the first thing that stuck out to me, and the authors didn't comment on it, unless they did and I missed it, is look at figure two. So figure two is the, um, subgroup analyses where you're sort of showing a similar graph to the one you showed earlier, right? Where you, you show the response rate or the change in response between the groups, and then you put the error bars on it, and this is where we talk about how, well, it's a 95% confidence interval, so t- does it touch the unity line? So these are called like tornado plots typically. And, um, what you'll notice is that in the top, you're looking at, um, um, sort of, uh, com- it's comparing the anti-CTLA-4 with GP100 versus the GP100, and in the bottom, you're looking at the anti-CTLA-4 versus the GP100. So at a glance, you can see GP100 is not doing anything. I mean, that's the, that's the first takeaway of comparing A to B. Um, what I find most interesting is look at the subgroup analysis of females. Notice that in females, while there's a trend towards risk reduction, and this is risk reduction for overall mortality. So again, I just want to restate that. The primary outcome of this trial was changed to overall survival, which I think is the better outcome, by the way. And overall, for all patients, in, when you compare anti-CTLA-4 plus placebo versus placebo, there was a 31% risk reduction in overall mortality. That's what, that's, that's the mathematical interpretation of what you're seeing at the tail end of that Kaplan-Meier curve.

    2. AHAndrew Huberman2:28:21

       So living longer.

    3. PAPeter Attia2:28:22

       Living longer.

    4. AHAndrew Huberman2:28:23

       And it's a, it sounds like a big difference. And in some sense it-

    5. PAPeter Attia2:28:25

       Sounds like a big difference

    6. AHAndrew Huberman2:28:25

       ... some sense it is a big difference.

    7. PAPeter Attia2:28:26

       Well, it, it is for those people because you're really looking at basically 0% surviving in the placebo group versus 20% of people are still alive at 56 months in the treatment group. But look, that means 80% have died, right? Um, but notice that, and, and, and, and sorry, when you just look at the anti-CTLA-4 plus GP100 in the subgroup B, that hazard ratio's even showing more compression. It's a 36% reduction in risk of death. Um, but notice that the females did not reach significance. So in the, in the first group, they barely do, and you can see that because the confidence interval runs from 0.55 to 0.92, and notice the error bar almost touches the line. And in the second one, it does not reach significance at all. So I actually went and kind of did a little reading on this after, and I said, "Hey, you know, how much did this study-- Was this an outlier study?" And it turned out it wasn't, um, and that about half the studies of anti-CTLA4 did indeed find that the drug was less effective in women than men, which I found interesting. Now, I couldn't find any great explanation for it, but the most plausible explanations fit into two categories. The first are maybe there are differences in the immune response to the drug if you're a man or a woman. The second, uh, comes down to dosing. I should have said this at the outset, but of course, these drugs are not like a pill where it's like everybody gets, you know, 50 milligrams of this. They're all dosed based on weight. So this study is dosed, I believe, at three milligrams per kilogram. And because most men are heavier than women, men are getting a higher dose than women. And weight and body surface area and immune system, like these things are not all perfectly linear. So I, I, I kind of wonder if this difference is simply explained by men on average getting a higher dose than women.

    8. AHAndrew Huberman2:30:34

       Interesting.

19. 2:30:35 – 2:36:48

    Adverse effects from treatment with an immune checkpoint inhibitor targeting CTLA-4

    1. PAPeter Attia2:30:37

       Last thing I want to talk about here is in table three. So table three, always an important table to look at in any paper, is what are the adverse outcomes, right? What are the adverse effects of the drug?

    2. AHAndrew Huberman2:30:53

       Yeah, I spent some, I spent a little bit of time with this, and I, I confess it, it, you know, I definitely don't want cancer to the extent that I can avoid it. But this table made me wonder whether or not I would also want to just avoid cancer treatment given the life extension provided. I mean, these adverse events are pretty uncomfortable. They sound like it, you know.

    3. PAPeter Attia2:31:13

       Yeah, so just, just to put, just to put in perspective, um, and you always have to kind of, you know, be mindful of how many of these adverse events are occurring in people just because their disease is progressing. So the first thing I always want to look at is total adverse events in all three groups, not just grade. So grade three and grade four are real toxicities, right? Grade four toxicity is life-threatening toxicity, by the way. Uh, grade three is pretty significant toxicity. Grade one and two, we typically just, you know, that's not that severe, right? A little rash, put some corticosteroids on it, it went away kind of thing. Okay, so in the, uh, treatment plus GP100 group, 98.4% of people reported some event, so all but 1.6%. In the anti-CTLA4 group alone, it was 96.7%, so only 3.1% did not. But in the placebo group, it's 97%. So it's important to keep in mind, like, o- you know, everybody's having some adverse effect. Okay, well, what if you say, "Well, let's just limit it to the most severe events"? Well, let's just talk about grade four toxicities. There were 6.1% of those in the placebo group, 8.4% in the anti-CTLA4 group, and 6.8% in the combined group. So not a huge difference-

    4. AHAndrew Huberman2:32:30

       No

    5. PAPeter Attia2:32:30

       ... in grade four toxicity.

    6. AHAndrew Huberman2:32:32

       Meaning that whatever adverse events are occurring may not be related to the treatment.

    7. PAPeter Attia2:32:37

       They may not be related to the treatment. The, again, these are, if you, if you think about it, and, and it's a very awful, sad, morbid thought to imagine, these are, you're looking at the adverse responses of people more than 80% of whom died during the course of a very, very short study. And so, you know, it's very difficult to disentangle what effects or what side effects a person is having just from that process, uh, as they are from the actual treatment. But if there is an area where there's a really clear difference, it's down in the autoimmune category. So if you look at any immune-related events, you can see that in the anti-CTLA4 plus GP100 group, it's about 60%. In both of those treatment groups versus 30%. And if you look at the grade three and four toxicities, it's 10% in the, uh, anti-CTLA-4, 15% in the, um, anti-CTLA-4 alone group, and only 3% in the treatment. So that's a real difference.

    8. AHAndrew Huberman2:33:41

       Mm. Well, it makes sense that people getting this drug plus placebo or just the drug would have autoimmune issues because this is an immunotherapy.

    9. PAPeter Attia2:33:51

       It's an immunomodulator. In fact, what is it doing? It is taking the brakes off the immune system.

    10. AHAndrew Huberman2:33:57

        But then again, the things that they list out, pr- pruritus, is that a irritation of the skin?

    11. PAPeter Attia2:34:03

        It, it-- Yeah, irritation of the skin.

    12. AHAndrew Huberman2:34:04

        Um, I'm not a physician, but I know that any itis is gonna be, like, an inflammation.

    13. PAPeter Attia2:34:08

        Yep, yep.

    14. AHAndrew Huberman2:34:08

        An oma, unfortunately, likely a cancer or cell replication. Um-

    15. PAPeter Attia2:34:12

        Look at the difference in vitiligo

    16. AHAndrew Huberman2:34:13

        ... rash and vitiligo, I mean, um, wow. Yeah, so very little-

    17. PAPeter Attia2:34:19

        Or, or sorry, sorry, look at the gastrointestinal differences. Yeah, and the vitiligo, right? So 3.7%, 2.3%, 0.8%. The GI stuff is the most common stuff you're gonna see there. Th-those are, those are the really big ones. Now-

    18. AHAndrew Huberman2:34:32

        And of course, there's diarrhea and there's diarrhea.

    19. PAPeter Attia2:34:34

        Oh, yeah, yeah.

    20. AHAndrew Huberman2:34:34

        Right? Like, like there's traveler's diarrhea, there's, you know-

    21. PAPeter Attia2:34:37

        Yeah. No, these, the-

    22. AHAndrew Huberman2:34:37

        ... ate, ate a overly, uh-

    23. PAPeter Attia2:34:38

        Yeah

    24. AHAndrew Huberman2:34:38

        ... spicy large meal-

    25. PAPeter Attia2:34:39

        And these people, I mean some-

    26. AHAndrew Huberman2:34:39

        ... the night before diarrhea, and then there's, like, can't really f- do anything besides make trips back and forth to the bathroom diarrhea.

    27. PAPeter Attia2:34:45

        Well, there's, there's, there's-- Put it this way, there's, you know, colitis here is diarrhea so significant these patients require IV fluids. Now, what, what you don't see here is how many of these patients actually required corticosteroids to reverse the autoimmunity. So a lot of times what'll happen here in these studies or with these drugs is the autoimmunity becomes so significant that y-you have to stop the drug and give corticosteroids. Do the exact opposite. You now have to shut the immune system down. So you just took the brakes off it with the drug, and now you need to shut it down with corticosteroids. Um, [lips smack] when I was-- Was I in med school? No. When I was in my, uh, fellowship, um, I wrote a paper about, um, autoimmunity correlating with response rate in anti-CTLA-4, uh, early on. This was during the phase II work. So, uh, when, w- you know, s-s-so the NCI was a very early, um, s- uh, uh, adopter of, uh, participating in these trials. And, um, [lips smack] you know, it was observed that, or at least hypothesized, this is what the paper basically wrote about, which was, is there any correlation between autoimmunity and response? Um, and it turned out the answer was yes. There was a very strong correlation. So [lips smack] there was no difference in autoimmunity between the doses and the-- So the paper we wrote was two dosing schedules, so it was basically the full dose, the three milligrams per kilogram, versus a low dose, one milligram per kilogram. This is a phase II trial. Those are your two arms. There turned out to be no difference in autoimmunity between them, but there was a big difference between, um, uh, the response rate that tied to autoimmunity. In other words, autoimmunity predicted response. Now, I think over time, these, uh, investigators, the doctors who administer these treatments, are getting better and better at catching these things earlier because these autoimmune conditions, uh, can actually be devastating. So

20. 2:36:48 – 2:48:18

    Why melanoma is especially responsive to immunotherapy, & the remarkable success story of immunotherapy for pancreatic cancer

    1. PAPeter Attia2:36:48

       on a very personal note, when Keytruda, uh, came out, I wanna say it was around 2011-- No, no, no, gosh, it must've been 2013, 2014, thereabouts. Um, again, it was for treatment of metastatic melanoma. [lips smack] I wanna come back and explain why melanoma gets all of the attention in autoimmune condition-- in, in, um, um, immunotherapy conditions, I'll state that. But, um, but anyway, a friend of mine [lips smack] got pancreatic cancer, and he got, um, the bad type of pancreatic cancer. So this is, uh, an, an, uh, like the, um, um, adenocarcinoma of the pancreas, right? So this, this is a, a non-survivable type of cancer. Furthermore, his was unresectable, so, um-

    2. AHAndrew Huberman2:37:34

       Can you explain what that is for-

    3. PAPeter Attia2:37:36

       Yeah. So the on- so about 20% of people who have pancreatic cancer technically have it in a way where you could still take out the head of the pancreas.

    4. AHAndrew Huberman2:37:45

       Right, the Whipple procedure.

    5. PAPeter Attia2:37:46

       The Whipple procedure.

    6. AHAndrew Huberman2:37:47

       Right.

    7. PAPeter Attia2:37:48

       Um, now, tragically, most of those patients will still recur.

    8. AHAndrew Huberman2:37:51

       My understanding, uh, is that pancreatic cancer progresses from anterior to posterior in the pancreas, and that the Whipple is a removal of the front and the anterior. That's the Whipple procedure. So if the cancer has progressed far enough caudal into the posterior, uh, pancreas, then there's nothing left to cut out, basically. Um, but-

    9. PAPeter Attia2:38:13

       Well, can we-

    10. AHAndrew Huberman2:38:13

        ... can we survive without a pancreas for any amount of time?

    11. PAPeter Attia2:38:16

        Oh, yeah, absolutely.

    12. AHAndrew Huberman2:38:17

        So why don't they just remove the whole pancreas?

    13. PAPeter Attia2:38:18

        Oh, b- that's my point. It's already micrometastasized, so it's not-- The, the surgical procedure is not the challenge anymore. It used to be. So, you know, at Johns Hopkins, which is one of the hospitals where this was pioneered, like, the, the 30-day mortality for a Whipple procedure was, I don't know, 80%. And the reason was to figure out how to suture a pancreas to the bowel without the-- So, so the pancreas is such an awful organ to operate on because its enzymes are designed to digest anything and everything. So imagine now you have to cut the pancreas in half, take out the head of the pancreas with the duodenum, and then somehow sew that open half of a raw pancreas, uh, to the end of the jejunum and not let it digest itself.

    14. AHAndrew Huberman2:39:09

        Someone at Hopkins figured this out?

    15. PAPeter Attia2:39:11

        Um, no, the first one was actually done by A.O. Whipple, but yes, at Hopkins is where they figured out the way to put drains in, the surgical technique, how to do it in two layers, what type of stitches to use. Like, all of the nuances of this were worked out in a few places, but I would say Hopkins more than any place else.

    16. AHAndrew Huberman2:39:31

        And are there physicians who, like, try this on non-human primates or something, or is this always just done on patients and if you keep getting-

    17. PAPeter Attia2:39:38

        Well, nowadays, I mean, put it this way, even 25 years ago at a, at a, at a major center like Hopkins, the, the mortality of that procedure was less than 1%.

    18. AHAndrew Huberman2:39:48

        Amazing.

    19. PAPeter Attia2:39:48

        Yeah. It, it totally ma-

    20. AHAndrew Huberman2:39:49

        So there have been some victories.

    21. PAPeter Attia2:39:50

        Well, yes, but here's my point. It-- that, that's no longer the bottleneck, right? Taking out the pancreas safely, as complicated and challenging as that is, and if you need a Whipple procedure, you only want to have it done by someone who just does that night and day, 'cause it's-- you don't want weekend warriors doing it. [lips smack] Um, that's not why people are living or dying. They're dying because the pan- the, the cancer just comes back. It was already spread to the liver by the time you did it. You just didn't realize it yet. So whether you took out the whole pancreas or the head of the pancreas or the tail of the pancreas, the location of the tumor [clears throat] is predictive of survival only in the extent that it basically is a window into how soon did symptoms occur. So pancreatic cancers in the tail tend to be more fatal, even though they're way easier surgically to take out, because by the time you develop symptoms of a tail pancreas cancer, it's, it's a big cancer.

    22. AHAndrew Huberman2:40:49

        So I was gonna ask this question later, but I'll just ask it now. Given the link between the immune system and these cancers, is there an idea in mind that people who are, let's say, 40 and older or 50 and older who don't yet n-- they're not diagnosed with any cancer, would periodically just stimulate their immune system to wipe out whatever early cancers might be cropping up? You know, just take a drug to just ramp up the immune system, even to the point where you start having a little diarrhea, maybe a few skin rashes, and then come off the drug. You know, just basically to, to fight back whatever little cell growths are starting to take place in skin or liver, you know, maybe for, you know, three weeks out of each year. I mean, why not?

    23. PAPeter Attia2:41:38

        Yeah, it's an interesting question. Um, I've, I've never thought of it through that lens. I suppose the question is, [clears throat] what can we do to keep our immune systems as healthy as possible as we age? Because-

    24. AHAndrew Huberman2:41:49

        Stay on a normal circadian schedule.

    25. PAPeter Attia2:41:51

        Y- well-

    26. AHAndrew Huberman2:41:51

        There's evidence for that.

    27. PAPeter Attia2:41:52

        Sure. No, there's evidence that certainly if it promotes sleep, anything that promotes better rest is going to promote immune health. Um, because if you ask the macro question, which is like, why does the prevalence of cancer increase so dramatically with age? Um, there are certain diseases where it's really obvious why the prevalence of the disease increases with age.

    28. AHAndrew Huberman2:42:14

        Yeah, like mac-- like, uh, age-related macular degeneration.

    29. PAPeter Attia2:42:17

        Sure. Or cardiovascular disease is by far the most obvious because it's an area under the curve exposure problem. The more exposure to lipoproteins and the more the endothelium gets damaged, the more likely you are to accumulate plaque. And a-a gain, it totally makes sense-

    30. AHAndrew Huberman2:42:30

        Mm-hmm

Episode duration: 2:56:43