#404 ‒ Mental health beyond neurotransmitters: the role of hormones in psychiatry, why symptom reduction isn't enough, and the future of psychedelic therapies | Linus Abrams, M.D.

29:12Peter Attia:Can you say more about how they differ and what the implication is? Sure, absolutely. Well, someone with unipolar depression will typically have a, if the trial succeeds, a favorable response. They'll feel better. Someone with bipolar depression could either have a negative response. It could trigger so-called mood cycling. They could become hypomanic in an unpleasant way, agitated, have trouble sleeping, have racing thoughts, a variety of symptoms. Or they could have a mixed state, a combination of depression that's very common. A combination of depressive symptoms, feeling sad, potentially hopeless, but also having feelings of agitation, physically feeling agitated and disconcerted.

30:10Peter Attia:And you're saying that if you fail to make the diagnosis of unipolar versus bipolar and you prescribe the same drug, the first line might be an SSRI. Well, there are ways to circumvent that. If you ask the right questions, you're less likely to prescribe the wrong drug. And what would be the wrong drug for the bipolar that might be the right drug for the unipolar? Sure. The wrong drug would be, I would say, any antidepressant instead of a mood stabilizer, like lamotrigine. I see. Because lamotrigine, sorry to interrupt, lamotrigine can be very effective about treating depression. People think of bipolar drugs as treating the elevated moods, But lithium and lamotrigine, for example, can be very effective at treating depression with monotherapy for many patients.

31:16Peter Attia:And that's lamictal, I assume? Yeah. What's the mechanism of that drug? I think it changes sodium channels. Okay. And do we know why lithium works? I don't believe so. Okay. Okay. So lithium monotherapy or lamictal in monotherapy is not just given to manage the mania, but you're saying it can also improve the depression. Well, it's the correct way to initiate pharmacotherapy with someone with bipolar depression. So sometimes it proves to be successful as monotherapy. Sometimes combination pharmacotherapy is required, and you have to consider adding on, for example, an antidepressant. But they have the - But you have to stabilize them first.

32:09Exactly. And it has the sealing effects for certain drugs and the floor effects. So it's less likely that adding an antidepressant will make them more depressed or hypomanic or put them into a mixed state.

32:25Peter Attia:Now, in an individual who you do not believe has bipolar disorder, but still has irritability and mood swings, can SSRIs or SNRIs stabilize mood? Well, irritability is such a huge category. And a lot of people with depression have a lot of irritability. So irritability can be part of a classic dysthymic disorder presentation. Irritability, pessimism, sadness, a lack of optimism, a lack of planning forward, those can all be part of dysthymic disorder. So irritability can exist in that context. In a bipolar context, it can be more dramatic. I would say the word would be volatility as opposed to irritability.

33:29That might be more descriptive of a typical patient with untreated or poorly treated bipolar disorder.

33:40Peter Attia:When you think about the world we live in today and you imagine a time machine that were to take you back in time 10 ,000 years, do you think we would still see the same prevalence of depression? I'm not going to focus on anxiety because I think the answer is we'd see a lot less anxiety. I don't have enough insight into bipolar to comment, but I want to focus specifically on depression. How much of depression do you think is purely biological and how much of it do you think is environmental?

34:12Well, it's hard to know. I would say there are probably evolutionary reasons that the genes have survived. And so if you think of diurnal variation, change of mood over the course of the day, and hypersomnia, excessive sleep, that might have been conserved evolutionarily because people stayed in their caves longer hours and only came out during the fewer daylight hours where there was more opportunity for mating, for acquisition of resources, food, obviously, and whatever other resources were sought for, and sought refuge in their caves or dwellings in a protective way so that their survival was likely to be enhanced.

35:10Peter Attia:So... Where do you think from an evolutionary perspective, depression specifically, or let's just say dysthymia or anhedonia, where do you think those would have been evolutionarily protective? Because I can sort of see anxiety having an evolutionary benefit for sure. That makes a ton of sense. I can clearly see why hypomania could have an enormous evolutionary benefit. And I'm not saying I don't agree that the others could. I just, I'm trying to think through the cases. Yeah. Well, it's very interesting. Specifically, I alluded to the theory of depression as being protective. Anxiety can be protective, but it can also be disadvantageous.

36:03Peter Attia:People's judgment can be impaired when they're anxious or when they're panicked, Let's say if someone is having a panic attack, instead of doing, undergoing a life protective behavior, they could be undergoing a foolish, impulsive behavior driven by their anxiety rather than a more objectively based appraisal of the dangers of the environment that they might be unnecessarily encountering. Yeah. I guess what I'm trying to understand is there are so many things that we can clearly say are pathology, even if natural selection had no point of view on them. So I'll give you an example. So atherosclerosis.

36:52Peter Attia:I don't think natural selection and evolution care to lick about it because it's a disease that doesn't really take hold until you're long past your reproductive age. and it just wasn't within the purview of it. So we've sort of created a luxury problem for ourselves, which is we've - Or that might have even been adaptive. Well, so that's an interesting question, right? How would it, I mean, I will tell you what part of atherosclerosis was adaptive. The fact that we are humans and we are one of the few species that can experience atherosclerosis, I will tell you the adaptive part of that is we are the ones that carry the ApoB lipoprotein.

37:32Peter Attia:And that's the thing that's causing atherosclerosis, but that's the thing that allowed us to have so much cholesterol to feed our huge brains in an environment where nutrients were scarce. So I can make the case that having LDL particles allowed us to have tons of cholesterol, even if we were starving, and that allowed us to never compromise our growth, including our brains. But now that we live in an environment where nutrients are plentiful, it's not serving us so well anymore and we get atherosclerosis. Is there kind of a case that can be made that says either we are pathologizing depression and in reality, again, I can't imagine any person likes feeling, I've experienced anhedonia, I've experienced dysthymia, I know what those things feel like.

38:22Peter Attia:They feel horrible. But is that, I hate to ask the dumb question, is that a bad thing? Is there a time and a place for experiencing those things so we can appreciate it when we don't feel those things? Let's take anhedonia out of it because that's a misunderstood concept. But I would say depression is bad. It takes a huge toll on people. It can be lethal. It definitely increases the risk factors for a lot of medical problems. And in that sense, it's very adaptive. From a psychological point of view, it can lead to a radical reappraisal of one's priorities and priors to get to a probabilistic model of thinking.

39:11It can serve almost as a giant shakeup of one's previous model of the world and their place in it. So it can ultimately serve a purpose. But I wouldn't want someone to have to suffer like that to achieve that goal. There are better ways of getting there than getting there through depression. Depression is not a good thing. We're talking about clinical depression. We're not talking about the depression of everyday life. That's a good thing.

39:47Peter Attia:Okay. So that's what I'm sort of getting at, right, is do you believe that there is a much higher incidence of clinical depression today than there would have been 10 ,000 years ago? That's one of those questions I could speculate about. But, you know, Peter, when I look at our world today and our children and the kind of world they're facing, they're facing enormous challenges existentially. What role am I going to have? Artificial intelligence is evolving. If our primary identity is our intellectual function and we're creating machines that are going to surpass our own intellectual function or certain examples have surpassed in certain areas, then how can I flourish?

40:48Peter Attia:But let's go back in time 10 years when nobody was thinking about that other than a few people. Okay. Wasn't the prevalence of major depression a decade ago comparable to today? And would that still have been significantly higher than it was thousands of years ago? I think it's going up because there are multiple simultaneous challenges. There's a lot of environmental anxiety. We see a lot of increased challenges to the environment, fires in the summer, fires even in the winter. in certain places in the cold. But again, when I think about those things, and I'm not disputing that those things are happening, but contrast that with how miserable it must have been.

41:34Peter Attia:Just imagine what it was like to be alive a thousand years ago. Yeah. Like, wouldn't you rather be the least wealthy person in the United States today than the King of England a thousand years ago? You know, it's very complicated. it. I'm just saying, for as lousy, and we can talk about all the things that make the world a lousy place today, it's still infinitely better than it was just a thousand years ago. From a bourgeois point of view, yes. But from a relational point of view - Well, so that's exactly where I'm trying to go with this, which is, what are the factors? What are the, I don't, the word environmental trigger, I think, is preventing me from really getting at the question.

42:18Peter Attia:Yeah, I think I was premature. Well, no, no, no. I'm just saying I'm genuinely curious as to what do we think is the causal relationship between mental health deteriorating and the world we inhabit? Well, I think a lot of it has to do with things that are spoken about social media, people being on digital devices, being isolated, and having a distorted view of the world created by commerce to be kind of sucked into their algorithms, and therefore isolated as a result. and people are having less sex. People are having fewer romantic relationships. People are using online pornography more in the absence of relationships.

43:21Fertility rates are going down. Reproductive rates are going down. There's this great divide socioeconomically that I think is having an outsized role too. So when the king was the king of England 10 ,000 years ago, whatever time frame you were alluding to - Yeah, 1 ,000. 1 ,000. That's a more historically accurate one. Thank you. Thanks for correcting that.

43:54probably everybody else didn't know anything different. And if there was better, they just accepted that's how it was. They weren't going to be kings. They lived in the moment more. They accepted the realities such as they were, perhaps. Again, this is all hypothetical. and so that enabled them to live more in the moment just like older people people who are close to the end of life without being ill are able to enjoy the moment more appreciate the moment more so i think that the great divide socioeconomically has created a lot of anxiety and demoralization. And when people have low adaptive capacity and low vulnerability thresholds for mental illness, that's when it starts to emerge.

44:57Peter Attia:Yeah, that makes sense to me. It makes sense to me that the relational component, the comparing component, the digital component, these things must be contributing. And in addition to everything you've said, and I've brought this up before on the podcast, I had a guest on many years ago. His name is Tom Katana. He's a physician who's a missionary in the Nuba Mountains of Sudan. And so he takes care of 1 million people there that are without any healthcare. And these are people that are particularly being targeted by their government. So they're literally being killed by their own government. And so they're being bombed and he's taking shrapnel out of their wounds in this hospital by himself with a couple of nurses.

45:43Remarkable.

45:44Peter Attia:Unbelievable. And I asked him, and I can't remember if I asked him this on the podcast or just when we were together having dinner at some point, but I said, you know, Tom, what's the prevalence of depression there? And he said, like, none. Like, there is no depression. You know, tight-knit families, common purpose. Yes, it's scary. When the airplanes come over, they all have to dive into a ditch. But basically, other than that, they're farming, they're doing their thing, and they don't know better is part of what it is. I'm not suggesting that we want that, that that needs to stop. But there's a price we pay for modernity.

46:27Peter Attia:Yes. And I wonder if this is the price. Very complicated. War seems to improve people's mental health, ironically. Yes, yes. With obviously dramatic exceptions for PTSD and other laws. But to say it's the price we pay for modernity, if you want to accept modernity as it is without challenging it, yes. But a lot of people are challenging modernity and let's say looking for alternative approaches such as living more in nature would be a great example of that. And getting off the grid would be an example. And when I say this is the price you pay for modernity, I think what I would say after that is, unless you start to take individual measures to control some of this.

47:28Peter Attia:So again, we have to make a greater effort to be outdoors today. I think there's tremendous benefit to our mental and emotional health in being outdoors. But it's no longer the default. You see, we used to live outdoors. Now we don't. So if you want to be outdoors anymore, you have to actually take the steps and do it. It's much easier to live in isolation today. 10 ,000 years ago, it was metaphysically impossible to live in isolation. You would have died very quickly. Today, you could live in isolation all you wanted. So if your tendency is to isolate, you actually have to work to overcome that.

48:00Peter Attia:Similarly, it's very easy today to see everything, to be overrun by information. If that's contributing to your mental health, you actually now have to take a deliberate step to pull away from media if that's part of the problem or whatever it is. So I'll give you an example. I did a podcast recently on sleep. And the way I sort of framed it was without having great evidence for this, but looking at sort of some of the literature on hunter gatherers, there's no evidence that hunter gatherers suffered from insomnia. They didn't necessarily sleep eight hours a night. There's some evidence that they slept in sort of shorter windows.

48:38Peter Attia:But the point is they weren't walking around struggling to fall asleep, waking up ruminating and suffering from a lot of the things that people suffer from today. And without rehashing the entirety of the podcast, I basically made the case that, look, it was really down to the things that drive sleep, circadian rhythm, adenosine, cortisol, all of these things have to be in sync for you to sleep. And the world back then allowed those things to be in sync. Fast forward to today, we've engineered a world that works against those things. It works against the rise and fall of cortisol, the rise and fall of adenosine, the rise and fall of melatonin.

49:18Peter Attia:All of those things are being countered by our environment. And so if you want to be able to sleep really, really well in the modern world, you have to do things that might feel unnatural, meaning you have to disconnect from your phone. You have to autocorrect the light in your environment. You have to force yourself - They're anti-normative. Exactly. They're anti-normative. That's a great way of saying it. So all of that is to say, it seems to me that the entire field of psychiatry, or at least part of it, could be viewed as an anti-normative response to a modern world, at least when it comes to certain things like anxiety and depression.

49:54Yeah. And it's interesting, you bring up sleep. I think all the foundational biological factors. So in my model of endocrinology, certainly hormones and the endocrine system are part of it, but also inflammation, metabolism, and stress circuitry, in addition to circadian biology and sleep architecture. All those factors are challenged by modernity. if we want to look at metabolism, diets, and people weren't needing to go on GLP-1s a thousand years ago, maybe unless they were the king.

50:39Peter Attia:That's right. We know the king had gout, but we don't know if anybody else did. You raise a great point, and I've discussed this also on the podcast in the past, this mental model of distress tolerance. And I wrote about this actually in my book, which was, this is the model that I use. It's how I think about my life. So when I'm irritable, which let's be honest, I can be quite irritable. I'm imagining kind of a window in which I occupy. And the window is my distress tolerance window. When that window is wide open, I can tolerate a lot. I can take a lot of bullets and I'm fine. When that window is narrow, even the littlest thing will sort of irk me.

51:23Peter Attia:If my kid does this or if my wife says this or an employee says this, I'll be irritable. Okay. So then I ask the question, what determines the width of my window? And what's amazing but obvious is what you just said. Your biology plays such a role in that window. If I exercised or didn't exercise, that's an enormous contributor to the width of my window. If I had a good night's sleep versus a bad night's sleep, huge contributor. If I'm in pain, I had a dental issue a year or two ago and it just lingered for weeks, like a low grade, six out of 10 pain. Death by a thousand cuts. And I didn't think anything of it, but as I found myself irritable two weeks into this, someone said, untreated pain is going to make you irritable.

52:16Peter Attia:I could rattle off all the things that do it. But everybody, I think, has to kind of discover what creates, what lengthens their window. And do you get the impression - Yes and no. I mean, it's part of the human condition that we all have these foundational biological factors and we have an adaptive capacity and that's always changing over time. How much of that is part of psychiatry? Obviously, you as a psychiatrist are attuned to that, but do you get the impression that that should be part of the foundational treatment, which is, yes, I know that you're depressed. I know that your anxiety is this way or the other way.

52:51Peter Attia:I know that you're irritable, but are we looking at your nutrition? Are we looking at how much you exercise? Are we trying to regulate your sleep? And are we actually treating some of those underlying foundations as well? Yeah. Well, I think a lot of psychiatrists are, and there are specialists, like for example, in nutrition and psychiatry, sleep and psychiatry, there's a lot of research being done on the pathophysiology of metabolism and its role in psychiatric illness. And I think most psychiatrists try hard to touch upon those things. So I'd be careful to say anybody wasn't doing it adequately to generalize.

53:40But I think we have to have a framework about how to think about it, that the brain doesn't operate in isolation. And it's part of this larger system with bidirectional feedback. And so when you have a toothache, that's obviously tapping into your stress circuitry, that's affecting your cortisol levels. That's affecting, potentially if it's going on, that's affecting your memory because it's toxic to the hippocampus. You're producing less BDNF, which is critical for neuroplasticity. So on many different levels, there are these continuous bi-directional interactions between what happens on a neurotransmitter level and what happens with the foundational biological factors.

54:37I just chose endocrinology as the one I wanted to focus on because it fascinated me particularly.

54:45Peter Attia:Well, that's great because that's exactly where I kind of wanted to go. So let's go back in time five years ago when this interest of yours started. Why did you pick endocrinology and how did you dip your toe in that water? Yeah. Well, I was always interested in endocrinology and I have some friends, colleagues who are endocrinologists, but I was really struck by the impact of the interpretation and the reinterpretation of the Women's Health Initiative and how that changed prescribing practices so profoundly in general medicine. it led me to think, well, if that happened in general medicine, how is it affecting the appreciation of endocrinology in psychiatry?

55:31And I concluded that endocrinology, from my perspective, tends to be, at least by me, previous to that, was significantly underappreciated in psychiatry, and that there are a number of reasons for that. But that was something I wanted to roll my sleeves up and get into. So I sort of went back to school, so to speak. I took a course in bioidentical hormone replacement therapy. I got certified as an advanced practitioner of BHRT, which just opened a window. and I did a number of other educational activities to learn more about it. And I found it to be fascinating, particularly how I feel the neural circuits and neurotransmitters are really inseparable from the endocrine system.

56:33Peter Attia:So I want to go back to something you said. you talked about the WHI. Your career has spanned pre and post-WHI. So 25 years ago, you got to witness the complete reduction in the prescription of estrogen for women during menopause. What was the impact you saw in your practice as you saw women go from receiving hormones at the time of menopause to women being deprived of hormones? Variable. Variable. And it was so long ago, and I was so relatively ignorant as to where I am now that I'd be hesitant to make any generalizations about it. But you brought it up as, hey, five years ago, which means you're 20 years post-WHI.

57:27Peter Attia:It was still kind of clearly there was still something there that made you think about it. Yeah, it made an impact on me. I had the impression that people, again, getting back to adaptive capacity, that women whose adaptive capacities were higher, their ability to self-regulate and adjust to internal and external threats and changes was being eroded off of estradiol. And similarly, for both sexes, that men who needed testosterone weren't getting it, were being told it wasn't safe, similarly had an erosion of their function across multiple domains. So I don't think there's a way that we can dive into this, Linus, without you explaining some of the biology of how estradiol and testosterone and maybe even progesterone or levofabroxene, like all of these things.

58:29Peter Attia:Yeah. Let's start with estradiol. I mean, I share your point of view. I feel very strongly that estradiol is one of the most important hormones in the brain, both for men and women. So maybe walk us through some of the reasons why that's the case, because it probably isn't intuitive to everybody. Definitely not. It wasn't to me. So in preparing for the podcast, I came up with a mouthful. But estradiol is a constitutive, pleiotropic multi-system regulator of neurotransmitters and neural circuits. So constitutive, what does that mean? It means part of the architecture evolved. Hormones were evolved by the brain for the brain.

59:20So there's no separation of the endocrine system and the brain at that level. Pleotropic, it has multiple actions at multiple levels throughout neurotransmission. So, for example, estradiol modulates not only serotonergic transmission profoundly, but also the dopamine system, the GABA system, acetylcholine, NMDA, and glutamate. So it's really profound. And it serves a regulatory function. While psychotropics are signal amplifiers, estradiol, for example, is a system modulator. It creates the conditions within which neurotransmission occurs.

1:00:17Peter Attia:Do we know how these hormones are regulated in the brain? We have a pretty good sense of how they're regulated in the periphery. We understand the feedback loops. It's actually hard to disentangle them because quite frankly, it's the pituitary gland that does so much of the regulation in the periphery through luteinizing hormone and follicle-stimulating hormone. How is that happening in the brain? Well, it's the HPG axis, the hypothalamic pituitary gonadal axis, and all the bidirectional feedback that occurs within that framework. In other words, is there actual estradiol in a synapse or is it removed from that given its size and it's regulating upstream of the actual synaptic contents between where the actual neurotransmitters live?

1:01:11No. There are receptors for it on the membranes of neurons. So they're well characterized. There's membrane estrogen receptor alpha and membrane estrogen receptor beta. And there are also transcriptional binding sites, estrogen response elements within our genomes. So estrogen is penetrating to the deepest level of our central nervous system where transcription is regulated. And that, for example, is how serotonin synthesis is upgraded through tryptophan hydroxylase. There are specific estrogen response elements that bind to promoting factors for tryptophan hydroxylase, therefore increasing serotonin.

1:02:04The same thing for dopamine through tyrosine hydroxylase. The same thing for acetylcholine through choline acetyltransferase. So it's right there. It's at ground zero of neuronal activity, which is fascinating. And that's part of why I find the whole thing just so remarkable, that it's embedded within the brain. I had another term that I was searching for imbued with and embedded within the brain is how I think about it.

1:02:42Peter Attia:And so let's now talk about the removal of that. So everything you said kind of explains the biology of what estrogen is doing. Yeah. But now let's characterize the phenotype. So if estrogen is reduced, all other things being equal, how does the brain experience that? Well, let's think of evolution. Estradiol evolved to be not only a sex hormone, but this pleiotropic regulator of other systems because for successful reproduction, It's not only conception that's required. It's nurturing. It's forming social bonds. It's acquiring resources. So therefore, this pleiotropic role has been evolutionarily very adaptive, that one hormone has these multi-system effects.

1:03:48And that's why you see women with low estrogen having multiple domain challenges from cognition to mood regulation to anxiety to a number of other challenges.

1:04:05Peter Attia:And why do you think it is so variable, Linus? I can't imagine you haven't seen what any doctor has seen in this situation, which is there are some women whose cognitive symptoms in the presence of estrogen withdrawal are incompatible with normal life. Yeah. And there are other women who barely notice it. Is it receptor density? Is there some other sensitivity? It's a combination of genetics for receptor morphology and function. But rather than absolute levels being determinative of psychopathology or emotional variability in response to change in estradiol levels. It's more the actual change and fluctuations and oscillations of those levels themselves.

1:05:05That's why PMDD is what it is, because allopregnanolone levels, a derivative of progesterone, go down significantly toward the end of the luteal phase. And therefore, Or there are some women, due to a variety of reasons, it's all biological. It has to do with receptor morphology, genetic influences, possible environment influences that have degraded their receptor modulation and responsivity. Some women are susceptible to a much greater degree. You know, you use the example of I have a toothache and I have an exercise and I'm feeling, you know, irritable as hell. Well, the same thing applies to all of us.

1:05:59We have different adaptive capacities. So a woman who's sleeping well, who has good social supports, who doesn't have huge caregiving burdens that are overwhelming, who doesn't have occupational stressors that are overwhelming, who has meaning and purpose in her life, she's more likely to have a higher adaptive capacity in general to menopausal changes. I'm not talking about PMDD now, going back to menopause. she's likely to have the bandwidth to withstand it than a woman who's incredibly burdened at work with terrible stress, who has huge caregiving burdens, let's say for a parent with Alzheimer's or the primary caregiver and that parent is living at home, someone who's metabolically challenged, overweight, not exercising.

1:06:55So all these factors play a role as well as medical illness as a generalization.

1:07:01Peter Attia:And then of course, it's complicated because a lot of times the loss of hormone makes it difficult to regulate metabolic health, makes it difficult to have motivation. It's a vicious cycle. It's a very vicious cycle and it amplifies the problem. Absolutely. Can you say anything about this in men? Because again, I think this is counterintuitive, but I don't think men are particularly less susceptible to this, both testosterone and estradiol. Yeah, well, let's start. Let me just say, men get their estradiol from testosterone, from the aromatization of testosterone. So testosterone is a pro-drug for estradiol, as well as, of course, being a primary drug for all the obvious reasons.

1:07:44But as a primary hormone. Testosterone modulates, there's a lot of system redundancy. So testosterone modulates dopamine in particular to a high degree. So losses in testosterone in men are much more typically, not always, typically andropause, which is the male version of menopause that some of the audience may not be familiar with the terminology. Andropause is more gradual and insidious and less likely as a result to be identified. But it can present with a sense of dulling, a loss of the dopamine-mediated functions. So the mesolimbic and mesocortical functions, Those are two pathways of the dopamine system.

1:08:41The mesolimbic has to do with reward salience, what goals are worth pursuing, and reward prediction. If I pursue this, how likely am I to get it? And the mesocortical system has to do with executive function, working memory, all the symptoms that are impaired in someone who has ADHD. So you can have so-called subclinical syndromes of cognitive dysfunction and ADHD-like symptoms in men with declining testosterone, in addition to the androgen-based, generally more vital, physically active, and libido-enhancing effects of testosterone.

1:09:32Peter Attia:And how much of that do you think women are also dependent on in terms of their testosterone? Yeah. Well, I think libido is a huge one. Women are almost entirely dependent on testosterone for libido. What about mood, sleep, or some of the other things where men receive a benefit? Men are more vulnerable in that department. Yeah. Why do you think that is? To testosterone. Yeah. Yeah. Why do you think women are less responsive to and or dependent on testosterone for some of those other things? Is it because estrogen - Evolution. Because they make so much less of it. Got it. Although they still make 10 times as much - I was about to say, they still make much more testosterone than estradiol.

1:10:20But compared to men. Yeah. Yeah. Yeah. Which for the audience, that might be worth your reiterating.

1:10:28Peter Attia:Yeah. I think what's always misleading when you look at a laboratory report is the number for estradiol is so much bigger than the number for testosterone in women. Right. But that's because testosterone is reported - In picograms per deciliter, right? Testosterone is reported in nanograms per deciliter. Estradiol is reported in picograms per deciliter. So you have to normalize those because they're off by a factor of a thousand. And when you do that, you realize that a woman's testosterone level is about 10 times higher than her estradiol level, although it's about one-tenth the level of a man.

1:11:04Peter Attia:As you no doubt know, there are various ways to increase testosterone in men. The most obvious and direct way is to give a man exogenous testosterone. That's a very safe and effective way to do it. It's also the easiest way to do it. But not all men want to receive testosterone that way. Sometimes they want to indirectly receive testosterone by taking hormones that will tell their body to make more endogenous testosterone. And the two most common ways to do that are giving HCG, which is giving effectively luteinizing hormone, telling the body to make testosterone. And then the other would be using drugs like Clomid or Clomiphene or Enclomiphene, which basically trick the brain by blocking at the hypothalamus, the receptors for estradiol and testosterone, such that the pituitary says, oh gosh, we're, we're, we're going to make more of this.

1:12:03Peter Attia:We're going to make more LH and FSH. Is there any reason to believe that that approach robs the brain of the very estrogen and testosterone that you're trying to give it? Well, I would say just empirically, men who take chromiphene tend to be dissatisfied. Even though their numbers are high in the periphery. Yes. Yeah, that's been our experience as well. There's a symptom laboratory mismatch. Yes. And I have no data to suggest why, but this has always been the question I've thought. Which is unfortunate because - It's an otherwise very convenient way to replace testosterone. Absolutely. Yeah. Yeah.

1:12:48Peter Attia:So, okay. I wondered if that was your experience. Let's mention the primary reason why clomiphene is typically prescribed. It's oral? As well as HCG. No, the rationale. Okay. So I think there's three rationales for clomiphene and n-clomiphene. But I think where you're going is you preserve endogenous production when you use either - Well, fertility. Yes. Which of course comes with it. Yeah. So that's a huge part of it. I think even when you consider HCG, which I think is a superior drug to clomiphene and n-clomiphene because because it's administered peripherally, it acts peripherally, and it doesn't have a central block.

1:13:32Peter Attia:But let's be honest, it's injectable. It's a very, very delicate peptide. It's very expensive. It's inconvenient. It's got all those problems. Clomid's cheap. It's oral. And by the way, a lot of people don't know this, it's not regulated. So testosterone and HCG are schedule 4, Clomid and Clomiphene are not regulated. For now. Yeah. So you don't have to go and see a doctor formally to do it. It can be kind of a jack-in-the-box online thing that can give it to you. But you're correct. The few times we have used it for patients who want to preserve fertility, want to rely on endogenous function, don't want to deal with needles, it really fixes the numbers.

1:14:14Peter Attia:It just doesn't seem to fix the symptoms. Yeah. That seems to be the case. Not always. There are some people who take it and do well, but compared to exogenous testosterone, testosterone cipionate injection, for example, dramatically better responses. Yeah. Let's talk a little bit about progesterone. You've already alluded to it in one very important capacity, which is in the case of a woman who is experiencing a somewhat regular menstrual cycle, you already mentioned that in the second half of the luteal phase, and I guess it's worth, it's always, it's sometimes easier if people can picture how the hormones cycle during, during a woman's cycle.

1:14:59Peter Attia:But progesterone is the easiest one, I think, to draw because for the first 14 days during the, yeah, during the follicular phase from the moment she has her period until she ovulates. There's nothing. It's flat lines. And then it rises as it prepares for implantation. It hits a peak, assuming there is no implantation. And it's important to mention why that is, because it comes from the corpus luteum, the follicle that is broken, and the lining of that follicle, I believe, is what secretes the progesterone. Right. In preparation for the follicle to be implanted. But once it's not implanted, the lining sheds, which is what the period is.

1:15:41Peter Attia:But the point that you're making is, but it's that progesterone that is crashing down. And what I find very interesting is that the woman didn't feel bad when her progesterone level was low, right? Because she felt fine during the follicular. No oscillation. Exactly. It's the fall back to low from high that causes the symptoms. This is incredibly fascinating. It is. And one of the most fascinating paradigms in human biology is postpartum, where progesterone goes from all-time highs, and so does estradiol. Estradiol goes from 30 ,000 to, let's say, 30. Yeah. Yeah. Progesterone goes from several hundred to less than one within 24 to 48 hours.

1:16:33It's amazing that women do as well as they do. I'm in awe of -

1:16:39Peter Attia:In other words, yeah. I just want to make sure the listener knows what you're saying. The more I learn about hormones, the more in awe of women I am. Yeah. You're in awe that more women don't experience postpartum depression. Yeah. But I'm in awe of all women for having to deal with these issues that guys don't have to deal with and how profound they are and how challenging they are. So do you think we understand why, and I know you've talked about it in terms of genetics, receptor density. Is there anything else we know about why some women will experience that drop in progesterone over the course of a week and the last part of their cycle and be really debilitated by it and while some will not notice it.

1:17:23Peter Attia:How genetic is it? I assume there's a strong concordance between mother-daughter? I believe it's highly genetic, yes. Do you know how predictive that is of postpartum depression or how predictive that is of cognitive or depressive symptoms during menopause when there's a depletion of both progesterone and estrogen? I'm not sure. I'm not sure. There is a correlation. I'm not sure how high a correlation there is. But I would think there would be a very high prevalence of women who have severe postpartum depression or psychosis who also have PMDD, but not the converse. Yeah. Let's talk about postpartum depression.

1:18:13Peter Attia:Do you see any women for that in your practice? Yes. Only because postpartum depression is a very heterogeneous condition. The most dramatic example of severe postpartum depression and psychosis happens within a week of childbirth. And it usually unfolds in a hospital where a woman goes from a normal frame of mind. And with estradiol levels and progesterone at their peaks, these women are, you know, women in general at the end of pregnancy are primed to be in wonderful moods. And they go from there to having the ones who are afflicted by severe cases of postpartum depression and psychosis start to become suspicious of the hospital personnel, become hypervigilant about where the baby is and have very intense separation anxiety, can have intrusive ideation about harming their own children themselves.

1:19:24without wanting to, but having some fear. It's an OCD-like phenomenon that they can have a fear that they can do something that they would never do.

1:19:34Peter Attia:And we don't know why this happens to some women. And fortunately, few women - It's being researched. Hopkins has a big program in that. Do you know the prevalence of that severe a level of postpartum depression? Um, fortunately less than 1%, much less. So those aren't the women you see because presumably those are the women that are under care of a psychiatrist within the hospital. You're seeing women who go home, everything seems fine. Yeah. And presumably over the next few weeks or even months. Yeah. They just don't get back to themselves. Yeah. Okay. So when a woman like that comes to you and let's assume she's never seen any psychiatrist before.

1:20:12Peter Attia:Yeah. How do you do the evaluation and how do you think about treating her? I do the evaluation the same way. Okay. I ask her what's troubling her, and I have a third ear for issues around the existential shift in identity of becoming a mother, either for the first time or subsequent times. It's a profound identity transition, and it affects different women differently. Different women have different levels of support from their spouses, if they have one, from their families, different levels of socioeconomic, really economic support. But what if there's been no change? So what if you have a case where a woman, it's not her first child, so the identity piece hasn't changed.

1:21:04Peter Attia:There's nothing obvious you can point to in her personal life from a support network or attention. In other words, does it sometimes just occur almost randomly? Yes, de novo. Yeah. It does. So how do you... Okay, let's say you make the diagnosis, which I assume is not impossible to make. What are the treatments... Even for a psychiatrist. What are you thinking about as you start to lay out treatment options? How much do you... And again, maybe I'll just make it a little straightforward and say, Let's assume there are no other comorbid conditions that would make the— Yeah, pretty similar to non-postpartum depression.

1:21:47It's only the acute type where there's a synthetic analog of that chemical that the body makes, the hormone, allopregnanolone, called xeranolone, which is now in a pill form. It used to be brexanolone, which was an intravenous infusion given in an ambulatory center where a woman had to stay there for a protected period of time.

1:22:17Peter Attia:Think about a woman who's having all these issues and has to be separated from her family and her baby. So fortunately, they came out with an oral form of it. The generic name is xeranolone. And it's a synthetic version of the neurosteroid allopregnanolone, which is the breakdown product of progesterone via 5-alpha reductase and 3-alpha hydroxysteroid hydrogenase. So would you give that as monotherapy or do you give that in combination with, for example, an SSRI? Oh, well, that's the one in the hospital. That starts in the hospital. Okay, but when she's - When she goes home. When she goes home, what do you?

1:23:01No. All other things being equal, you just give that.

1:23:05Peter Attia:You just give that. Yeah. Okay. Yeah. If someone is on an SSRI, I wouldn't take them off of it. Okay. But you wouldn't start an SSRI then. Okay. No. And in your experience, for that woman in the case we've described, who's presenting to you in the weeks or months following her pregnancy, how long does she typically require treatment before depression? We're talking about a different category than the synthetic neurosteroid category, which is that acute immediate. Yes, I'm talking about the woman who presents to you outside. Yeah, that's a very heterogeneous population. If they had so-called premorbid history of depression, history of depression before their pregnancy, for example, or if they have bipolar disorder.

1:24:01Peter Attia:Let's say they didn't have either. Then I was going to say they're at higher risk. If they had neither, then you would treat them pretty much like any other patient with depression. And when you're talking to that patient and setting expectations and they say to you, doctor, how long am I going to need this medication until I'm back to myself? What would you say? When people ask me questions like that, which I get all the time, I go back to what their previous baseline is. So if they were well for 34 years and then they have this one episode, I would say, oh, evidence-based medicine would suggest that you stay on this medication for somewhere on the order of 8 to 12 months.

1:24:53And then we could, depending on if you respond well, we could taper you off of it slowly and see how you do. But I wouldn't think at all that you have to be on this medication indefinitely. But if they said that they went into it and they had dysthymic tendencies that weren't diagnosed, like pessimism, constant irritability, just sadness, and they felt that their mood was beneath baseline for most of it, then I would say, well, let's see what you want. It isn't what you need. It's more a quality of life issue. Because often what happens in a situation like that is a woman goes on a medication for an acute depression, and she finds her new baseline is better than her premorbid baseline.

1:25:50So she feels better than she did before she ever started taking the psychotropic or had the, certainly better than before she had the major depression.

1:26:01Peter Attia:So in other words, the pregnancy may have unmasked something that she was just sort of stoically pushing through before? It served, it exacerbated it. Yeah. Okay. I want to pivot to another endocrine system on that same HPA axis or HPX is not the A part, the thyroid system, right? So everybody's heard of TSH and everybody kind of understands more or less the thyroid. We did a great podcast on it recently. I think it's kind of intuitive to people that, well, maybe it's not actually, maybe it's not. So let's just take it away with how does T3 and T4 and TSH interact with the psychiatric system overall?

1:26:46Sure. Well, just to give an overview of it, TSH is what the pituitary thinks of the thyroid access. And what I find is that a lot of people with quote-unquote normal values of TSH, which is often what the average internist measures and the average psychiatrist, people with normal range TSH, let's say in the top 50 % of that range, So if the normal range is 0.8 to 5.0, people, let's say in the range of 2.5 to 5, are often considered normal and dismissed. But that's often indicative of a real foundational deficiency in thyroid hormone, because that's only a signal to the thyroid to produce thyroid hormone.

1:27:56In thyroid hormone, there are two types, T4, which has two functions. It's a prodrug, and it gets into the central nervous system to be converted centrally there to T3. And it's also a prodrug in the periphery. So there are two different types of diaginases, enzymes that convert them. So free T4 is a very, very important value. And if free T4 is suboptimal in a patient with depression, it's a signal to me that that person should have an endocrine consult or I myself should directly prescribe them thyroid supplementation.

1:28:47Peter Attia:So do you rely more on the TSH level or the free T4 level? Yeah, free T4 and free T3. Yeah, but primarily free T4. And if the TSH level is in the middle or low end of the range, but the free T4 is low, how do you act? Versus if the TSH is in the higher end of the range, but the free T4 is also in the higher end of the range, how do you act in those two settings? Well, I'm not concerned about the TSH. I'm concerned about the free C4. So that's the biomarker that's more of interest. For me, yes. And then tell me, in your experience, when this is being missed, so if this is being ignored, where is it most showing up?

1:29:45Peter Attia:Is it showing up more on the depressive side of the axis? Is it showing up more in the anxiety side or the OCD side? Well, hypothyroidism, low thyroid, is showing up as depression. Hyperthyroidism is showing up more typically and rarely. Yeah, rarely. I see very little of that. But that's more likely to manifest with anxiety. And there's a dramatic example of that called thyroid storm, where someone, I know you're familiar with that, but for the audience, how would you describe it? I've only seen one case of it, believe it or not. But of course, in my practice, it wouldn't be common. But it was a patient that had a nodule in their thyroid that was making so much thyroid hormone that they showed up.

1:30:33Peter Attia:And on their first evaluation, their TSH was zero, like literally zero. Their free T4 was quite elevated, although not so elevated that you would think anything was going on. But on questioning, they had palpitations of their heart. Their resting heart rate was quite high. They were sweating quite a bit. And so that was a patient that we very quickly got into an endocrinologist for the appropriate medical management of that hot thyroid nodule. Yeah. There can be a hypertensive crisis, right? Yeah. That's a good point. He had slight hypertension, but he wasn't in kind of a crisis. It required medication, but it was easy to manage on one drug.

1:31:12Peter Attia:Yeah. So I've actually never seen it in my practice. But less dramatic hyperthyroidism I have seen. And that can absolutely manifest in anxiety. And it's very physiologic. So it's less the cognitive anxiety, worry, rumination, social anxiety, and whatnot. And it's somatic anxiety, anxiety in the body, racing heart, restlessness, agitation, insomnia. That sort of anxiety is what's manifesting. And so focusing on the hypo, because that's the far, far more common one that you see, and we would all see, of course, is your approach to treating this with monotherapy, T4 monotherapy? Do you like to use T4 and T3 together?

1:32:02Peter Attia:Do you like to use desiccated formulations that combine them in fixed ratios? Or how do you choose off the menu? Yeah. I like to use a combination of T4 and T3 where I can have more control over the exact dosage. And in the cases where you're prescribing it, presumably it's because of the psychiatric underlying belief or case that you're treating. Are those the symptoms you are titrating the drug to or do you look at something else such as the biomarker? No, the symptoms. Symptom, yeah. I check the labs. Yeah. I absolutely check the labs. But I'm focusing mainly on symptoms. And by the way, there are exceptions where I sometimes only prescribe T3 for treatment-resistant depression.

1:32:54Peter Attia:Yeah. Yeah. Say more about that. It seems to, for whatever reason, there's been research done on it for many years. It's a longstanding treatment for treatment-resistant depression. Because it boosts metabolism and energy. And when you say T3 for the listener, can you differentiate between the FDA-approved T3 cytomel, which is very short-acting, versus the compounded formulations that are more time-released? Yeah. I avoid the compounded ones. and I usually recommend twice a day, like first thing in the morning and then six to eight hours later, not too late because it could cause insomnia. Got it.

1:33:43Peter Attia:And what doses? I mean, we're talking five micrograms. These are presumably relatively modest doses. Yeah, I start low. I can even start at 2.5 twice a day, but sometimes it goes high. It can go to 25 twice a day. 25 micrograms of immediate release T3. For someone who's very depressed and responds to it and has normal blood pressure and pulse. Yeah. So give me an example of a patient. Can you recall a case of a patient that required that much T3? Yeah. So what had you tried before? I tried a series of monotherapies with antidepressants in combination therapies with antidepressants and mood stabilizers and let's say lithium, which is a so-called augmentation strategy.

1:34:42Peter Attia:But this was not bipolar. Not bipolar. No. Yeah. Unipolar depression. Unipolar depression. And I assume you're trying monoamine oxidase inhibitors. No. No. You were all SSRI or SNRI? Yeah. Yeah. Or bupropane. Okay, which is Welbutrin for the listener. So each of those therapies in monotherapy had not been successful. And then even when you layered on presumably not a bipolar dose of lithium - Or an atypical antipsychotic, because those are also indicated for treatment-resistant depression. Drugs like Rixalty, there are a number of them that are used now. Abilify, Yep. Rixalti is brexpiprazole, aripiprazole, zyprexa, olanzapine.

1:35:32Those drugs are often quite effective as augmentation strategies, adding on top of an antidepressant.

1:35:40Peter Attia:And despite all those combinations, he remained depressed? Suboptimal. Okay. So he got somewhat better, but not - Yeah. I think mentally I'm conflating several patients. Understood. And when you used the T3, did you discontinue the other drugs or did you - I always try to be as minimalistic as possible. But when someone is depressed and has a partial response, I'm not going to take them off. You can't remove - Yeah. Later on, when they're feeling good is the time where you have the luxury of peeling the layers of the onion. So in that particular example that you've got your mind on, when the T3 brought symptom relief, do you recall if you were also able to get any of the other agents off?

1:36:32Well, I know in the long run, I tend to try to taper someone off if their regimen looks ungainly.

1:36:46Peter Attia:And presumably, there's an order in, I mean, do you try to remove drugs in the order of side effects? So for example - The order of efficacy. In the order of efficacy. Okay. So we are a slave to efficacy first, side effects second. It's up to the patient. Okay. It's shared decision-making. Because some of those drugs like Abilify have unwanted side effects like appetite increase or things like that, correct? Well, much potentially worse than that. They can have delayed neurotoxic side effects. So what I mean by that is they can cause tardive dyskinesia, tardive dystonia. Tardive dyskinesia is a particularly disturbing side effect for someone to have.

1:37:25Potentially irreversible. Now there are actual drugs to treat it with. Wow. But it's uncontrollable movement of the mouth, tongue, and throat muscles that can be really disturbing and even dangerous. It can interfere with eating.

1:37:45Peter Attia:Yeah, so the stakes are high if you're going down that route. Well, yes, they are. And I always let the patient know. And that's a rare side effect. And it has to do with dose and length of exposure really over years. Now, in a patient that ultimately ends up needing that much T3, did their thyroid labs look that dramatic? or not necessarily? Not necessarily. So that is not necessarily a patient that showed up with a TSH of seven. No. Oh, yeah. Notice I refer to endocrinology. I wouldn't go near that. Okay. This is remarkable to me. Why do you think in the case of those few patients that have required or who's...

1:38:33Many patients who are depressed and have low normal free T4 and or free T3 seem to respond quite well to thyroid hormone supplementation.

1:38:49Peter Attia:And you believe that the reason is primarily through upregulation of metabolism and increased metabolic rate more than it is... It could be central. I mean, thyroid upregulates catecholamine receptor response. So it could be norepinephrine. They're getting more norepinephrine. And dopamine. It could also be serotonin. Thyroid increases serotonin receptors, density, serotonin receptor density. It also increases mitochondrial biogenesis on a genetic level. See, here we go again. Yeah, the probability is it's doing more than one thing. How deep these hormones go, right? In terms of the overlap and the commingling with neurotransmission and neural circuits.

1:39:39Peter Attia:So when I talk to patients about hormones, I usually say, I think of them as four axes. Yeah. Okay. So I think of the thyroid axis, the androgen axis, the adrenal cortical axis, and the fuel partitioning axis. So your insulin, glucagon, et cetera. I think the one that is most challenging is the third one in that list I gave, which is the cortisol pathway. Because most people are experiencing too much and not too little, and we don't have a pill that is an antidote. You can't treat it directly. Right. So you have every one of those other systems we can treat directly. We have so many amazing ways to treat because there are usually problems of too little and we know how to fix it.

1:40:25Peter Attia:Over here, it's usually too much and we now know how to fix it. It's really a signal. It's a signal that that person is under enormous stress because evolutionarily, the cortisol system, the HPA axis evolved for survival, for threat detection, hypervigilance, diverting resources to the moment, away from the immune system even, fragmented sleep architecture to maintain safety. All those things are adaptive in an acute context, but when they become chronic, it becomes very maladaptive. Yeah. And yet, I would bet that amongst the people listening to us today, and perhaps even the people that come into your office, that would be the most common underlying endocrine condition that is underpinning whatever other psychiatric or mental health condition we have.

1:41:25Peter Attia:It's hyper arousal that should be reserved for a chronic state, but is instead - For an acute state. For an acute state, sorry, that is instead in a chronic state. Yeah. And as we've just danced around, we don't have a pill to block it. We can't say, go and take this pill and it'll make it go away. And even if we did, that may not really solve the problem. So how do you, with your endocrinology hat on, not your psychiatry hat on, think about that? Or do you just say, I can only solve this with my psychiatry hat on? I don't think that way. In other words, I don't see any dichotomy between psychiatry and endocrinology.

1:42:11And so I don't have different hats, just to be transparent about it. But I think I solve it. I don't solve it. I collaborate with a patient if that patient is willing to attack it at its source. So if whatever the source of the hyperarousal that's maladaptive, whether it's a caregiving burden, whether that person at work is taking on way too much, which I see a lot of, whether it's medical illness that they're not paying sufficient attention to that's causing hyperarousal to address it at the source. The cortisol is a signal as far as I'm concerned. It's not really the primary problem. It's a secondary manifestation of a primary stress problem that isn't being managed adaptively.

1:43:09Peter Attia:And are you discussing it that way with a patient in the same way? Because if you're giving a patient estrogen, you're explaining to them why, right? This is what estrogen is doing. This is why we're replacing it. I have to. If you're giving a patient levothyroxine or Cytomel, this is why and this is what it's going to do. So when the patient, when you suspect that, hey, a big part of what's going on here is hyperarousal. I don't tell the patient that. You don't? No. Okay. No, because I don't think, I don't have an endocrine-centric vocabulary. So I just talk, people talk. Like, you know, that boss, you and that boss, you know, have you asked for a transfer?

1:43:58Or, you know, I know you're a very dedicated daughter, but, you know, your father with Alzheimer's, he's very wealthy. You could hire nurses around the clock. You could still have him live at your house, but you don't have to do all the work. A more common sense approach.

1:44:22Peter Attia:So let's think about a couple of ways to illustrate this for folks and tie it all together, right? Which is thinking about the psychic pharmacology of the modern tools that you have. plus some of these endocrine adaptive tools. And is there a case or two that come to your mind where, I mean, we've already discussed one, right? And it was potentially a few patients merged into one, but this case of recalcitrant depression that responded to what in my world would have been a very high dose of T3, and yet that was the unlock. Do you have any other cases like that that come to your mind. Let's say a woman who comes to me, perimenopausal age, who said, doctor, I need hormones.

1:45:14And I say, what's going on? And she says, well, I've always been the strongest person handling my emotions as far back as I can remember, but menopause is overwhelming me. So then I asked her, well, you've always been the strongest, had the strongest emotions. What does that mean? Well, I'm just a high-energy person. I said, well, tell me about your 20s and 30s. Oh, okay. And she smiles and says, well, they were chaotic. I started several companies. I traveled. I spent a lot of money. I had a lot of ideas. Sometimes thoughts would race through my mind faster than I could write them down. And I would ask more questions.

1:46:15And in this particular example, menopause was really happening. I investigated the hormones and the gonadotropins, and it lines up, as well as the symptomatology. But menopause was a clue to longstanding neglected bipolar disorder. So I started her on Lamotrigine, and that was a road to restitution of her life's narrative. She didn't know what was happening to her, her entire adult life. And with that organizing hypothesis, she understood all the difficulties she had sustained. And now looking forward, she had reason to believe things would be a lot different.

1:47:00Peter Attia:Now, in the case of that woman, did she talk about any of the depressive? Yes. Okay. Yes. she had gone to a previous psychiatrist for a, I would call it a bipolar depression, an episode of depression that happened in her 30s after she had a extended hypomanic period of incredible productivity. She crashed and could barely get out of bed and went to the psychiatrist. He prescribed an antidepressant. This gets back to what we were talking to earlier. what happened well first it was miraculous she says then a couple weeks later i started having those racing thoughts again and they were the worst i'd ever had and i couldn't sleep at all so i stopped it and never went back to that doctor she stopped the medication and what happened back to baseline the same roller coaster hypomania oh yeah okay the roller coaster yeah By the way, do we know how much of what's happening in her brain is, do we know biologically, receptor-wise, what's happening in her brain that is causing the hypomania?

1:48:16No.

1:48:19Peter Attia:Isn't that amazing? Yeah. I mean, I can't imagine for you how amazing that is. For me, it's amazing, and I don't treat these patients, and yet you're looking at this person and you're watching their experience. Yeah. Well, it's clearly some limbic dysregulation. But it's, I mean, this is why I think psychiatry is such an incredible field and such a challenging field is like, can you imagine a diabetologist not understanding that there's a beta cell that makes insulin? And yet they have to somehow treat this person. Yeah. Yeah. Well, on a molecular level, it's probably understood better than I'm describing in terms of ion channel function and whatnot, but it's very abstruse.

1:49:12And I don't think it's helpful for our audience to go there.

1:49:17Peter Attia:So I want to ask you, well, do you have another case you want to talk about? Because I have another question that goes back to kind of depression. Oh, tell me your question. Okay. So you talked about recalcitrant depression. But one drug we haven't talked about that's getting a lot of interest these days is ketamine. Yes. So can you tell me your experience with seeing patients go through ketamine therapy for difficult to treat depression or just, yeah, give me your thoughts on the subject. Do you want me to tell you how it works? That would be great. Sure. So ketamine is a so-called NMDA receptor antagonist.

1:49:56So when -

1:49:57Peter Attia:And we should just make sure people listening, that is not the same as MDMA. This is totally, totally unrelated, but I know people hear it and they think, oh, is that the same? Is that, has that any relationship to MDMA? But it does not. No, no, no. So it antagonizes, it blocks those receptors, which are actually normally inhibiting GABA interneurons that attach to glutamate. So what it does is it results in this massive release of glutamate and the excitatory response, as well as the mTOR pathway and protein synthesis and synaptic remodeling. So sudden, dramatic, epic neuroplasticity. So it happens remarkably fast, and it stops remarkably fast.

1:50:49So what's incredible about it is you can have a patient who's on the edge of being committable, requiring hospitalization because they can't contain their suicidal feelings, and you can send them for a ketamine infusion, and the suicidal risk dissipates, you know, dramatically, dramatically better. The depression doesn't necessarily. So basically, in my experience, I've used it sort of as a bridge to finding the solution for that patient, rather than it being the solution. Occasionally, it is the solution, and the patient goes for ketamine treatments and goes into remission from their depression.

1:51:34But more often than not, in my experience, they don't. And you have to find the right drug or the right other approach. to definitively treat their depression on a longer time basis.

1:51:50Peter Attia:Do patients become resistant to the effect over time? Is there a tachyphylaxis that develops? Yeah. I'm not that expert in ketamine, honestly, so I'm not sure. I haven't seen that. And for the patients - Practically, it's very time-consuming, expensive, and inconvenient. The patients that you would send for this treatment, how is it administered? Is it administered intravenously? Yeah, with monitoring. Yep. And in the most severe cases, what is the frequency with which they would need those treatments if you are relying on that treatment solely to ameliorate symptoms? Yeah. Well, that depends on the infusion center and the practitioner.

1:52:43I mean, some people might be willing to give it three or more times a week.

1:52:49Peter Attia:Oh, I was asking it more through the lens of how long the relief can last. Oh, heterogeneous. For some people - Clearly, it can be only days if that's what you're saying. Yeah, yeah. Okay. Yeah. And on the long end of that spectrum? Dr. David P. People can go, you know, people go into remission for all kinds of reasons, either that are unknowable in any given individual. It could be spontaneous remission, it could be a placebo, it could be a true drug effect. You know, it's hard to know. This is an emerging field. Dr. David P. And how is it, is the dose given in such a way that it's dissociative to the patient?

1:53:30Peter Attia:Dr. David P. Yes, yes. I see. I mean, it is a dissociative anesthetic. Yeah, I just didn't know if it was given so, I mean, I didn't realize the patient was completely dissociating because obviously you could be given at a lower dose, right? Well, I wouldn't say completely dissociating. I would say typically from what I hear, because I don't administer it, they're partially dissociated. Sometimes profoundly. But fully doesn't really apply. I don't think, but I think there's a spectrum. And I'm not sure if there's a correlation like there is for psychedelic medicine where the degree of the experiential effects of the psychedelic correlate to the therapeutic effects, supposedly.

1:54:20That's the latest thinking from my understanding.

1:54:22Peter Attia:So do you have any concern about what appears to be a lot of recreational use of ketamine outside of these clinical settings? Absolutely. I mean, as we've established, it's a dissociative anesthetic. So people who take it and dissociate from it have reactions from that. Plus, it can have its well-established mood-changing effects that could go good or bad. It absolutely needs to be controlled and supervised. If taken randomly, it's playing Russian roulette as far as I'm concerned. Have you seen any patients who have had negative experiences and have sought you out as a result of it? You know, something - No, but I have friends who've referred patients like that for addiction treatment.

1:55:13Peter Attia:I see. Okay. And, you know, you've sort of opened the door to psychedelics. Did you see that study probably in the last few months about a patient with Alzheimer's disease who was given five grams, which is a full therapeutic dose of psilocybin that had some memory recovery? Well, it was more than that. It was that Japanese woman who, and this is the ultimate N of one study, by the way. Yeah, yeah, yeah. But so interesting. Yeah. Well, so... Yes. So she got the five grams of psilocybin, but she supposedly had a diagnosis of severe Alzheimer's for a decade, which strikes me as unusual, to say the least.

1:56:08And she had no urinary function. She was completely incontinent. She spoke at most monosyllabically. She couldn't talk beyond that. She couldn't have interactions. And then she took this dose of psilocybin and behaved dramatically differently and became somewhat normal after

1:56:40Peter Attia:it. And how long did it last? I don't recall. Well, it was a very confusing case report because all it says is something to the effect of it lasted until the second administration of three grams of psilocybin. And it doesn't say anything more than that. There were no studies. There were no metrics. There was no neuroimaging. There was no anything with the study. So it's the ultimate end of one. I have an alternative hypothesis as to what the etiology was of the problem. Some people with post-traumatic stress disorder, particularly if they have mild cognitive impairment or mild Alzheimer's, can regress.

1:57:33And let me just preface to say, someone having severe Alzheimer's and surviving 10 years don't go together, in my experience. What do you think about that?

1:57:44Peter Attia:I don't think I have enough experience to say, but yeah. Again, it's a bit of a subjective title, right? Yeah. Yeah. But yes, usually if it's so severe that a, well, again, part of it comes down to basically airway protection. It's unclear how capable she was. So this N of 1 study is something I can't draw any conclusion from, but I find it theoretically interesting that so much adaptive capacity could be restored. So if PTSD was the etiology and she would regress and this interfered and turned around the regression, that's wonderful. Whatever it is, if it helped this patient, it's a wonderful initial response.

1:58:35I'd be very cautious about generalizing that neurodegenerative disease. The Robin Carhart Harris rebus model, relaxed belief under psychedelics, is about neuroplasticity for adjusting maladaptive priors, people who have beliefs that are problematic for them and the underpinnings of a lot of depressive and anxiety disorders. And administering classic psychedelics provides a therapeutic window within which a lot of neuroplasticity occurs and with the right response either within the individual or between the individual and family or formal therapists, change can occur in that critical window. And I find that of interest because, of course, estradiol creates a lot of neuroplasticity because it acts through BDNF and NMD and glutamate.

1:59:48And so the hormones that change the conditions within which neurotransmitters operate are very plastic under the right circumstances. Optimal estradiol levels, for example. And administering a psychedelic medication can also alter neuroplasticity, is intended really to alter neuroplasticity in the studies of psychedelics for the most part. Not all, but a lot of them are thinking of that set and setting model, which is based on a concept of neuroplasticity. Now, what's your experience been of psychedelics?

2:00:40Peter Attia:I have tried in as clinical a setting as I think possible several of these psychedelic agents. So I have tried ketamine under therapeutic conditions once. I didn't find it to be a positive experience and I will never repeat it. Do you want to elaborate about the negative aspects of it?

2:01:08Peter Attia:I described it to a friend after as Guantanamo Bay for my soul and my psyche. I mean, absolutely devastating. So just an endless spiral of death. Did anything positive come out of that subsequently? Not a single positive thing came out of that. So you had a profoundly adverse reaction. Perhaps the only positive thing I would say is it gives me enormous caution when I talk to my patients who themselves are very curious about these things. I just caution them and say, look, you simply don't know how you're going to respond to these things. The therapeutic windows on these things are quite narrow.

2:01:54Peter Attia:And they're just not well understood. It's not like, hey, if we're going to give you Prozac, we sort of know that most people respond at this dose. Some people need it to be at this dose. Some people need it to be at this dose. These are the side effects. If this happens, we're going to stop. You're onto my Russian roulette concept. Yeah, yeah. So I think with these agents, I mean, with the exception of MDMA, I think all of these so-called psychedelics, I think are – And again, I've used psilocybin in a therapeutic setting that was incredibly positive. I've also had - Well, let's - If you want to, let's talk about that.

2:02:34Peter Attia:Yeah, but I've had experiences on psilocybin that were brutal. I mean, I had one experience on psilocybin where I, you know, it's hard to know exactly how much time was passing, but certainly for hours, I had a reoccurring experience of being in a guillotine where the blade was dropping. And so what I was experiencing was the sound of the blade as it's getting closer to the back of my neck, but it would always stop just before it hit my neck. So that would provide a modicum of relief, but then the blade would go back up and it would happen again. So that was absolutely awful. Again, nothing positive came of that experience.

2:03:15Peter Attia:But I've had very positive experiences on guided MDMA and with another psilocybin experience. And I think - What made the positive experience positive? um well again i think with mdma no with the psilocybin um it was i mean it's hard to describe i think it's it's this is over 10 years this is about 10 years ago it was an out-of-body experience meaning i was only witnessing myself from outside of myself but at different places in my life but they were very vivid. These were not vague images. This was, you are back in this room at this moment in your life when you were 12 years old. And this is exactly what's happening.

2:04:09Peter Attia:But what was very powerful about this was I was not experiencing it through my lived experience, but through the other person in the room, in this case, a parent. And for me, that gave incredible empathy to what was going on with the other person during an experience in my life. Yes. So that, and the durability of that is a decade later, that will be lifelong durability. So I think because that's a fascinating description, beautifully expressed about something fundamental about people maybe in a different category who revisit a traumatic experience from a more developed perspective in their lives.

2:05:07and they're able to re-assimilate it from certainly a more advanced view and even have compassion for someone who may have... So this was an interesting experience.

2:05:20Peter Attia:This was not a traumatic experience in my life at all. And so therefore, it's very unclear to me in this particular instance why I went to that place. But instead, what it gave me was, and it might have been that I was at the exact same age as my parent. In other words, in my life, I was the same age as my parent in this vision. But now all of a sudden, I was able to appreciate their life and how much harder it was than my life. But in a way that I could never articulate now. I can't describe it now. I understand. It was the feeling of, wow, their life was so much harder than my life. And everything I have is because of them and their sacrifice.

2:06:14Peter Attia:And all of the things that have frustrated me are frustrations of someone who's never fully appreciated. It's about gratitude. Yes. And it was, so it was, I think one of the most beautiful experiences I've ever had in my life. And what's interesting is it was the first experience. And therefore, when you have such a positive first experience, what do you want to do? You want to go back to that well every few years. Yeah. Because if it was that transformative in this one regard, imagine what it could do for other relationships in my life. And unfortunately, it has never come close to reproducing that.

2:06:54Peter Attia:It has been anywhere from neutral to negative. And so I made a decision about two years ago that I was probably never going to do that again. I was sort of, and I won't describe the litany of things I've tried, but I will never, I just don't. I think that's very wise. I've extracted something incredibly valuable. Yes. I don't want to tarnish it with anything negative. Well, it's beautiful that you got what you did out of it and also that you knew when to stop. Well, I wish I could say I did. I went back to the well a couple of times and paid a very heavy price for it. But that's it. But that's also, you know, the intellectual part of me, the scientist, right, is completely interested in why.

2:07:40Peter Attia:There's nothing I can point to in set and setting and dose and delivery. Like there's nothing I can point to that was different. There's a certain randomness. No, there's – yes, exactly. And that's what makes it so terrifying. In fact, the last time I did this was the most prepared I've ever been. The amount of work I did with the therapist ahead of time. Yeah. The amount of journaling. I've never had a greater intention going into this, right? I mean, I – You expected a masterpiece to come out of it. Yes, this was Michelangelo going into the chapel. I mean, this was going to be the final elucidation of the three things, the three questions that still I deal with.

2:08:24Peter Attia:Yes. And instead, I got put into a tumbler and ripped into pieces and spit out the back. And I just, I mean, it was very, very difficult. It took me months to recover. I've always been innately scared of those medications and have avoided them. Yeah, I think it's, I think there's a part of me that still remains optimistic that as more and more research is being done, the benefits of these things will outweigh the harms. I think there's one point I should make just for listeners who are wondering who would say, wow, Peter, that's crazy that you would have those experiences. There is an issue with me that has been an issue when it comes to any medication or drug or anything that would alter consciousness.

2:09:17Peter Attia:Or frankly, any drug. I am highly resistant to every medication for which there's variability in dose. So whether we're talking about caffeine, whether we're talking about alcohol, any medication you can put into a human body, I just need two to three X what every other person needs to experience in effect. Yeah. So I could drink four drinks and I wouldn't feel a buzz. I can drink four cups of coffee and I don't feel anything. So the doses of these agents that I require to feel anything are much higher than other people. And so maybe the reason my experiences have been so different is we're at a point on the PK of that drug that is just well beyond normal behavior.

2:10:16Peter Attia:every time I have used psilocybin, it has been north of 10 grams because the standard five grams produces nothing. So in other words, I say all of that to say - Maybe you need more estrogen for the - Yeah. Well, I mean, it might just be that my horror stories have to do more with my dose, where I am on the dose response group. It's interesting. I had a discussion yesterday with a patient about estradiol. He had been under the care of a doctor before he came into our practice that was trying to give him a Remedex, which for the listener is a drug that prevents the aromatization of testosterone into estradiol.

2:10:55Peter Attia:And he had been taught, so to speak, that estrogen was bad and you want high testosterone and low estrogen. So needless to say, we had a great discussion about why that was a very bad idea. Yeah. What hope do you hold out for the utilization, the proper utilization of psychedelics in psychiatric medicine over the next 10 to 20 years? Well, part of it relates to your positive experience. It's extraordinary that a single administration of a drug can produce a durable effect that you're projecting will last a lifetime. I'm 100 % convinced it will last the rest of my life. And I'm 100 % convinced by you of the power of that experience and how transformative it is.

2:11:46So I find it remarkably exciting and promising, but I also appreciate the dangers and unpredictability. So I'm hoping that they'll find a strategy. they meaning the researchers in that field, will find either a molecule that preserves the risk-benefit ratio shifting much more favorably, or a set-in-setting strategy that modifies, or some other strategy, maybe combination pharmacotherapy, because it is a pharmacotherapy, It's the use of a psychotropic medication, maybe concurrent use of other medications that don't block the serotonin 2A receptor that it has to bind to. That's where the classic psychedelic binds to.

2:12:41So if you block that receptor with another drug, instead of needing twice as much, you may need 20 times as much. So that's not reasonable, but finding an appropriate pharmacologic strategy that augments the efficacy and mitigates the risk.

2:13:02Peter Attia:Of all of the indications that are being talked about for these drugs, the two that to me seem the most exciting are obviously MDMA and PTSD and psilocybin in end-of-life depression. or frankly just all end-of-life related therapy. What do you think, how much more evidence do you think the medical community, I mean the FDA aside, there's a whole issue with the FDA there, but from a medical scientific standpoint, where do you sit on those two indications which are quite specific? Yeah. Well, end-of-life treatment, the risk-reward shifts a little bit. if someone is struggling with existential anxiety on an absolute order, I think if there's something that could help them with that, they deserve the option of exercising that.

2:14:02Because there aren't

2:14:04Peter Attia:many things - But we don't want to make it worse. We don't want to, but it's pretty bad to begin with. So the risk-reward may shift. It depends on your medical ethical model. If the baseline would shift the risk-reward calculus about that, I'm not sure. Something worth thinking about. But then the same would apply to significant PTSD. Yeah, but I suspect that it's not MDMA that's going to be the most effective for that. Do you think it will be psilocybin? Perhaps, or certainly other drugs. I think MDMA is a so-called empathogen. It increases empathy. certain types of PTSD. PTSD, like so many things, is a very heterogeneous category.

2:15:02I think when empathy is called for related to reconciliation of relationships or traumatic experiences, it might have a very strong role. So much remains to be determined. But I do find it exciting that medications can have such a durable and powerful effect. And I find it intimidating and disturbing that it can also go in the other direction. But I'm very optimistic that something positive will be found to reconcile that discrepancy. yeah i think i would agree with all of that um but i do i do always feel the need to caution people i think it's one of those things where people hear a lot of the good stories i think

2:16:00Peter Attia:they don't hear enough of the bad stories and i think there's i agree with you i think there's they are drugs and uh every drug has a side effect absolutely and including the ones i prescribe yeah Yeah. Well, Linus, this has been a really fascinating discussion. I've learned a lot, and so I'm hoping by extension everybody listening has learned a lot as well. So thank you very much for your visit and for more importantly sharing your wisdom. Thank you so much. It's been an enormous pleasure for me. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash show notes.

2:16:42Peter Attia:If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only, and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

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