Skip to content
Peter Attia MDPeter Attia MD

404 ‒ Mental health beyond neurotransmitters: hormones in psychiatry, psychedelic therapies, & more

In this episode, Peter sits down with Dr. Linus Abrams, a psychiatrist with nearly 35 years of clinical experience specializing in mood disorders and psychopharmacology, to explore how our understanding of mental health is evolving beyond the traditional neurotransmitter model. After decades in practice, Linus began questioning many of the assumptions underlying modern psychiatry, leading him to investigate how hormones, metabolism, inflammation, circadian biology, and the endocrine system shape mood and cognition. Together, Peter and Linus examine why psychiatric care should aim not only to reduce symptoms but also to restore the full human experience. They discuss how psychiatric medications work, where they fall short, and why distinguishing bipolar disorder from unipolar depression is essential for effective treatment. The conversation also explores the growing mental health burden of social isolationn associated with digital devices and social media, along with the biological factors—nutrition, exercise, sleep, and chronic stress—that influence resilience and distress tolerance. 0:00:00 - Intro 0:00:11 - Linus's passion for understanding his patients and going beyond traditional psychiatry 0:10:24 - A short primer on the different classes of drugs used in psychiatry 0:24:12 - Evaluation of a patient with bipolar disorder 0:32:00 - An evolutionary perspective on depression 0:39:41 - Changes in the modern world triggering mental health problems 0:47:15 - An evolutionary perspective on insomnia 0:48:54 - Peter's window analogy to understand distress tolerance and irritability 0:51:46 - The impact of foundational biological factors on psychiatry: nutrition, exercise, sleep, and endocrinology 0:57:54 - The effect of estradiol on neurotransmitters in the brain 1:11:05 - Options for increasing testosterone in men, and why clomiphene is inferior to exogenous testosterone 1:14:37 - The rapid drop in progesterone is linked to both premenstrual dysphoric disorder (PMDD) and postpartum depression 1:18:18 - Treatment of postpartum depression 1:26:53 - Hypothyroidism presenting as depression: how Linus makes the diagnosis and what he uses for treatment 1:40:47 - The link between hyperarousal and chronically elevated cortisol 1:45:52 - A case where the menopause transition uncovers bipolar disorder 1:50:58 - Ketamine as a tool to treat recalcitrant depression, and concerns about its recreational use 1:57:07 - Case study: an Alzheimer's patient who improved after psilocybin, and why Linus is cautious about drawing conclusions from it 2:02:37 - Peter's experience with psychedelics, and the myth that estrogen is bad for men 2:13:36 - The therapeutic potential of psychedelics in psychiatry View show notes here: https://peterattiamd.com/linusabrams/ Become a member to receive exclusive content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ -------- About: The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, and all that goes into that from physical to cognitive to emotional health. With over 90 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, and much more. Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan and simultaneously improving their healthspan. Learn more: https://peterattiamd.com Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Podcasts: http://bit.ly/TheDriveGoogle Disclaimer: 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. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit my website where I keep an up-to-date and active list of such companies. For a full list of our registered and unregistered trademarks, trade names, and service marks, please review our Terms of Use: https://peterattiamd.com/terms-of-use/

Peter AttiahostDr. Linus Abramsguest
Aug 17, 20262h 19mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 0:11

    Intro

    1. PA

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. [upbeat music]

  2. 0:11 – 10:24

    Linus's passion for understanding his patients and going beyond traditional psychiatry

    1. PA

      Linus, thank you for coming to Austin. So wonderful to see you.

    2. LA

      Same here, Peter. Thanks for having me.

    3. PA

      You have a very interesting practice in psychiatry, or at least I should say a very, um, unique perspective on the integration of all of the traditional tools and insights of psychiatry, along with those of endocrinology. Um, is that a relatively recent fascination for you?

    4. LA

      Yes.

    5. PA

      You've been in practice for, what, 30 years?

    6. LA

      Going on 35.

    7. PA

      Okay.

    8. LA

      Yeah. Yeah. I did a pivot after 30 years. I felt like I was in a bit of a rut. Like I was, um, enj- enjoying my practice, but I felt I wasn't learning as much as I wanted to learn. And there are a number of factors that we can talk about that drove me in this direction, but, um, the, the pivot is quite recent, and I'm learning about endocrinology as we speak. It, it, it's been a recently evolving trend, but I've thought about it deeply, and I, I hope some of that comes across in the podcast today.

    9. PA

      So tell me what it was during the first 30 years of your practice that, A, that gave you satisfaction and that you loved or, a- and, sorry, B, that you were beginning to fatigue of or question or feel was insufficient to help your patients.

    10. LA

      I see myself basically as a kind of humanistic, existential-oriented psychiatrist who happens to be practicing psychopharmacology as a way to make a living and having an expertise in bipolar spectrum disorders. Um, but I found that psychopharmacology was perceived ambivalently for the most part, even in very successful cases from an objective point of view in terms of symptom reduction, that the patient felt it was undesirable even if they had a spectacular reduction in symptoms. And it led me to think about what was contributing to that. And what I finally, um, decided was the organizing principle was that psychiatry aims at reduction of symptoms, but not restoration of the full human experience that makes life most worthwhile.

    11. PA

      That's a pretty profound statement. Um, I, I don't-- I, I wouldn't say I'm pushing back on it. I'm only asking out of genuine curiosity. If you were at a dinner with nine other psychiatrists, do you-- would they share that view as well? Is that, is that a largely and commonly held view amongst your peers?

    12. LA

      Probably not. Probably not, but I don't go around asking that question.

    13. PA

      Mm. But it's kind of an important question.

    14. LA

      It is an important question. Um, but I, I would say they would agree with me that there's an unusual amount of struggle, even in cases where there's a dramatic improvement, where people come with horrible levels of suffering and a psychopharmacologic intervention results in a dramatic reduction of that suffering, that it, it's often still a struggle to encourage a patient to continue with an ongoing regimen when it's needed. And there, there are certain conditions that require chronic treatment, and I mentioned bipolar disorder. That's, you know, a certainly a-

    15. PA

      Chief among them

    16. LA

      ... yeah, a hallmark case of why that would be necessary. So I don't wanna undersell psychopharmacology. And by the way, I've had-- I feel blessed to have had such a wonderful career and experience of psychiatry. I love the field of psychiatry, and I don't mean to, um, cr- criticize psychiatry per se. This is more about adding an additional lens of perspective than detracting anything in any way from psychiatry, 'cause psychiatry is a remarkable field. Um, I w- I was lucky to have been not so dumb to make the choice to become a psychiatrist and to have, um, taken advantage of the wonderful opportunities to get to know human beings on a deeper level, which you asked me before what's been fulfilling. I would say that's been probably the most fulfilling aspect of my career is to really get to know people in depth who are remarkable human beings. And th- that's what inspired me to go into psychiatry in the first place, because u- understanding the patient is always greater than my ability or any, um, provider, to use that word, any provider's ability To understand them, because the nature of a human being is so u-unique and remarkable. So it's progressive layers of insight and progressive attempts to understand and reinterpret our misinterpretations, if you will.

    17. PA

      I mean, one of the things about psychiatry that is quite unique to medicine when you consider all of the medical subspecialties and the surgical subspecialties, is the lack of measurable biomarkers or objective findings that could be measured on imaging, for example.

    18. LA

      Sure.

    19. PA

      So when you think through per-presumably the spectrum of conditions that a psychiatrist would be, uh, treating, from anxiety to depression to hypomania, bipolar disorder, all of the different clustered... All of these things, there's nothing that's gonna show up on a CT scan or an MRI of the brain-

    20. LA

      Mm-hmm, mm-hmm

    21. PA

      ... that makes that diagnosis. There isn't a blood-based biomarker that's gonna say, "Oh, this," you know, "this person has high ferritin," or, "This person has low this or low that."

    22. LA

      Not yet.

    23. PA

      Yep. So, so yet, in other words, something you said a moment ago rings very important, which is even though you, you've used the term psychopharmacologist several times already, implying that the tool, the main tool you use is a pharmacologic tool, the human story piece of it is the diagnosis, right? I mean, presumably part of the diagnosis is ratified through a hypothesis of, "Hey, I think the... If, if my... If I'm right on the diagnosis, this medication should make things a little bit better." But you have to have a very good hypothesis based on your subjective interaction with that patient.

    24. LA

      Yes and no, um, o-on both counts. Um, first of all, I do a lot of psychotherapy too, 'cause I'm one of those rare people, not in, in a special way, but, um, in a self-directed way, who chose a residency program at Harvard that trained both psychotherapy and psychopharmacology. And I did that quite intentionally because I wanted to have a lot of cases where I was doing both-

    25. PA

      Mm

    26. LA

      ... as opposed to, um, dividing and partitioning a patient's care, because that lent to my curiosity and the psychotherapeutic aspect of it.

    27. PA

      Yeah. Do you think that that's, um... I know, I know from other friends who have done psychiatry residencies at Harvard that a- at least according to them, and, and I'm asking you for that to clarify, is, is Harvard unique in that, in that it still preserves that legacy of-

    28. LA

      Ha- Harvard is a very heterogeneous institution, and, uh, i- it really depends on which area of, uh, which particular hospital, which training program, 'cause there are a number of different training programs.

    29. PA

      Even within psychiatry?

    30. LA

      Yeah, within psychiatry.

  3. 10:24 – 24:12

    A short primer on the different classes of drugs used in psychiatry

    1. PA

      Let's maybe talk a little bit about some of the, I hate the term, but kind of the bread and butter tools of the, uh, o- of the, of the psychiatrist in the, in the, in the, in the pharmaco, um, tool bucket. So everybody listening to us right now, Linus, has heard of an SSRI.

    2. LA

      Yeah.

    3. PA

      Right? There's nobody that hasn't heard of them, and if they ev- if they haven't heard that term, they've certainly heard the drugs within that class. Um, your career is such that you've seen the, if not the birth of that class of drug, certainly the proliferation of that class of drug.

    4. LA

      Both.

    5. PA

      Yeah. Um, presumably during your training, we were dealing with MAOIs, we were dealing with-

    6. LA

      Mm-hmm

    7. PA

      ... tricyclics, we were dealing with-

    8. LA

      Yes

    9. PA

      ... drugs that actually still probably have great efficacy-

    10. LA

      Mm-hmm

    11. PA

      ... provided the indication is, is understood. Um, what is the best way to help get our listeners up to speed on these different classes of drugs without clobbering them with [chuckles] -

    12. LA

      Yeah

    13. PA

      ... uh, with, with too much of the mechanistic stuff, but I think enough that they'll understand, 'cause I think we have to understand serotonin if we're gonna talk about the endocrine system and, and how estradiol and serotonin factor into this. Like, so I wanna make sure-

    14. LA

      Yeah

    15. PA

      ... we get everybody up to a certain level of-

    16. LA

      Sure

    17. PA

      ... understanding, and I think the drugs help us do that.

    18. LA

      On a foundational level, um, psychotropics historically have worked at the level of intervening on neurotransmitter modulation, and particularly the monoamines: serotonin, dopamine, and norepinephrine. And SSRIs are drugs that selectively, for the most part, target serotonin in modulating serotonin neurotransmission through signal. They ha- have mechanisms, one particular me- mechanism, glad to mention it if you'd like me to, but one particular mechanism to kind of amplify the signal, and th- that's how it works for that drug. Now, there are also probably familiar to many of the audience, a, a newer class called SNRIs, serotonin and norepinephrine reuptake inhibitors, and that gives a certain balance because raising serotonin can decrease dopamine. So someone, let's say, with attention deficit disorder who has low dopamine as part of the problem of their attention issues, if they go on an SSRI, they could exacerbate it. And people often talk in terms of side effects about SSRIs. Now, again, I, I, I love all medications that help people, and SSRIs have helped millions of people. But, um, raising serotonin can decrease dopamine, and taking s- an SSRI alone can often make people feel a little bit blunted, um, uh, not fully vital to the extent that they're desiring.

    19. PA

      Now, that, that seems a little counterintuitive given at least at the sort of-

    20. LA

      It's a paradox.

    21. PA

      It's a paradox. So let's make sure the listener understands why. So we-- [chuckles] Well, there's so much I want to unpack on this, but, but if we buy the idea that more serotonin is better and therefore a drug that inhibits the reuptake of serotonin will leave-

    22. LA

      Some serotonin is better.

    23. PA

      Yeah, yeah, yeah. [chuckles] So-

    24. LA

      Serotonin syndrome-

    25. PA

      Yes

    26. LA

      ... is when there's-

    27. PA

      Devastating.

    28. LA

      Yeah.

    29. PA

      Yeah. But, but in the case of if the hypothesis is that this person is suffering from depression because they don't have enough serotonin around their neurotransmitters, we're gonna give this drug, we're going to inhibit the reuptake of it, we're gonna leave more serotonin around. But then you're saying, "Yeah, but you know what? That also reduces dopamine," and we should maybe talk about why that's the case.

    30. LA

      And norepinephrine.

  4. 24:12 – 32:00

    Evaluation of a patient with bipolar disorder

    1. PA

      you evaluate a patient, um, that's coming to you for a given condition, and we can even just broadly pick several conditions. We could start with bipolar because that's obviously-

    2. LA

      Yeah

    3. PA

      ... very complicated, and it's something that I know you have a lot of experience with. So it-- how often is it that a person is coming to you for the first presentation of bipolar disorder rather than someone who's coming to you because they've Had, you know, they've been recalcitrant to lots of therapy and they're sort of winding up, uh, as a-- seeing you as, as sort of a last resort hope

    4. LA

      Y- the interesting thing, Peter, if they're coming to me for bipolar, most of the time they don't know they have bipolar

    5. PA

      Okay, so you're the one that's sort of creating the framework around this

    6. LA

      Yeah. I'm the one who's, um, throwing out that hypothesis

    7. PA

      Okay. So tell me about what a person... Again, it's hard to pick an average, but pick, you know, sort of u-use your experience to come up-

    8. LA

      Well, let me put it a different way if, if that's okay

    9. PA

      Yeah

    10. LA

      I don't, uh, typically, unless I have a patient in crisis where I'm worried about their safety or, um, self-harm or harm to others, uh, someone who's in an extreme radical situation where I have to focus on safety and protection, I really don't approach a, a consultation that differently. For all patients, it's all-- it all starts with how, how can I be of help? Um, w-what are you thinking about, um, in terms of talking with me and trying to feel better? And that, that's always the starting point, and I let the patient lead me to the problem

    11. PA

      So a person with undiagnosed bipolar will typically voice what concerns? Are they more troubled by the manic symptoms? Are they more troubled by the depressive symptoms?

    12. LA

      Well, in the population I see, they're more troubled by depression. And the, um, type of bipolar we're alluding to is so-called bipolar II. Like bipolar, much more common form of it, where the manic part is not a true full-blown mania, it's so-called hypomania, and that can be very adaptive

    13. PA

      Yeah

    14. LA

      As a matter of fact, I tru- I would say maybe over the course of my career, maybe a third of my patient population have been incredibly successful people who've used their hypomanic drive to achieve remarkable things. And so it can be very adaptive. But when they get depressed, they respond differently to antidepressants than someone who has non-bipolar depression. So unipolar depression, which is non-bipolar depression, and bipolar depression have different pharmacologic response profiles

    15. PA

      Can you say more about how they differ and what the implication is?

    16. LA

      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 an, a negative response. It could trigger so-called mood cycling. They could become hypomanic in an unpleasant way, like a-agitated, have trouble sleeping, have racing thoughts, um, 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, um, potentially, um, hopeless, but also having feelings of agitation, physically feeling agitated and disconcerted

    17. PA

      And you're saying that if the, if you, if you fail to make the diagnosis of unipolar versus bipolar and you prescribe the same drug-

    18. LA

      Yeah

    19. PA

      ... and the first line might be an SSRI

    20. LA

      Well, there are ways to circumvent that. If you ask the right questions, you're less likely to r- prescribe the wrong drug

    21. PA

      And what would be the wrong drug for the bipolar that might be the right drug for the unipolar?

    22. LA

      The wrong drug would be, I would say any antidepressant instead of a mood stabilizer, like lamotrigine

    23. PA

      I see. So-

    24. LA

      Because lamotrigine-- Sorry to interrupt. Lamotrigine can be very effective about treating depression. People think of bipolar drugs as treating the elevated moods, but, um, lithium a-and lamotrigine, for example, can be very effective at treating depression with monotherapy for many patients

    25. PA

      That's Lamictal, I assume?

    26. LA

      Yeah. Yeah

    27. PA

      What's the mechanism of that drug?

    28. LA

      I think it changes sodium channels

    29. PA

      Okay. And do we know why lithium works?

    30. LA

      I don't believe so

  5. 32:00 – 39:41

    An evolutionary perspective on depression

    1. PA

      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 gonna focus on anxiety because I, I think the answer is we'd see a lot less anxiety. I don't have enough insight into bipolar to comment, but I, I wanna focus specifically on depression. How much of depression do you think is purely biological and how much of it do you think is environmental?

    2. LA

      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, um, refuge in their caves or dwellings in a protective way so that their survival was likely to be enhanced.

    3. PA

      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? 'Cause I can sort of see anxiety having an evolutionary benefit-

    4. LA

      Uh-huh

    5. PA

      ... um, for sure.

    6. LA

      Yeah.

    7. PA

      That makes a ton of sense.

    8. LA

      Yeah.

    9. PA

      I can clearly see why hypomania could have an enormous evolutionary benefit.

    10. LA

      Yeah.

    11. PA

      Um, and I'm not saying I don't agree that the others could, I just, I'm trying to think through the cases.

    12. LA

      Yeah. Well, you know, you know, it's very interesting. Um, specifically, I alluded to the theory of depression as being protective. Um, anxiety, um, can be protective, but it can also be disadvantageous. People's judgment can be impaired-

    13. PA

      Mm-hmm

    14. LA

      ... when they're anxious or when they're panicked. Let's say if someone is having a panic attack, instead of doing, um, 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.

    15. PA

      Yeah. I, I, I guess what I'm trying to understand is, um, 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.

    16. LA

      Mm-hmm.

    17. PA

      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.

    18. LA

      Exactly.

    19. PA

      And it's just, it just wasn't within the purview of it. So-

    20. LA

      Yeah

    21. PA

      ... we've, we've sort of created a luxury problem for ourselves which is we've, we've sa-

    22. LA

      Or that might have even been adaptive.

    23. PA

      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 ad- adaptive part of that is we are the ones that carry the ApoB lipoprotein 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.

    24. LA

      Mm-hmm.

    25. PA

      So I can make the case that having LDL particles allowed us to have tons of cholesterol even if we were starving and that w- allowed us to never compromise our, our growth par- 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. Um, is there, is there kind of a case that can be made that says either we are pathologizing depression and in reality, uh, again, I, I can't imagine any person likes feeling... I've, I've experienced anhedonia, I've experienced dysthymia [chuckles] , I know what those things feel like. They feel horrible. But, 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-

    26. LA

      Yeah

    27. PA

      ... so that we act- so we can appreciate it when we don't feel those things?

    28. LA

      Well, let's take anhedonia out of it because that, that's a misunderstood concept. But I would say depression is bad. It, um, it, it takes a huge toll on people. It can be lethal. Um, it can, it, it definitely increases the risk factors for a lot of medical problems. And, um, uh, 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. Um, it can serve almost a- a- as a giant shakeup of one's pr- 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 de- depression. Depression is not a good thing. We're talking about clinical depression.

    29. PA

      Yeah.

    30. LA

      We're not talking about the depression of everyday life.

  6. 39:41 – 47:15

    Changes in the modern world triggering mental health problems

    1. LA

      There's a lot of environmental anxiety that w- we, we see a lot of increased, um, challenges to the environment, fires in the summer, fires even in the winter in certain places, in the cold.

    2. PA

      But, but again, I, I, I, 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. Like, just imagine what it was like to be alive 1,000 years ago.

    3. LA

      Yeah.

    4. PA

      Like, wouldn't you rather be the least wealthy person in the United States today than the King of England 1,000 years ago?

    5. LA

      You know, uh, it's very complicated. [laughs]

    6. PA

      I'm just saying, like, as, for as lousy, and we can talk about all the things that make the world a lousy place today-

    7. LA

      Yeah

    8. PA

      ... it's still infinitely better than it was just 1,000 years ago.

    9. LA

      From a bourgeois point of view, yes. But from a relational point of view-

    10. PA

      Well, so that's, that's a, that's, 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-

    11. LA

      Yeah

    12. PA

      ... I think is, is, is, is preventing me from really getting at the question.

    13. LA

      Yeah, I think I was premature in focusing on that.

    14. PA

      Well, no, no, no, I, I, I'm just saying, like, I'm genuinely curious as to what, what do we think is the causal relationship between mental health deteriorating, um, and the world we inhabit?

    15. LA

      I think a lot of it has to do with things that are spoken about, social media, um, p- 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 i- in the absence of re- relationships. Fertility 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, well, you know, what- whatever timeframe you were alluding to.

    16. PA

      Yeah, 1,000, sorry.

    17. LA

      One- 1,000. That's a more historically [laughs] accurate one. Thank you. Th- thanks for correcting that. Um, pr- probably ev- everybody else didn't know anything different. And if there was-

    18. PA

      Yeah

    19. LA

      ... better, they just accepted that was the n- that's how it was. They weren't going to be kings. Um, they, they lived in the moment more. They accepted the realities such as they were perhaps. You know, again, this is all hypothetical Um, the, a- and so that enabled them to live more in the moment. Just like older people, people who are close to the end of life, um, wi- without being ill, um, are able to enjoy the moment more, appreciate the moment more. Um, 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.

    20. PA

      Yeah, I, I, I... That, 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. Um, and in addition to everything you've said, I, and I've brought this up before on the podcast, I, I had a, a guest on many years ago. His name is Tom Catena. He's a, a physician who's a missionary in, um, uh, the Nuba Mountains of Sudan, and so he takes care of one million people there that are without any healthcare, and these are people that are particularly being targeted by their government, so they're, they're literally being killed by their own government. And so, you know, they're being bombed, and he's taking shrapnel out of their wounds in this hospital by himself with a couple of nurses.

    21. LA

      Remarkable.

    22. PA

      Un- unbelievable. Um, and I asked him, um, 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, um, "You know, Tom, what, what's the prevalence of depression there?" And he said, like, "None." Like, there is no depression. You know, um, it... Tight-knit families, common purpose. Uh, yes, it's scary. When the, when the airplanes come over, they all have to dive into a ditch, but basically other than that, they're, they're farming, they're doing their thing, and, um, they don't know better is, is part of the-

    23. LA

      Yeah

    24. PA

      ... is part, is part of what it is.

    25. LA

      Uh, um-

    26. PA

      Now, I'm not suggesting that we should, that we want that, that that's, we, w- that needs to stop.

    27. LA

      No, I understand.

    28. PA

      But, but, but there's a-

    29. LA

      It's a good point

    30. PA

      ... there's a, there's a price we pay for modernity.

  7. 47:15 – 48:54

    An evolutionary perspective on insomnia

    1. PA

      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. Um, they didn't necessarily sleep eight hours a night. They, they, they, there's some evidence that they slept in, in sort of shorter windows, but the point is, they weren't walking around struggling to fall asleep, waking up ruminating, and, and suffering from a lot of the things that people suffer from today. Um, 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-

    2. LA

      Yeah

    3. PA

      ... the rise and fall of cortisol, the rise and fall of adenosine, the rise and fall of melatonin. The, all of those things are being countered by our environment.

    4. LA

      Agreed.

    5. PA

      And so if you wanna 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-

    6. LA

      Yeah

    7. PA

      ... autocorrect the light in your environment. You have to force yourself-

    8. LA

      They're anti-norm- normative.

    9. PA

      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.

    10. LA

      Yeah.

    11. PA

      At least when it comes to certain things like anxiety and depression.

    12. LA

      Yeah.

  8. 48:54 – 51:46

    Peter's window analogy to understand distress tolerance and irritability

    1. LA

      Uh, and it's interesting you bring up sleep. Um, I think all the foundational biological factors Uh, so i- in my model of endocrinology, cer- certainly hormones and the endocrine system are part of it, but also inflammation, metabolism, and stress circuitry, in addition to circadian biology-

    2. PA

      Mm

    3. LA

      ... and sleep architecture. All those factors are challenged by m- modernity. Um, if we want to look at metabolism, diets, and, you know, um, uh, uh, p- people weren't needing to go on GLP-1s a thousand years ago.

    4. PA

      Right.

    5. LA

      Maybe unless they were the king.

    6. PA

      [laughs] That's right. We know the king had gout, but we don't know if anybody else did.

    7. LA

      [laughs]

    8. PA

      Um, you know, you raise a great point, and, um, I've, I've discussed this also on the podcast in the past, this, uh, this mental model of distress tolerance. So I, I sort of... And I wrote about this actually in my book, which was, um, I-- this is the model that I use. It's how I think about my life.

    9. LA

      Yeah.

    10. PA

      So when I'm irritable-

    11. LA

      Yeah

    12. PA

      ... which, let's be honest, I can be quite irritable, I'm imagining-

    13. LA

      Me too

    14. PA

      ... I'm imagining kind of, um, a, a, a window in which I occupy, and it-- the window is my distress tolerance window. When that window is wide open-

    15. LA

      Yeah

    16. PA

      ... I can tolerate a lot.

    17. LA

      Yeah.

    18. PA

      I can take a lot of-

    19. LA

      Yeah

    20. PA

      ... bullets, and I'm fine.

    21. LA

      Yeah.

    22. PA

      When that window is narrow, even the littlest thing-

    23. LA

      Yeah

    24. PA

      ... will sort of-

    25. LA

      Right

    26. PA

      ... irk me. If my kid does this, or if my wife says this-

    27. LA

      Sure

    28. PA

      ... or an employee says this, I'll be irritable. Okay. So then I ask the question: What determines the width of my window? And, and what's amazing but obvious is what you just said. Your biology plays such a role in that window.

    29. LA

      Yeah.

    30. PA

      If I exercised or didn't exercise-

  9. 51:46 – 57:54

    The impact of foundational biological factors on psychiatry: nutrition, exercise, sleep, and endocrinology

    1. LA

      over time. Do, um, adaptive-

    2. PA

      But how much of that is part, how much of that is part of psychiatry? Like you, obviously, you as a psychiatrist are attuned to that, but do you, 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, 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?"

    3. LA

      Yeah. Well, I think a lot of psychiatrists are. Um, and there are specialists, like, for example, um, in nutrition and psychiatry, um, sleep and psychiatry. Um, there's a lot of research being done on the pathophysiology of m- metabolism and its role in psychiatric illness. And I think most psychiatrists try hard to touch upon those things, so I'd be careful, um, t- to say anybody wasn't doing it adequately to generalize. But I think we have to have a framework about how to think about it, that the brain doesn't o- operate in isolation, and it, it's part of this larger system with bidirectional feedback.

    4. PA

      Mm-hmm.

    5. LA

      And so wh- when, when you have a toothache, that's, um, obviously tapping into your stress circuitry. That's affecting your cortisol levels. That, that's affecting, potentially, if it's going on, that's, uh, 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, um, th- there are these continuous bidirectional interactions between what, what happens on a neurotransmitter level and what happens with the foundational biological factors. I just chose endocrinology as the one I wanted to focus on because it fascinated me particularly.

    6. PA

      Well, that's, that's, that's great 'cause that's exactly where I kinda wanted to go. So let's go back in time five years ago when this interest of you, uh, of yours started.

    7. LA

      Yeah.

    8. PA

      Why did you pick endocrinology, and how did you dip your toe in that water?

    9. LA

      Yeah. Well, I was always interested in endocrinology, and I have some friends, colleagues who are endocrinologists. But I, 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?" And I concluded that endocrinology, from my perspective, tends to be, or at least by me, previous to that, was significantly underappreciated in psychiatry, and that There are a number of reasons for that, but that, 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, um, neural circuits and neurotransmitters are really inseparable from the endocrine system.

    10. PA

      So I wanna go back to something you said. You talked about the WHI. Um, your career has spanned pre and post-WHI.

    11. LA

      Yeah.

    12. PA

      So, so-

    13. LA

      I started-

    14. PA

      Twenty-five years ago-

    15. LA

      Yeah

    16. PA

      ... you got to witness the complete reduction in the prescription of estrogen, um, for women, uh, during menopause.

    17. LA

      Correct.

    18. PA

      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?

    19. LA

      Variable. And, uh, 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.

    20. PA

      But you brought it up as, "Hey, five years ago," which means you're 20 years post-WHI.

    21. LA

      Yeah.

    22. PA

      It was still kind of-- Clearly, there was still something there that made you think about it.

    23. LA

      Yeah, it made an impact on me.

    24. PA

      Yeah.

    25. LA

      I had the impression that it-- People, you know, again, getting back to adaptive capacity, that, um, w-women whose adaptive capacities were higher, their ability to self-regulate and adjust to internal and ex-external threats and changes, was being eroded off of estradiol. And similarly, it-- for both sexes, that m-um, uh, men who needed testosterone weren't getting it, were being told it wasn't safe, um, similarly had an erosion of their function across multiple domains.

    26. PA

      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, uh, levothyroxine-

    27. LA

      Oh, yeah. They're all-

    28. PA

      Like all of these things. Yeah

    29. LA

      Yeah.

    30. PA

      Like, let's start with estradiol. I mean, I,

  10. 57:54 – 1:11:05

    The effect of estradiol on neurotransmitters in the brain

    1. PA

      I, 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. Um-

    2. LA

      Mm-hmm

    3. PA

      ... so, um, maybe walk us through kind of some of the reasons why that's the case and-

    4. LA

      Sure

    5. PA

      ... 'cause it, it probably isn't intuitive to everybody.

    6. LA

      D-definitely not. It wasn't to me. Um, so in preparing for the podcast, I c-came up with a mouthful, but, um, estradiol is a constitutive pleiotropic multi-system regulator of neurotransmitters and neural circuits. So constitutive, what does that mean? It means, um, part of the architecture, um, evolved-- Hormones were evolved by the brain for the brain, so there's no separation of the endocrine system and the brain at that level. Pleiotropic, it has multiple actions, um, at multiple levels th-throughout neurotransmission. So for example, estradiol mo-modulates not only serotonergic transmission profoundly, but also the, the dopamine system, the GABA system, acetylcholine, NMDA, and glutamate. Um, so it, it's really br-profound. Um, and it's-- It, it serves a regulatory function. While psychotropics are signal amplifiers, um, estradiol, for example, is a system modulator. It, um, creates the conditions within which neurotransmission occurs.

    7. PA

      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. We-- It's, it's actually hard to disentangle them because, quite frankly, it's the pituitary gland that does so much of the regulation-

    8. LA

      Yeah

    9. PA

      ... uh, in, in the periphery through luteinizing hormone and-

    10. LA

      Yeah

    11. PA

      ... follicle-stimulating hormone. How is that happening in the brain?

    12. LA

      Well, it's the HPG axis, the hy-hypothalamic-pituitary-gonadal axis, and all the bidirectional feedback that occurs wi-wi-within that, um, framework.

    13. PA

      In other words, is there actual estradiol in a synapse, or is it removed from that given its size and it's regulating it-- It's, it's, it's regulating upstream of the, of the actual synaptic, uh, c-contents between, you know, where the actual neurotransmitters live.

    14. LA

      Um, w- No. Um, it, it, there are receptors for it on the membranes of neurons. So they're, they're well-characterized. There's, um, me-membrane estrogen receptor alpha and membrane es-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.

    15. PA

      Hmm.

    16. LA

      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. The same thing for dopamine through tyrosine hydroxylase. Um, the same thing f- for acetylcholine through choline acetyltransferase. So it's right there. It's, you know, 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, uh, uh, um, w- with, with, embedded w- within the brain. I, I, I had another term for it that I, that I was searching for. Um, you know, uh, imbued with and embedded within the, the brain is how I think about it.

    17. PA

      Let's now talk about the removal of that. So everything you said kind of explains the biology of what estrogen is doing.

    18. LA

      Yeah.

    19. PA

      But now let's characterize the phenotype. So if estrogen is reduced, all other things being equal, how does that-- how does the brain experience that?

    20. LA

      Well, let's think of evolution. Um, e- 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 a- acquiring resources. So therefore, this pleiotropic role has been evolutionarily very adaptive, that one hormone has these multi-system effects. And that's why you see women with low estrogen having multiple domain challenges, from cognition to mood regulation to anxiety to, um, uh, you know, uh, a, a number of other challenges.

    21. PA

      And why do you think it is so variable, Linus? There are-- I, I, 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.

    22. LA

      Yeah.

    23. PA

      And there are other women who barely notice it. Is it receptor density? Is there some other sensitivity-

    24. LA

      It, it's a combination of genetics for receptor morphology, um, and function. Rather than absolute levels being determinative of psychopathology or emotional variability in response to change in estradiol levels, it's more the a- actual change and fluctuations and oscillations of those levels themselves. That'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, there, there are some women, due to a, a variety of reasons, it's all biological. It has to do with receptor morphology, ge- genetic influences, possible environment influences that have degraded their receptor modulation and responsivity. Um, some, some women are, are susceptible to a much greater degree. You know, you use the example of, you know, uh, I, I have a toothache and, uh, I haven't exercised and I'm feeling, uh, you know, ir- irritable as hell. Well, the, the same thing applies to all of us. We 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.

    25. PA

      Yep.

    26. LA

      Going back to menopause. She's likely to have the bandwidth to withstand it than a woman who's incredibly burdened, uh, at work w- w- 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, um, metabolically challenged, overweight, not exercising. Um, so a- all these factors play a role, as well as medical illness as a generalization.

    27. PA

      And then of course, it's, it's complicated because a lot of times the loss of hormone makes it difficult to regulate metabolic health, makes it difficult to have the motivation-

    28. LA

      It's a vicious cycle.

    29. PA

      It's a v- it's a very vicious cycle, and it amplifies the problem.

    30. LA

      Absolutely.

  11. 1:11:05 – 1:14:37

    Options for increasing testosterone in men, and why clomiphene is inferior to exogenous testosterone

    1. PA

      Um, as you no doubt know, there are various ways to increase testosterone in men. Um, the most obvious and direct way is to give a man exogenous testosterone.

    2. LA

      Mm-hmm.

    3. PA

      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-

    4. LA

      Yeah

    5. PA

      ... endogenous testosterone. And the two most common ways to do that are giving HCG-

    6. LA

      Mm-hmm

    7. PA

      ... which is giving effectively luteinizing hormone-

    8. LA

      Yeah

    9. PA

      ... telling the body to make testosterone, and then the other would be using, uh, drugs like Clomid-

    10. LA

      Yeah

    11. PA

      ... or-

    12. LA

      Clomiphene.

    13. PA

      Yeah, clomiphene or enclomiphene-

    14. LA

      Yeah

    15. PA

      ... 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-"

    16. LA

      Let's r-

    17. PA

      "We gotta make more of this."

    18. LA

      Yeah.

    19. PA

      "We're gonna make more LH and FSH." Is there any reason to believe that that approach robs the brain of the es- the very estrogen and testosterone that you're trying to give it?

    20. LA

      I would say just empirically, men who t- take clomiphene ten- tend to be dissatisfied as to-

    21. PA

      Even though their numbers are high-

    22. LA

      Yes

    23. PA

      ... in the periphery?

    24. LA

      Yes.

    25. PA

      Yeah, that's been our experience as well.

    26. LA

      There's a symptom-laboratory mismatch.

    27. PA

      Yep. Yes. That, that-- And I, and I, I have, I have no data to suggest why, but this has always been the question I've thought is-

    28. LA

      Yeah. Which is unfortunate because-

    29. PA

      It's an otherwise very convenient way to replace testosterone.

    30. LA

      Absolutely. Yeah.

  12. 1:14:37 – 1:18:18

    The rapid drop in progesterone is linked to both premenstrual dysphoric disorder (PMDD) and postpartum depression

    1. PA

      Let's, um, let's talk a little bit about progesterone.

    2. LA

      Sure.

    3. PA

      Um, you've already alluded to it in one very important capacity, which is, um, in the case of a woman who is experiencing a somewhat regular menstrual cycle, you already mentioned that, um, in the second half of the luteal phase, and I guess it's worth... It's always, it's als- sometimes easier if people can picture how the hormones cycle during, during, uh, a woman's cycle. But progesterone's the easiest one, I think, to draw, because for the first 14 days during the... Yeah-

    4. LA

      Yeah

    5. PA

      ... during the follicular phase, from the moment she has her period until she ovulates-

    6. LA

      Yeah

    7. PA

      ... there's nothing.

    8. LA

      It's flat lined.

    9. PA

      And then it rises as it prepares for implantation.

    10. LA

      Yeah

    11. PA

      It hits a peak-

    12. LA

      Yeah

    13. PA

      ... assuming there is no implantation.

    14. LA

      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.

    15. PA

      Right. In preparation for the follicle to be implanted.

    16. LA

      Yeah

    17. PA

      But once it's not implanted, the lining sheds, which is what the period is, but the point that you're making is, but it's that progesterone that is crashing down.

    18. LA

      Yeah.

    19. PA

      And what I find very interesting is that it's, it's -- the woman didn't feel bad when her progesterone level was low, right? 'Cause she, she felt fine during the follicular phase.

    20. LA

      Right. No oscillation.

    21. PA

      Exactly. It's the fall-

    22. LA

      Yes

    23. PA

      ... back to low from-

    24. LA

      Yeah

    25. PA

      ... high that causes the symptoms.

    26. LA

      Exactly.

    27. PA

      This is, this is incredibly fascinating.

    28. LA

      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.

    29. PA

      Yeah.

    30. LA

      Um, progesterone goes from several hundred to less than one within 24 to 48 hours. It's amazing that women do as well as they do. I'm in awe of-

  13. 1:18:18 – 1:26:53

    Treatment of postpartum depression

    1. PA

      depression. Um-

    2. LA

      Yeah

    3. PA

      ... do you see any women for that in your practice?

    4. LA

      Yes, becau- only because postpartum depression is a very heterogeneous condition. The, 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 w- with estradiol levels and progesterone at their peaks.

    5. PA

      Yep.

    6. LA

      These women are, you know, w- women in general at the end of pregnancy are primed to be in wonderful moods.

    7. PA

      Yep.

    8. LA

      And they go from there to having, um, th- the ones who are afflicted by severe, um, [lips smack] cases of postpartum depression and psychosis start to become suspicious of Um, the hospital personnel become hypervigilant about where the baby is and have i- very intense separation anxiety, can have intrusive ideation about their, uh, harming their own children themselves without wanting to, but having some fear. It, it's an OCD-like phenomenon that they can have a fear that they can do something that they would never do.

    9. PA

      And we don't know why this happens to some women, and fortunately, few women-

    10. LA

      It's being researched.

    11. PA

      Um-

    12. LA

      Hopkins has a big program in that.

    13. PA

      What... Do you know the prevalence of that severe a level of postpartum depression?

    14. LA

      Um, fortunately, it, it, it less than 1%.

    15. PA

      Okay.

    16. LA

      Much less.

    17. PA

      So those aren't the women you see because presumably those are the women that are under care of a psychiatrist within the hospital.

    18. LA

      Yeah, exactly.

    19. PA

      You're seeing women who go home, everything seems fine-

    20. LA

      Yeah

    21. PA

      ... and presumably over the next few weeks or even months-

    22. LA

      Yeah

    23. PA

      ... they just don't get back to themselves?

    24. LA

      Yeah.

    25. PA

      Okay.

    26. LA

      Yeah.

    27. PA

      So when a woman like that comes to you, and let's assume she's never seen any psychiatrist before-

    28. LA

      Yeah

    29. PA

      ... how do you do the evaluation and how do you think about treating her?

    30. LA

      Um, I do the evaluation the same way.

  14. 1:26:53 – 1:40:47

    Hypothyroidism presenting as depression: how Linus makes the diagnosis and what he uses for treatment

    1. PA

      pivot to another endocrine system on that same HPA axis, or HP axis, not the A part, the, uh, the thyroid system, right?

    2. LA

      Oh, yeah. Yeah.

    3. PA

      So, so let's... Everybody's heard of TSH, and everybody kind of understands more or less the thyroid. We, we did a great podcast on it recently.

    4. LA

      Yeah.

    5. PA

      Um, I think it's kind of intuitive to people that-- Well, maybe it's not, actually. May- maybe it's not. So let's just take it away with how does the, how did T, how does T3 and T4 and TSH interact with, with the, uh, with, with the system, with the psychiatric system overall?

    6. LA

      Just to give an overview of it, um, TSH is what the pituitary thinks of the thyroid axis. And what, um, what I find is that a lot of people with, quote-unquote, "normal values" of TSH, which is often what the average internist measures in the average psychiatrist, um, people with normal range TSH, let's say in the top 50% of that range. So if the normal range is .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 th- thyroid to produce thyroid hormone. And thyroid hormone, there are two types: C4, which, um, 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. Uh, so there are two different types of deiodi- iodinases, the 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.

    7. PA

      So do you rely more on the TSH level or the free T4 level?

    8. LA

      Yeah. Uh, free T4 and free T3. Yeah, but primarily free T4.

    9. PA

      And if the TSH level is, um, in the middle or low end of the range, but the free T4 is low, how do you act?

    10. LA

      Yeah.

    11. PA

      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?

    12. LA

      I'm not concerned about the TSH. I'm concerned about the free T4.

    13. PA

      So that's the biomarker that's more of interest.

    14. LA

      For me, yes.

    15. PA

      And then tell me, in your experience, where-- When this is being missed, right?

    16. LA

      Yeah.

    17. PA

      So if this is being ignored-

    18. LA

      Yeah

    19. PA

      ... where is it most showing up? Is it being, 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?

    20. LA

      Yeah. Hypothyroidism, low thyroid, is showing up a- as depression. Hyperthyroidism is showing up more typically and rarely.

    21. PA

      Yeah, rarely.

    22. LA

      I, 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-

    23. PA

      Yeah

    24. LA

      ... where someone y- I know you're familiar with that, but for the audience, how, how would you describe it?

    25. PA

      Uh, 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, and on their first evaluation, their TSH was zero. Um, like literally zero.

    26. LA

      Yeah.

    27. PA

      Um, their free T4 was quite elevated, although not so elevated that you would think anything was going on. But They, when-- On questioning, they were, they had lots, you know, they had palpitations of their heart. Their resting heart rate was quite high. Uh, they were sweating quite a bit. And so that was a patient that we very quickly got into an endocrinologist-

    28. LA

      Hmm

    29. PA

      ... uh, for the appropriate medical management of that-

    30. LA

      Yeah

  15. 1:40:47 – 1:45:52

    The link between hyperarousal and chronically elevated cortisol

    1. LA

      neural circuits.

    2. PA

      So of all the hormone-- So when I, when I talk to patients about hormones, I usually say I think of them as four axes.

    3. LA

      Yeah. Yeah.

    4. PA

      Okay. So I think of the, the, the, the thyroid axis, the androgen axis-

    5. LA

      Mm-hmm

    6. PA

      ... um, the, uh, adrenal cortical axis, and the fuel partitioning axis, so your insulin, glucagon, et cetera. Um, I think the one that is most challenging is the third one in that list I gave, which is the, the cortisol pathway. Because-

    7. LA

      Yeah

    8. PA

      ... um, most people are experiencing too much and not too little, and we don't have a pill that is an antidote.

    9. LA

      You can't treat it directly.

    10. PA

      Right. So you have all-- Every one of those other systems we can treat directly. We have so many amazing ways to treat-

    11. LA

      Yeah

    12. PA

      ... 'cause, you know, it's-- they're usually problems-

    13. LA

      Yeah

    14. PA

      ... of too little and we know how to fix it.

    15. LA

      Yeah.

    16. PA

      Um, over here it's usually too much-

    17. LA

      Yeah

    18. PA

      ... and we now know how to fix it.

    19. LA

      But it, it's really a signal.

    20. PA

      Yeah.

    21. LA

      It's a signal that that person is under enormous stress. Because the ada- evolutionarily, the cortisol system, the HPA axis evolved for survival, for threat detection, hypervigilance, d- um, diverting resources to the moment away from the immune system-

    22. PA

      Yeah

    23. LA

      ... even. Um, fragmented sleep architecture to maintain safety. All those things are adaptive in an acute context, but when they become chronic, it becomes very maladaptive.

    24. PA

      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-

    25. LA

      Mm-hmm

    26. PA

      ... psychiatric or mental health c- condition we have. It's hyperarousal-

    27. LA

      Yeah

    28. PA

      ... that should be reserved for a chronic state, but is instead-

    29. LA

      For an acute state

    30. PA

      ... for an acute state, sorry, that is instead in a, in a chronic state.

  16. 1:45:52 – 1:50:58

    A case where the menopause transition uncovers bipolar disorder

    1. PA

      So let's think about a couple of ways to illustrate this for folks and tie it all together, right? Which is, um, thinking about the, the psychic pharmacology of the modern tools that you have-

    2. LA

      Yeah

    3. PA

      ... plus some of these endocrine adaptive tools.

    4. LA

      Yeah.

    5. PA

      And m- m- is there a case or two that come to your mind where... I mean, we've already discussed one, right? Which is-- and it was potentially a, a few patients merged into one.

    6. LA

      Yeah.

    7. PA

      But this, this case of recalcitrant depression that responded to what I-- in my world would have been a very high dose of T3, and yet that was the, that was the-

    8. LA

      Yeah

    9. PA

      ... unlock. Do you have a- a- any other cases like that that come to your mind?

    10. LA

      Well, let's say a woman who comes to me perimenopausal age, who said, "Doctor, I need hormones." And 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 ask 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, I started several companies. Um, I traveled, I spent a lot of money. I, I had a lot of ideas. Sometimes thoughts would race through my mind faster than I could write them down." And, you know, I, I would ask m- more questions. And, um, in this particular example, menopause was really happening. I investigated the hormones and the gonadotropins, and it lines up as well as the symptom- symptomatology. But the, um, 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.

    11. PA

      Now, in the case of that woman, did she talk about any of the depressive, um-

    12. LA

      Yes.

    13. PA

      Okay.

    14. LA

      Yes. She had gone to a previous psychiatrist for a, um, I would call it a bipolar depression, um, an episode of depression that happened in her 30s after she had a extended hypomanic period of incredible pr- productivity. She crashed and could barely get out of bed and went to the psychiatrist. He prescribes an antidepressant. This goes back to what we were talking to earlier.

    15. PA

      Yeah.

    16. LA

      What happened? "Well, first it was miraculous," she says. "Then a couple of 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."

    17. PA

      She stopped the medication, and what happened?

    18. LA

      Back to baseline The, the same rollercoaster

    19. PA

      Based on hyp- hypomania. Oh, yeah

    20. LA

      The rollercoaster, yeah

    21. PA

      By the way, what... Do we know how much of what's happening in her brain is... Like, do we know biologically, receptor-wise, what's happening in her brain that is causing the hypomania?

    22. LA

      No

    23. PA

      Isn't that amazing?

    24. LA

      Yeah

    25. PA

      I mean, I can't imagine for you how amazing that is. Like, for me, it's amazing, and I don't treat these patients, and yet-

    26. LA

      Yeah

    27. PA

      ... you're looking at this person and you're watching their experience.

    28. LA

      Yeah. Well, it's clearly some limbic dysregulation

    29. PA

      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 [chuckles] that there's a beta cell that makes insulin?

    30. LA

      No

  17. 1:50:58 – 1:57:07

    Ketamine as a tool to treat recalcitrant depression, and concerns about its recreational use

    1. PA

      So I wanna ask you... Well, do you have another case you wanna talk about? 'Cause I have another question that goes back to kind of depression

    2. LA

      Oh, tell me your question

    3. PA

      Okay. So you talked about recalcitrant depression

    4. LA

      Yeah

    5. PA

      But one drug we haven't talked about that's getting a lot of interest these days is ketamine

    6. LA

      Yes

    7. PA

      So can you tell me your experience with seeing patients go through, um, ketamine therapy for, um, difficult to treat depression or-

    8. LA

      Yeah

    9. PA

      ... just, just, yeah, give me your, your thoughts-

    10. LA

      Sure

    11. PA

      ... on the subject

    12. LA

      Do you want me to tell you how it works?

    13. PA

      That would be great

    14. LA

      Sure. So ketamine is an so-called NMDA receptor antagonist. So when-

    15. PA

      And we should just make sure people listening, that is not the same as MDMA. This is-

    16. LA

      [laughs]

    17. PA

      ... totally, totally unrelated, but I know people hear it and they think, "Oh, is that the same?" Is that, does it have any relationship to MDMA? But it does not

    18. LA

      No. None, none whatsoever. So, um, it antagonizes, it blocks those receptors which are actually normally inhibiting GABA inter- 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, um, uh, uh, um, mTOR pathway, um, and protein synthesis and synaptic re- remodeling. So sudden dramatic epic neuroplasticity. So it happens remarkably fast, and it stops remarkably fast. So 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 in- in- infusion, and the suicidal risk dissipates, you know, dramatically, dramatically better. The depression doesn't necessarily. So, um, basically, in, 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. But more often from 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

    19. PA

      Do patients become, um, resistant to the effect over time? Is there a tachyphylaxis that develops?

    20. LA

      Yeah. Um, I'm not th- that expert in ketamine, honestly, so I'm not sure. I haven't seen that

    21. PA

      And for the patients-

    22. LA

      Because practically, it's very time-consuming, e- expensive, and inconvenient

    23. PA

      The patients that you would send for this treatment, how is it administered? Is it administered intravenously?

    24. LA

      Intravenously. Yeah. With, with monitoring

    25. PA

      Yep. And what... In the, 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?

    26. LA

      That depends on the infusion center and, and the practitioner. I mean, so- some people might be willing to give it three or more times a week

    27. PA

      Oh, I was asking it more through the lens of how long the relief can last

    28. LA

      Oh, oh. Um, heterogeneous. For, for some people-

    29. PA

      But clearly it can be only days, if that's what you're saying

    30. LA

      Yeah, yeah, yeah

  18. 1:57:07 – 2:02:37

    Case study: an Alzheimer's patient who improved after psilocybin, and why Linus is cautious about drawing conclusions from it

    1. PA

      you sort of opened the door to, 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-

    2. LA

      Yeah

    3. PA

      ... which is a full, you know, therapeutic dose of psilocybin-

    4. LA

      Yeah

    5. PA

      ... that had some memory recovery?

    6. LA

      Well, it was more than that. It was that Japanese woman who... And this is the ultimate N of one study-

    7. PA

      Yes

    8. LA

      ... by the way.

    9. PA

      Yeah, yeah, yeah. But so interesting.

    10. LA

      Yes. So she got the five grams of s- psilocybin, but she supposedly had, uh, a diagnosis of severe Alzheimer's for a decade-

    11. PA

      Yeah

    12. LA

      ... which strikes me as unusual, to say the least. And she had no urinary function. She was completely incontinent. She spoke at most monosyllabically. She couldn't talk, um, beyond that. She couldn't have interactions. And then she took this dose of psilocybin and behaved dramatically differently and became somewhat normal, um, after it. And it-

    13. PA

      And how long did it last? I don't recall.

    14. LA

      Well, it, it, it was a very confusing case report because it... All it says is something to the effect of it lasted until the second administration of three grams of psilocybin, and it, it doesn't say anything more than that. And there was no-- there were no, um, uh, studies. There, there, there were no metrics. There was no neuroimaging. There was no anything with the study. So it's the ultimate N of one. I, I, I have an alternative hypothesis as to what the etiology was-

    15. PA

      Mm

    16. LA

      ... of the problem. Some, some people with post-traumatic stress disorder, particularly if they have mild cognitive impairment or mild Alzheimer's, can regress.

    17. PA

      Hmm.

    18. LA

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

    19. PA

      I don't think I have enough experience to say, but, um, yeah. A- a- again, it's a bit of a subjective title, right?

    20. LA

      Yeah.

    21. PA

      Yeah.

    22. LA

      Yeah. Um-

    23. PA

      But yes, usually if, if it's so severe that a, that a... Well, again, part of it comes down to basically airway protection. You know, I don't-- It's, it's unclear-

    24. LA

      Yeah

    25. PA

      ... how, how capable she was.

    26. LA

      So, um, this N of one 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, if, um, if PTSD was the etiology and she would re- re- regress, and this interfered and turned around the regression, that's wonderful. What- whatever it is, if it helped-

    27. PA

      Yeah. That's, that's, that's very interesting

    28. LA

      ... this patient is, is a wonderful initial response. I'd be very cautious about generalizing that to, uh, neurodegenerative disease. You know, the Robin Carhart-Harris REBUS model, Relaxed Belief Under Psychedelics, is about neuroplasticity for adjusting maladaptive priors, um, people who have, um, b- beliefs that are, um, problematic for them in 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, um, 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, and NMD and glutamate. And so the hormones that change the conditions with, within which neurotransmitters operate are very plastic under the right circumstances. Optimal estradiol levels, for example. And giving, administering a psychedelic medication can also alter neuroplasticity, is intended really, um, 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,

  19. 2:02:37 – 2:13:36

    Peter's experience with psychedelics, and the myth that estrogen is bad for men

    1. LA

      what, what's your experience been of psychedelics?

    2. PA

      I have tried, um, in as clinical a setting as, as, as I think possible, several of these, um, psychedelic agents. Um, so I have, I have tried, um, ketamine under therapeutic conditions once. It was, um, it was... I didn't find it to be a positive experience, and I will never repeat it.

    3. LA

      Do you want to elaborate about the negative aspects of it?

    4. PA

      Um, I, you know, I described it to a friend after as Guantanamo Bay for my soul and my psyche. I mean, ab- absolutely devastating. So just a endless-

    5. LA

      Wow

    6. PA

      ... spiral of death. Um-

    7. LA

      Did anything positive come out of that subsequently?

    8. PA

      Not, not a, not a single positive thing came out of that experience.

    9. LA

      So you had a profoundly adverse reaction.

    10. PA

      Uh, other, I mean, per- perhaps the only positive thing I would say is it, it gives me enormous, um, caution when I, when I talk to my patients who themselves are, are very curious about these things. I, I just caution them and, and, and say, "Look, you, you know, you, you simply don't know how you're going to respond to these things." The therapeutic windows on these things are quite narrow. It's... And, and they- they're just not well understood.

    11. LA

      Yeah.

    12. PA

      It's not like, "Hey, if we're going to give you, you know, we're gonna 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."

    13. LA

      Yeah.

    14. PA

      "These are the side effects."

    15. LA

      Yeah.

    16. PA

      "If this happens, we're gonna stop."

    17. LA

      You're onto my Russian roulette concept.

    18. PA

      Yeah, yeah. So, so I think with these, with these agents, I mean, with the exception of MDMA, I think all of these-

    19. LA

      Yeah

    20. PA

      ... um, these so-called psychedelics, I think are... Uh, and again, there are, you know, I've, I've used psilocybin in a therapeutic setting that was incredibly positive.

    21. LA

      Mm-hmm.

    22. PA

      I've also had-

    23. LA

      Well, let's, let, let's-

    24. PA

      Yeah, I've had-

    25. LA

      If you want to, let's talk about that

    26. PA

      ... yeah, I've, 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, was, was passing, but, but certainly for hours. It, it, um, I had a reoccurring, um, 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.

    27. LA

      Wow.

    28. PA

      So that was absolutely awful.

    29. LA

      Wow.

    30. PA

      Again, nothing positive came of that experience. Um, uh, but I've had a, I've had very positive experiences on, um, uh, guided MDMA and, and with, uh, with, with, with another psilocybin experience.

  20. 2:13:36 – 2:19:20

    The therapeutic potential of psychedelics in psychiatry

    1. PA

      Um, what hope do you hold out for the utilization, the proper utilization of psychedelics in psychiatric medicine over the next 10 to 20 years?

    2. LA

      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

    3. PA

      I'm 100% convinced-

    4. LA

      Yeah

    5. PA

      ... it will last the rest of my life

    6. LA

      And I belie-

    7. PA

      Yeah

    8. LA

      ... I'm 100% convinced by you of the power of that experience and how transformative it is. So 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, the researchers in that field, will find either a molecule that preserves the risk-benefit ratio shifting much more favorably, or a set and setting strategy that modifies, or some other strategy, m- maybe combination, um, pharmacotherapy, 'cause it is a pharmacotherapy. It's the use of a psychotropic-

    9. PA

      Yeah

    10. LA

      ... 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 bi- binds to. So if you block that receptor with another drug, instead of you needing twice as much, you may need 20 times as much. So that's not reasonable. Um, but f- finding an appropriate pharmacologic strategy that augments and augments the efficacy and mitigates the risk.

    11. PA

      Of all of the indications that are being talked about for these drugs-

    12. LA

      Yeah

    13. PA

      ... the two that to me seem the most exciting-

    14. LA

      Yeah

    15. PA

      ... are obviously MDMA and PTSD-

    16. LA

      Mm-hmm

    17. PA

      ... um, and psilocybin in end-of-life depression or frankly, just a- all-

    18. LA

      All

    19. PA

      ... end-of-life related therapy.

    20. LA

      Yeah.

    21. PA

      Um, w- what do you think... Do you... How much more evidence do you think the, the, the, the medical community, I mean, the FDA aside, the, the, there's a whole-

    22. LA

      Yeah

    23. PA

      ... issue with the FDA there.

    24. LA

      Yeah.

    25. PA

      But, but from a, from a medical scientific standpoint, where do you sit on those two indications, which are quite specific?

    26. LA

      Yeah. 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-

    27. PA

      Yeah

    28. LA

      ... exercising that 'cause th- there aren't many things-

    29. PA

      But we don't wanna h- we don't wanna make it worse, so it's, yeah

    30. LA

      We, we don't want to, but it's pretty bad to begin with.

Episode duration: 2:19:20

Install uListen for AI-powered chat & search across the full episode — Get Full Transcript

Transcript of episode fs89fhQCfj4

Get more out of YouTube videos.

Read along on your phone, search it beside the video, or ask your favorite AI app what was said.

iOSAndroidClaudeChromeChatGPTComing soon