#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.

View the Show Notes Page for This Episode https://peterattiamd.com/linusabrams/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260817-pod-linusabrams&utm_content=260817-pod-linusabrams-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&%20linusabrams%20=referral&utm_campaign=260817-pod-linusabrams&utm_content=260817-pod-linusabrams-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260817-pod-linusabrams&utm_content=260817-pod-linusabrams-podfeed 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. Linus explains the powerful roles of estrogen, progesterone, testosterone, and thyroid hormone in regulating mood and cognition across the lifespan. Finally, Peter and Linus review the promise and limitations of ketamine and psychedelic therapies, and why the future of psychiatry may lie in integrating neuroscience, endocrinology, and whole-body physiology to better understand, diagnose, and treat mental illness. We discuss: Linus's passion for understanding his patients and going beyond traditional psychiatry [2:45]; A short primer on the different classes of drugs used in psychiatry [12:45]; Evaluation of a patient with bipolar disorder [26:00]; An evolutionary perspective on depression [33:30]; Changes in the modern world triggering mental health problems [41:00]; An evolutionary perspective on insomnia [48:15]; Peter's window analogy to understand distress tolerance and irritability [49:45]; The impact of foundational biological factors on psychiatry: nutrition, exercise, sleep, and endocrinology [52:30]; The effect of estradiol on neurotransmitters in the brain [58:15]; Options for increasing testosterone in men, and why clomiphene is inferior to exogenous testosterone [1:11:00]; The rapid drop in progesterone is linked to both premenstrual dysphoric disorder (PMDD) and postpartum depression [1:14:30]; Treatment of postpartum depression [1:18:00]; Hypothyroidism presenting as depression: how Linus makes the diagnosis and what he uses for treatment [1:26:00]; The link between hyperarousal and chronically elevated cortisol [1:39:30]; A case where the menopause transition uncovers bipolar disorder [1:44:15]; Ketamine as a tool to treat recalcitrant depression, and concerns about its recreational use [1:49:15]; Case study: an Alzheimer's patient who improved after psilocybin, and why Linus is cautious about drawing conclusions from it [1:55:15]; Peter's experience with psychedelics, and the myth that estrogen is bad for men [2:00:30]; The therapeutic potential of psychedelics in psychiatry [2:11:00]; and More. Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive, member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription.

• 0:54Dr. Peter Attia?

  If you want to learn more about the benefits of our premium membership, head over to peterattia MD.com/subscribe.

• 1:04Dr. Peter Attia?

  My guest this week is Dr. Linus Abrams, a psychiatrist with nearly 35 years of clinical experience specializing in mood disorders and psychopharmacology. After three decades in practice, Linus began rethinking many of the assumptions underlying modern psychiatry, leading him to explore how hormones, metabolism, inflammation, circadian biology, and the endocrine system reshape or shape mental health. Today, his work integrates traditional psychiatry with endocrinology, offering a broader framework for understanding the conditions such as depression, anxiety, bipolar disorder, and the profound effects of hormonal changes throughout life. I wanted to have Linus on because his work challenges some of our assumptions about how we think about mental health. We spend a lot of time talking about neurotransmitters

• 1:49Dr. Peter Attia?

  and psychiatric medications, but I wanted to explore whether we're overlooking other important drivers of brain health and what that means for how we diagnose and treat patients. So in this episode, we talk about why psychiatry should focus not only on reducing symptoms, but also on restoring the full human experience, how psychiatric medications work, their limitations, including why correctly diagnosing bipolar disorder versus unipolar depression is very important, as one example, the role hormones, including estrogen, progesterone, testosterone, and thyroid hormone play in mood, cognition, and mental health across different stages of life, how sleep, metabolism, inflammation, and chronic stress influences

• 2:29Dr. Peter Attia?

  mental health, the promise and risk of ketamine and psychedelic therapies in psychiatric medicine, and why the future of psychiatric care may lie in integrating neuroscience, endocrinology, and whole-body physiology. So without further delay, please enjoy my conversation with Dr. Linus Abrams.

• 2:52Dr. Peter Attia?

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

• 2:55Speaker 01

  Same here, Peter. Thanks for having me.

• 2:58Dr. Peter Attia?

  You have a very interesting practice in psychiatry, or at least I should say, a very unique perspective on the integration of all of the traditional tools and insights of psychiatry, along with those of endocrinology. Is that a relatively recent fascination for you? You've been in practice for, what, 30 years?

• 3:18Speaker 01

  Going on 35.

• 3:20Dr. Peter Attia?

  Okay.

• 3:21Speaker 01

  Yeah. Yeah. I did a pivot. After 30 years, I felt like I was in a bit of a rut. Like, I was 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 the pivot is quite recent, and I'm learning about endocrinology as we speak. It's been a recently evolving trend, but I've thought about it deeply, and I hope

• 4:04Speaker 01

  some of that comes across in the podcast today.

• 4:08Dr. Peter Attia?

  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, and, sorry, B, that you were beginning to fatigue of or question or feel was insufficient to help your patients?

• 4:27Speaker 01

  Sure. Well, 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. 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,

• 5:12Speaker 01

  even if they had a spectacular reduction in symptoms. And it led me to think about what was contributing to that. What I finally 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.

• 5:44Dr. Peter Attia?

  That's a pretty profound statement. 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, would they share that view as well? Is that a largely and commonly held view amongst your peers?

• 6:01Speaker 01

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

• 6:07Dr. Peter Attia?

  But it's kind of an important question.

• 6:09Speaker 01

  It is an important question. 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's often still a struggle to encourage a patient to continue with an ongoing regimen when it's needed. And there are certain

• 6:51Speaker 01

  conditions that require chronic treatment, and I mentioned bipolar disorder. That's, you know, certainly a...

• 6:59Dr. Peter Attia?

  ...be among them.

• 7:00Speaker 01

  Yeah, a hallmark case of why that would be necessary. So I don't want to 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 criticize psychiatry per se. This is more about adding an additional lens of perspective than detracting anything in any way from psychiatry, because psychiatry is a remarkable field. I was lucky to have been not so dumb to make the choice to become a psychiatrist

• 7:45Speaker 01

  and to have 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 that's what inspired me to go into psychiatry in the first place, because understanding the patient is always greater than my ability

• 8:23Speaker 01

  or any provider, to use that word, any provider's ability to understand them, because the nature of a human being is so unique and remarkable. So it's progressive layers of insight and progressive attempts to understand and reinterpret our misinterpretations, if you will.

• 8:51Dr. Peter Attia?

  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.

• 9:11Speaker 01

  Sure.

• 9:12Dr. Peter Attia?

  So when you think through presumably the spectrum of conditions that a psychiatrist would be treating, from anxiety to depression to hypomania, bipolar disorder, all of the different clustered, all of these things, there's nothing that's going to show up on a CT scan or an MRI of the brain that makes that diagnosis. There isn't a blood-based biomarker that's going to say, oh, this, you know, this person has high ferritin, or this person has low this or low that.

• 9:39Speaker 01

  Not yet.

• 9:40Dr. Peter Attia?

  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, 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.

• 10:16Speaker 01

  Yes and no. Yes and no, on both counts. First of all, I do a lot of psychotherapy, too, because I'm one of...

• 10:26Speaker 01

  Those rare people, not in a special way, but 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, as opposed to dividing and partitioning a patient's care. Because that lent to my curiosity and the psychotherapeutic aspect of it.

• 11:00Dr. Peter Attia?

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

• 11:17Speaker 01

  Harvard is a very heterogeneous institution. And it really depends on which area of, which particular hospital, which training program, because there are a number of different training programs.

• 11:33Dr. Peter Attia?

  Even within psychiatry?

• 11:35Speaker 01

  Yeah, within psychiatry.

• 11:36Dr. Peter Attia?

  Got it. Okay.

• 11:38Speaker 01

  Now, getting to the other aspect of your question, diagnosis and psychopharmacology don't always go that hands in hands. One would think that they would, but not necessarily. There's a certain art of psychopharmacology that's somewhat intuitive and somewhat evidence-based. And I find that part interesting. And all the information that one gets from a trial of a psychotropic medication is useful information. So it isn't categorical. This is a good drug for this person, or a bad drug.

• 12:23Speaker 01

  Well, of course, that can be true on a certain level. But an adverse response gives us potentially actionable information going forward and should be part of the record permanently to advise any future physician about how to best help that individual.

• 12:46Dr. Peter Attia?

  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 psychiatrist in the pharmacoe- tool bucket. So, everybody listening to us right now, Linus, has heard of an SSRI.

• 13:01Speaker 01

  Yeah.

• 13:01Dr. Peter Attia?

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

• 13:17Speaker 01

  Both.

• 13:17Dr. Peter Attia?

  Yeah. Presumably during your training, we were dealing with MAOIs, we were dealing with tricyclics, we were dealing with drugs that actually still probably have great efficacy, provided the indication is understood. What is the best way to help get our listeners up to speed on these different classes of drugs without clobbering them with too much of the mechanistic stuff? But I think enough that they'll understand. Because I think we have to understand serotonin, if we're going to talk about the endocrine system and how estradiol and serotonin factor into it. So I want to make sure we get everybody up to a certain level of understanding, and I think the drugs help us do that.

• 13:53Speaker 01

  Sure. Well, on a foundational level, 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 and modulating serotonin neurotransmission through signal. They have mechanisms, one particular mechanism,

• 14:36Speaker 01

  glad to mention it if you'd like me to, but one particular mechanism to kind of amplify the signal. And that's how it works for that drug. Now, there are also, probably familiar to many of the audience, a newer class called SNRI's, 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,

• 15:21Speaker 01

  if they go on an SSRI, they could exacerbate it. And people often talk in terms of side effects about SSRIs. Now, again, I love all medications that help people, and SSRIs have helped millions of people. But raising serotonin can decrease dopamine. And taking an SSRI alone can often make people feel a little bit blunted, not fully vital to the extent that they're desiring.

• 15:59Dr. Peter Attia?

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

• 16:04Speaker 01

  It's a paradox.

• 16:06Dr. Peter Attia?

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

• 16:19Speaker 01

  Some serotonin is better.

• 16:21Dr. Peter Attia?

  Yeah, yeah, yeah.

• 16:22Speaker 01

  Serotonin syndrome.

• 16:24Dr. Peter Attia?

  Yes.

• 16:24Speaker 01

  Is when there's...

• 16:25Dr. Peter Attia?

  Devastating. Yeah, yeah. 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 going to give this drug, we're going to inhibit the reuptake of it, we're going to 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.

• 16:47Speaker 01

  And norepinephrine.

• 16:48Dr. Peter Attia?

  And norepinephrine. Because presumably it's competing for the substrate of the... I mean, they're all monoamines, as you said, so...

• 16:56Speaker 01

  Yeah.

• 16:56Dr. Peter Attia?

  Is there a feedback loop? Is that why serotonin...

• 16:59Speaker 01

  Well, I think there's receptor up-regulation, down-regulation. It's a multifactorial process.

• 17:06Dr. Peter Attia?

  So if you have less dopamine and less norepinephrine, you're going to feel the exact types of symptoms that you might have been seeking the drug in the first place?

• 17:17Speaker 01

  Not necessarily, but you'll experience, the typical patient might experience, if the trial is successful, an alleviation of the target symptoms. Let's say anxiety, depression. They might feel less symptomatic and better. But they might feel, at the same time, despite feeling better, God, I feel better, I'm glad I'm taking the drug, but I wish I felt a little more oomph.

• 17:49Dr. Peter Attia?

  Okay. So they... And of course, we didn't even talk about sexual side effects, appetitive side effects, which are probably very common, and we should discuss those. And you also mentioned anxiety, right? So a lot of people might not associate SSRIs with treatment of anxiety. Do you think that the term antidepressant is a bad marketing term for an SSRI, given the breadth of conditions that it can be useful for?

• 18:19Speaker 01

  Absolutely. Yeah. And it's actually a class of drugs that is more effective for anxiety than it is for depression. Not to say that it's not effective for a lot of depression. It was actually a sort of, the first SSRI, fluoxetine, was a...

• 18:41Dr. Peter Attia?

  Which is Prozac?

• 18:42Speaker 01

  Yes, exactly. Generic Prozac, developed by Eli Lilly in a targeted way to block the serotonin reuptake pump. And they succeeded, and it's very targeted at that. Not all SSRIs are pure SSRIs. For example, sertraline, generic Zoloft, also blocks dopamine. It's also a mild dopamine reuptake inhibitor. So they have some so-called secondary pharmacologic properties in certain cases.

• 19:18Dr. Peter Attia?

  So when you think about then the differences between a drug that gets formally labeled an SSRI versus a drug that gets formally labeled an SNRI,

• 19:27Speaker 01

  Yeah.

• 19:28Dr. Peter Attia?

  it's really just a continuum, because they can... It's basically saying, like, I mean, I'm being a little bit cheeky, but if on a scale of one to 10,

• 19:37Speaker 01

  Yeah.

• 19:37Dr. Peter Attia?

  you're a 10 out of 10 on serotonin, and a 3 out of 10 on norepinephrine, and a 4 out of 10 on norepinephrine, at some point, we just say, oh, well, we're going to start classifying you as an SNRI.

• 19:46Speaker 01

  That's true.

• 19:47Dr. Peter Attia?

  Yeah.

• 19:48Speaker 01

  I think it's underappreciated. You know, there are certain more pure SSRIs.

• 19:53Dr. Peter Attia?

  So it sounds like Prozac was a very pure SSRI?

• 19:58Speaker 01

  Perhaps generic Lexapro, estetalopram, might be the best example.

• 20:03Dr. Peter Attia?

  Got it.

• 20:04Speaker 01

  From my understanding right now of a pure SSRI, serotonin reuptake blocker without any secondary pharmacologic properties to my knowledge.

• 20:15Dr. Peter Attia?

  Well, I'd like to ask you a little bit about that because Lexapro seems to be a drug that I've seen a lot of use.

• 20:22Speaker 01

  Yeah.

• 20:24Dr. Peter Attia?

  It's a drug that a lot of non psychiatrists are very comfortable prescribing, which I think speaks to its relative safety.

• 20:30Speaker 01

  Yeah.

• 20:31Dr. Peter Attia?

  And ease of use. It's a drug that, as far as I can tell, really is administered at only two doses typically, 10 and 20 milligrams, although I guess you could cut the 10 in half and start at five. But those seem to be the two doses. The other thing I've noticed is it seems to be a drug that's often prescribed not for depression, but rather for almost like rumination or.

• 20:57Speaker 01

  OCD?

• 20:57Dr. Peter Attia?

  Yeah, yeah, a little bit of OCD.

• 20:59Speaker 01

  That's an anxiety disorder.

• 21:00Dr. Peter Attia?

  Yes, so it's just saying it's more in the anxiety cluster than depressive.

• 21:03Speaker 01

  No, no, it works for both. So it was developed really for what we now call dysthymia disorder. So which is.

• 21:10Dr. Peter Attia?

  Which really I do think of as depressive. I mean dysthymia and anhedonia seem to be really core parts of depression, right?

• 21:18Speaker 01

  They're different, though.

• 21:19Dr. Peter Attia?

  Yes.

• 21:19Speaker 01

  Dysthymia is a chronic, low-grade depressive tendency. And as opposed to a major depressive episode. So major depression is more, has a bigger amplitude, but typically a lower frequency. Dysthymia is a chronic tendency, if you were to draw a graph of it, where the mood would be below the baseline to a degree that takes a toll on the quality of life of the person who has it. And the goal of the medication is to elevate that toward the mean.

• 21:59Dr. Peter Attia?

  And it's interesting that something as describable as dysthymia responds to a, to purely more serotonin without necessarily more, and if anything, less dopamine and norepinephrine, if presumably there's a compensation and they go down.

• 22:17Speaker 01

  Not necessarily, but the side effect profile tends to be better. So remember, when fluoxetine came out, the first SSRI, really the first of the next generation of anti-anxiety antidepressants, to call them dual intended targets. So it isn't that SSRIs are unique in helping dysthymia, but when they were invented, the existing medications on the market, the tricyclic antidepressants, had typically much more severe side effects, much more severe, and were dangerous in overdose.

• 23:02Speaker 01

  So they were potentially lethal in overdose. And they had side effects, like anticholinergic side effects, but to a severe degree that affected, that gave people terrible constipation, dry mouth, orthostatic hypotension, a host of symptoms that was problematic. And so that class was problematic. MEO inhibitors, another potentially dangerous drug if combined with a food containing tyramine, the so-called, like the cheese reaction. So people had to be on diets, monitoring their intake of tyramine-containing foods.

• 23:47Speaker 01

  And it was very anxiety provoking for those patients. Ironically, let's say someone with anxiety or panic disorder, who's taking a medication that they know can give them a hypertensive crisis. So that was the backdrop from which SSRIs came. And SSRIs are really remarkably benign from a side effect profile compared to those older classes of drugs. And then the SNRI's, which I was starting to allude to, if you want me to pivot to that. Their balance between serotonin and norepinephrine, and the major ones are venlafaxine and desvenlafaxine,

• 24:32Speaker 01

  Cymbalta and Pristiq. Yeah. And those can be very effective and potentially less likely to cause the cognitive dulling or affective blunting that people sometimes get with SSRIs. Or the cognitive exacerbation, let's say of an underlying subclinical or full-blown clinical diagnosis of ADHD.

• 25:01Dr. Peter Attia?

  So when would an SNRI, which, again, you always think the newer the drug, the better it is, but when would you turn to an SSRI over an SNRI?

• 25:14Speaker 01

  I would turn to an SSRI if I wanted to max out the serotonergic components. And for example, OCD is a condition that responds better to aggressive serotonergic modulation. Or I shouldn't use that word because later I'm going to use a different vocabulary to describe it, but signal amplification. You really want to turn up that serotonin signal with OCD. And also with PTSD, you want to turn it up. And these are generalizations.

• 25:54Speaker 01

  You know, everyone is different, but as a generalization, I would say that's the case from my experience.

• 26:02Dr. Peter Attia?

  So help me think about how you evaluate a patient 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 very complicated and it's something that I know you have a lot of experience with. So 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, they've been recalcitrant to lots of therapy and they're sort of winding up seeing you as, as sort of a last resort hope?

• 26:35Speaker 01

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

• 26:42Dr. Peter Attia?

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

• 26:46Speaker 01

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

• 26:51Dr. Peter Attia?

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

• 27:01Speaker 01

  Let me put it a different way, if that's okay.

• 27:04Dr. Peter Attia?

  Yeah.

• 27:04Speaker 01

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

• 27:48Dr. Peter Attia?

  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?

• 28:00Speaker 01

  Well, in the population I see, they're more troubled by depression. And the type of bipolar we're alluding to is so-called bipolar two, 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.

• 28:26Dr. Peter Attia?

  Yeah.

• 28:27Speaker 01

  As a matter of fact, 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.

• 29:12Dr. Peter Attia?

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

• 29:15Speaker 01

  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, like 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.

• 29:53Speaker 01

  A combination of depressive symptoms, feeling sad, potentially hopeless, but also having feelings of agitation, physically feeling agitated and disconcerted.

• 30:10Dr. Peter Attia?

  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, and the first line might be an SSRI?

• 30:22Speaker 01

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

• 30:32Dr. Peter Attia?

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

• 30:38Speaker 01

  Sure. The, the wrong drug would be, I would say, any antidepressant instead of a mood stabilizer, like Lamotrigine.

• 30:49Dr. Peter Attia?

  I see.

• 30:50Speaker 01

  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.

• 31:15Dr. Peter Attia?

  And that's Lamictal, I assume?

• 31:18Speaker 01

  Yeah, yeah.

• 31:19Dr. Peter Attia?

  What's the mechanism of that drug?

• 31:21Speaker 01

  I think it changes sodium channels.

• 31:24Dr. Peter Attia?

  Okay. And do we know why lithium works?

• 31:28Speaker 01

  I don't believe so.

• 31:29Dr. Peter Attia?

  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?

• 31:43Speaker 01

  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-

• 32:07Dr. Peter Attia?

  But you have to stabilize them first.

• 32:08Speaker 01

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

• 32:25Dr. Peter 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?

• 32:39Speaker 01

  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. But, so irritability can exist in that context.

• 33:20Speaker 01

  In a bipolar context, it's, it can be more dramatic. It can be, I would say the word would be volatility, as opposed to irritability, that might be more descriptive of a typical patient with untreated or poorly treated bipolar disorder.

• 33:39Dr. Peter 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, 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?

• 34:09Speaker 01

  Well, 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

• 34:48Speaker 01

  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.

• 35:09Dr. Peter 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.

• 35:42Speaker 01

  Yeah. Well, you know, 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. 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,

• 36:24Speaker 01

  rather than a more objectively based appraisal of the dangers of the environment that they might be unnecessarily encountering.

• 36:33Dr. Peter Attia?

  Yeah. I, 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. 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's just, it just wasn't within the purview of it. So we've, we've sort of created a luxury problem for ourselves, which is we've, we've-

• 37:10Speaker 01

  Or that might have even been adaptive.

• 37:13Dr. Peter Attia?

  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, 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

• 37:53Dr. Peter Attia?

  to never compromise our, 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, I've experienced anhedonia, I've experienced dysthymia, 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, so that we, so we can appreciate it when we don't feel those things?

• 38:33Speaker 01

  Let's take anhedonia out of it, because that's a misunderstood concept. But I would say, depression is bad. It, it takes a huge toll on people. It can be lethal. It can, 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. It can

• 39:13Speaker 01

  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.

• 39:45Dr. Peter Attia?

  Yeah.

• 39:46Speaker 01

  That's a good thing.

• 39:47Dr. Peter 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?

• 39:59Speaker 01

  That's one of those questions I could speculate about. But, you know, Peter, when I look at our world today, and-

• 40:11Speaker 01

  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 we, if our primary identity is our intellectual function and we're creating machines that are going to surpass our own intellectual function, or in certain examples have surpassed in certain areas, then how can I flourish?

• 40:48Dr. Peter Attia?

  But, but let's go back in time 10 years when nobody was thinking about that.

• 40:52Speaker 01

  Okay.

• 40:53Dr. Peter Attia?

  Other than a few people.

• 40:54Speaker 01

  Okay.

• 40:55Dr. Peter Attia?

  Wouldn't the, 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?

• 41:02Speaker 01

  I think it's going up because there are multiple, multiple simultaneous challenges. There's a lot of environmental anxiety that 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.

• 41:25Dr. Peter Attia?

  But again, 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 a thousand years ago.

• 41:37Speaker 01

  Yeah.

• 41:38Dr. Peter Attia?

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

• 41:47Speaker 01

  You know, it's very complicated.

• 41:49Dr. Peter Attia?

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

• 41:56Speaker 01

  Yeah.

• 41:57Dr. Peter Attia?

  It's still infinitely better than it was just a thousand years ago.

• 42:00Speaker 01

  From a bourgeois point of view, yes, but from a relational point of view.

• 42:05Dr. Peter Attia?

  Well, so that's, that's, 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, I think, is, is, is preventing me from really getting at the question.

• 42:18Speaker 01

  Yeah, I think I was premature.

• 42:19Dr. Peter Attia?

  Well, no, no, no, 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 and the world we inhabit?

• 42:34Speaker 01

  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

• 43:15Speaker 01

  are using online pornography more in the absence of 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, whatever timeframe you were alluding to.

• 43:44Dr. Peter Attia?

  Yeah, 1,000.

• 43:45Speaker 01

  1,000, that's a more historically accurate, but thank you, thanks for correcting that. Probably everybody else didn't know anything different. And if there was better, they just accepted that was the, 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

• 44:26Speaker 01

  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.

• 44:56Dr. Peter Attia?

  Yeah, 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. 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 Catena, 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, 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

• 45:40Dr. Peter Attia?

  in the hospital by himself with a couple of nurses.

• 45:43Speaker 01

  Remarkable.

• 45:44Dr. Peter 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, 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, 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 they don't know better is, is part of the, is part of, is part of what it is. No, I'm not suggesting that we should, that we want that, that that's, that needs to stop.

• 46:24Speaker 01

  No, I understand.

• 46:25Dr. Peter Attia?

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

• 46:27Speaker 01

  Yes.

• 46:28Dr. Peter Attia?

  And I wonder if this is the price.

• 46:30Speaker 01

  Very complicated. War seems to improve people's mental health ironically.

• 46:35Dr. Peter Attia?

  Yes, yes.

• 46:36Speaker 01

  With obviously dramatic exceptions for PTSD and other loss. 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 in, let's say, looking for alternative approaches such as living more in nature.

• 47:10Dr. Peter Attia?

  Yeah.

• 47:11Speaker 01

  Would be a great example of that. And getting off the grid would be.

• 47:15Dr. Peter Attia?

  Yes, yeah. And I, when I say that the, the, you know, this is the, this is the price you pay for modernity, I think what I, what I would say after that is unless you start to take individual measures to control some of this. 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.

• 47:36Speaker 01

  Absolutely.

• 47:37Dr. Peter Attia?

  But it's no longer the default. You see, we used to live outdoors.

• 47:40Speaker 01

  Yeah.

• 47:41Dr. Peter Attia?

  Now we don't.

• 47:42Speaker 01

  Yeah.

• 47:43Dr. Peter Attia?

  So if you want to be outdoors anymore, you have to actually take the steps into 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.

• 47:55Speaker 01

  Yeah.

• 47:56Dr. Peter Attia?

  So if your tendency is to isolate, you actually have to work to overcome that. Similarly, it's very easy today to see everything, to be overrun by information. If, 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, 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. They, there's some evidence that they slept in, in sort of shorter windows, but the point

• 48:39Dr. Peter Attia?

  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.

• 49:12Speaker 01

  Yeah.

• 49:13Dr. Peter Attia?

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

• 49:22Speaker 01

  Agreed.

• 49:23Dr. Peter Attia?

  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.

• 49:38Speaker 01

  They're anti-normative.

• 49:39Dr. Peter Attia?

  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.

• 49:51Speaker 01

  Yeah.

• 49:52Dr. Peter Attia?

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

• 49:54Speaker 01

  Yeah. 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, you know, people weren't needing to go on GLP-1s a thousand years ago.

• 50:36Dr. Peter Attia?

  Right.

• 50:37Speaker 01

  Maybe unless they were the king.

• 50:39Dr. Peter Attia?

  That's right. We know the king had gout, but we don't know if anybody else did. You know, you raise a great point, and I've discussed this also on the podcast in the past, this, uh, this mental model of distress tolerance. So I sort of, and I wrote about this actually in my book, which was, I, 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, I'm imagining kind of, um, a, a, a window in which I occupy in it. 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.

• 51:23Dr. Peter 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, 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.

• 51:48Speaker 01

  Oh, yeah.

• 51:49Dr. Peter Attia?

  If I had a good night's sleep versus a bad night's sleep, huge contributor. If I'm in pain, you know, 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.

• 52:05Speaker 01

  Death by a thousand cuts.

• 52:06Dr. Peter Attia?

  And I didn't think anything of it, but as I found myself irritable two weeks into this, you know, someone said, like, untreated pain is going to make you irritable. It, I could, I could rattle off all the things that do it. But, but everybody, I think, has to kind of discover what creates, what lengthens their window. And do you get the impression?

• 52:25Speaker 01

  Yes and no. I mean, it's part of the human condition, that we, we all have these foundational biological factors, and we, we have an adaptive capacity, and that's always changing over time.

• 52:39Dr. Peter Attia?

  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?

• 53:02Speaker 01

  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. But I think we have to have a framework about how to think about it, that the brain doesn't

• 53:47Speaker 01

  operate in isolation, and it's, 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 bidirectional interactions

• 54:29Speaker 01

  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.

• 54:45Dr. Peter Attia?

  Well, that's, that's, 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 you, of yours started. Why did you pick endocrinology and how did you dip your toe in that water?

• 54:58Speaker 01

  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? And I concluded that endocrinology, from my perspective, tends to be, at least by me,

• 55:41Speaker 01

  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 bio-identical 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

• 56:17Speaker 01

  it. And I found it to be fascinating, particularly how I feel the neural circuits and neurotransmitters are really inseparable from the endocrine system.

• 56:34Dr. Peter Attia?

  So I want to go back to something you said. You talked about the WHOI. Your career has spanned pre and post WHOI. 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?

• 57:05Speaker 01

  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.

• 57:22Dr. Peter Attia?

  But you brought it up as, hey, five years ago, which means you're 20 years post WHOI. It was still kind of, clearly there was still something there that you think about.

• 57:31Speaker 01

  It made an impact on me. I had the impression that people, you know, 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.

• 58:15Dr. Peter Attia?

  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 levofluorocyan, like all of these things. Yeah, like, let's start with estradiol. I mean, I, 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. So maybe walk us through kind of some of the reasons why that's the case, and, because it probably isn't intuitive to everybody.

• 58:51Speaker 01

  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. So there's no separation of the endocrine system and the brain at that level. Pleiotropic, it has multiple actions at multiple levels throughout neurotransmission.

• 59:35Speaker 01

  So, for example, estradiol modulates not only serotonergic transmission profoundly, but also the dopamine system, the GABA system, acetylcholine, NMDA, and glutamate. So it, it's really profound. And it's, 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.

• 1:00:18Dr. Peter 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?

• 1:00:40Speaker 01

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

• 1:00:52Dr. Peter Attia?

  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?

• 1:01:09Speaker 01

  No, 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.

• 1:01:52Speaker 01

  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. 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, embedded within the brain. I had another term for it that I was searching for.

• 1:02:36Speaker 01

  imbued with and embedded within the brain is how I think about it.

• 1:02:41Dr. Peter 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. But now let's characterize the phenotype. So if estrogen is reduced, all other things being equal, how does the brain experience that?

• 1:03:06Speaker 01

  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.

• 1:03:49Speaker 01

  And 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.

• 1:04:05Dr. Peter 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?

• 1:04:24Speaker 01

  Yeah.

• 1:04:25Dr. Peter Attia?

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

• 1:04:34Speaker 01

  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 in 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

• 1:05:18Speaker 01

  the end of the luteal phase. And therefore, 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 through receptor modulation and responsiveness. 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 irritable as hell. Well, the same thing applies to all of us. We have different adaptive capacities.

• 1:06:01Speaker 01

  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

• 1:06:43Speaker 01

  with Alzheimer's or the primary caregiver, and that parent is living at home, someone who's metabolically challenged, overweight, not exercising. So all these factors play a role, as well as medical illness as a generalization.

• 1:07:01Dr. Peter 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.

• 1:07:12Speaker 01

  It's a vicious cycle.

• 1:07:13Dr. Peter Attia?

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

• 1:07:14Speaker 01

  Absolutely.

• 1:07:15Dr. Peter Attia?

  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.

• 1:07:26Speaker 01

  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. But 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,

• 1:08:10Speaker 01

  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 function. So the mesolimbic and mesocortical functions, those are two pathways of the dopamine system. The 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?

• 1:08:53Speaker 01

  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 like 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.

• 1:09:31Dr. Peter Attia?

  And how much of that do you think women are also dependent on in terms of their testosterone?

• 1:09:38Speaker 01

  Yeah. Well, I think libido is a huge one. That women are almost entirely dependent on testosterone for libido.

• 1:09:50Dr. Peter Attia?

  What about mood, sleep, or some of the other things where men receive a benefit?

• 1:09:56Speaker 01

  Less so. Men are more vulnerable in that department. Yeah.

• 1:10:01Dr. Peter Attia?

  Why do you think that is?

• 1:10:02Speaker 01

  To testosterone.

• 1:10:03Dr. Peter Attia?

  Yeah, yeah. Why do you, why do you think women are less responsive to and or dependent on testosterone for some of those other things? Is it because estrogen over?

• 1:10:10Speaker 01

  Evolution, because they make so much less of it.

• 1:10:13Dr. Peter Attia?

  Got it.

• 1:10:13Speaker 01

  Although, um, they, they still make 10 times as much.

• 1:10:17Dr. Peter Attia?

  I was about to say, they still make much more testosterone than estradiol.

• 1:10:20Speaker 01

  But compared to men.

• 1:10:21Dr. Peter Attia?

  Yeah.

• 1:10:21Speaker 01

  Yeah.

• 1:10:23Speaker 01

  Which, for the audience, that might be worth your reiter- reiterating.

• 1:10:28Dr. Peter 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.

• 1:10:37Speaker 01

  Yeah.

• 1:10:38Dr. Peter Attia?

  In women.

• 1:10:38Speaker 01

  Right.

• 1:10:39Dr. Peter Attia?

  But that's because testosterone is reported.

• 1:10:41Speaker 01

  In picograms per mil- per deciliter, right?

• 1:10:44Dr. Peter Attia?

  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.

• 1:10:59Speaker 01

  Yeah.

• 1:10:59Dr. Peter Attia?

  Although it's about one-tenth the level of a man.

• 1:11:02Speaker 01

  Yeah, yeah.

• 1:11:04Dr. Peter 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.

• 1:11:15Speaker 01

  Mm-hmm.

• 1:11:15Dr. Peter Attia?

  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.

• 1:11:32Speaker 01

  Yeah.

• 1:11:33Dr. Peter Attia?

  Endogenous testosterone. And the two most common ways to do that are giving HCG, which is giving, effectively luteinizing hormone.

• 1:11:40Speaker 01

  Yeah.

• 1:11:41Dr. Peter Attia?

  Telling the body to make testosterone. And then the other would be using drugs like Clomid or.

• 1:11:47Speaker 01

  Clomiphene.

• 1:11:47Dr. Peter Attia?

  Yeah, Clomiphene or Nclomiphene.

• 1:11:49Speaker 01

  Yeah.

• 1:11:49Dr. Peter Attia?

  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.

• 1:12:01Speaker 01

  Let's.

• 1:12:02Dr. Peter Attia?

  We've got to make more of this. We're going to make more LH and FSH. Is there any reason to believe that that approach robs the brain of the, the very estrogen and testosterone that you're trying to give it?

• 1:12:16Speaker 01

  Well, I would say just empirically, men who take Clomiphene tend, tend to be dissatisfied.

• 1:12:27Dr. Peter Attia?

  Even though their numbers are high.

• 1:12:29Speaker 01

  Yes.

• 1:12:30Dr. Peter Attia?

  In the periphery.

• 1:12:31Speaker 01

  Yes.

• 1:12:31Dr. Peter Attia?

  Yeah, that's been our experience as well.

• 1:12:33Speaker 01

  There's a symptom laboratory mismatch.

• 1:12:34Dr. Peter Attia?

  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.

• 1:12:41Speaker 01

  Which is unfortunate because.

• 1:12:43Dr. Peter Attia?

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

• 1:12:46Speaker 01

  Absolutely, yeah.

• 1:12:47Dr. Peter Attia?

  Yeah. So, okay, I wondered if that, if that was your experience.

• 1:12:50Speaker 01

  Let's mention the primary reason why Clomiphene is typically prescribed.

• 1:12:57Dr. Peter Attia?

  It's oral.

• 1:12:57Speaker 01

  And as well as HCG, no, no, the rationale.

• 1:13:00Dr. Peter Attia?

  Okay, so there's, I think there's three rationales for Clomiphene and Nclomiphene. But I think where you're going is you preserve endogenous production when you use either.

• 1:13:12Speaker 01

  Well, fertility.

• 1:13:13Dr. Peter Attia?

  Yes, which of course comes with it, yeah.

• 1:13:16Speaker 01

  Yeah.

• 1:13:16Dr. Peter Attia?

  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 Nclomiphene, because it's administered peripherally, it acts peripherally and it doesn't have a central block.

• 1:13:31Speaker 01

  Yeah.

• 1:13:32Dr. Peter Attia?

  But it, 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.

• 1:13:47Speaker 01

  Right.

• 1:13:48Dr. Peter Attia?

  Testosterone and HCG are schedule four, Clomid and Clomiphene are not regulated.

• 1:13:52Speaker 01

  For now.

• 1:13:53Dr. Peter Attia?

  Yeah. So, any, you don't have to go and see a, 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, it just doesn't seem to fix the symptoms.

• 1:14:16Speaker 01

  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 cypionate injection, for example, dramatically better responses.

• 1:14:35Dr. Peter Attia?

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

• 1:14:38Speaker 01

  Sure.

• 1:14:39Dr. Peter Attia?

  Um, 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, but progesterone's 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.

• 1:15:08Speaker 01

  Yeah.

• 1:15:08Dr. Peter Attia?

  There's nothing.

• 1:15:09Speaker 01

  It's flat lines.

• 1:15:10Dr. Peter Attia?

  And then it rises as it prepares for implantation.

• 1:15:13Speaker 01

  Yeah.

• 1:15:14Dr. Peter Attia?

  It hits a peak.

• 1:15:15Speaker 01

  Yeah.

• 1:15:15Dr. Peter Attia?

  Assuming there is no implantation.

• 1:15:17Speaker 01

  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.

• 1:15:32Dr. Peter Attia?

  Right, in preparation for the follicle to be implanted.

• 1:15:36Speaker 01

  Yeah.

• 1:15:36Dr. Peter Attia?

  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.

• 1:15:46Speaker 01

  Yeah.

• 1:15:46Dr. Peter Attia?

  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? Because she, she felt fine during the follicular.

• 1:15:59Speaker 01

  Right, no oscillation.

• 1:16:00Dr. Peter Attia?

  Exactly. It's the fall.

• 1:16:02Speaker 01

  Yes.

• 1:16:02Dr. Peter Attia?

  Back to low from high that causes the symptoms.

• 1:16:05Speaker 01

  Exactly.

• 1:16:05Dr. Peter Attia?

  This is incredibly fascinating.

• 1:16:07Speaker 01

  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.

• 1:16:26Dr. Peter Attia?

  Yeah.

• 1:16:26Speaker 01

  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.

• 1:16:39Dr. Peter Attia?

  You're, in other words, yeah, I just want to make sure the listener knows what you're saying.

• 1:16:41Speaker 01

  The more I learn about hormones, the more in awe of women I am.

• 1:16:44Dr. Peter Attia?

  Yeah, you're, you're in awe that more women don't experience postpartum depression.

• 1:16:48Speaker 01

  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.

• 1:17:01Dr. Peter Attia?

  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? How genetic is it? I assume it's quite, there's a strong concordance between mother, daughter?

• 1:17:28Speaker 01

  I believe it's highly genetic, yes.

• 1:17:31Dr. Peter Attia?

  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, progesterone and estrogen?

• 1:17:46Speaker 01

  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 post, severe postpartum depression or psychosis, who also have PMDD.

• 1:18:09Dr. Peter Attia?

  Let's talk about.

• 1:18:10Speaker 01

  But not the converse.

• 1:18:11Dr. Peter Attia?

  Yeah, let's talk about postpartum depression.

• 1:18:13Speaker 01

  Yeah.

• 1:18:14Dr. Peter Attia?

  Do you see any women for that in your practice?

• 1:18:17Speaker 01

  Yes, because, 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 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

• 1:19:01Speaker 01

  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 without 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.

• 1:19:34Dr. Peter Attia?

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

• 1:19:39Speaker 01

  It's being researched. Hopkins has a big program in that.

• 1:19:44Dr. Peter Attia?

  What, do you know the prevalence of that severe a level of postpartum depression?

• 1:19:48Speaker 01

  Unfortunately, less than 1%, much less.

• 1:19:52Dr. Peter Attia?

  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 and presumably over the next few weeks or even months, they just don't get back to themselves?

• 1:20:06Speaker 01

  Yeah.

• 1:20:06Dr. Peter Attia?

  Okay. So when a woman like that comes to you, and let's assume she's never seen any psychiatrist before, how do you do the evaluation and how do you think about treating her?

• 1:20:15Speaker 01

  I do the evaluation the same way.

• 1:20:17Dr. Peter Attia?

  Okay.

• 1:20:17Speaker 01

  I ask her what's troubling her and I have a third year 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 socio-economic, really economic support.

• 1:20:55Dr. Peter Attia?

  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, there's nothing obvious you can point to in her personal life from a support network or attention in other, in other words, like, does it sometimes just occur almost randomly?

• 1:21:16Speaker 01

  Yes, de novo.

• 1:21:17Dr. Peter Attia?

  Yeah. And so how do you, okay, let's say you make the diagnosis, which I assume is not impossible to make. What are the, what are the?

• 1:21:26Speaker 01

  Even for a psychiatrist.

• 1:21:27Dr. Peter Attia?

  What are the, 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.

• 1:21:42Speaker 01

  Pretty similar to non-postpartum depression. It's only the acute type where there's a synthetic analog of that chemical that the body makes, the hormone, allopregnanolone, called zeranolone, 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, you know, a protected period of time. Think about a woman who's having all these issues and has to be separated from her family and her baby, you know. So fortunately, they

• 1:22:26Speaker 01

  came out with an oral form of it. The generic name is zeranolone and it's a synthetic version of the neuro steroid allopregnanolone, which is the breakdown product of progesterone, the five alpha reductase and three alpha hydroxy steroid hydrogenase.

• 1:22:48Dr. Peter Attia?

  So would you give that as monotherapy or do you give that in combination with, for example, an SSRI?

• 1:22:54Speaker 01

  Oh, well, that's the one in the hospital. That starts in the hospital.

• 1:22:58Dr. Peter Attia?

  Okay, but when she's?

• 1:22:59Speaker 01

  When she goes home.

• 1:23:00Dr. Peter Attia?

  When she goes home, what do you?

• 1:23:01Speaker 01

  No, all other things being equal, you just give that.

• 1:23:05Dr. Peter Attia?

  You just give that?

• 1:23:06Speaker 01

  Yeah.

• 1:23:06Dr. Peter Attia?

  Okay.

• 1:23:07Speaker 01

  Yeah. If someone is on an SSRI, I wouldn't take them off of it, but you wouldn't start an SSRI then.

• 1:23:15Dr. Peter Attia?

  Okay.

• 1:23:15Speaker 01

  No.

• 1:23:16Dr. Peter Attia?

  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?

• 1:23:27Speaker 01

  Yeah.

• 1:23:28Dr. Peter Attia?

  How long does she typically require treatment before the depression?

• 1:23:32Speaker 01

  Okay, but we're talking about a different category than the synthetic neuro steroid category, which is that acute immediate.

• 1:23:40Dr. Peter Attia?

  Yes, I'm talking about the, I'm talking about the woman who presents to you outside.

• 1:23:44Speaker 01

  Yeah, that's a very heterogeneous population. If they had so-called pre-morbid history of depression, history of depression before their pregnancy, for example, or if they have bipolar disorder.

• 1:24:01Dr. Peter Attia?

  Let's say they didn't have either.

• 1:24:02Speaker 01

  Then, I was gonna say they're at higher risk. If they had neither, then you would treat them pretty much like any other patient with depression.

• 1:24:12Dr. Peter Attia?

  And when you're talking to that patient and setting expectations and they say to you, "Doctor, how long am I gonna need this medication until I'm back to myself?" What would, what would you say?

• 1:24:24Speaker 01

  Yeah. When people ask me questions like that, which I get all the time, I go back to what their previous baseline is. So if, 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 eight to 12 months and then we could, depending 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.

• 1:25:08Speaker 01

  But if they said that they went into it and they, 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 and, for an acute depression, and she finds her new baseline is better than her pre-morbid baseline.

• 1:25:50Speaker 01

  So she's, 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.

• 1:26:01Dr. Peter Attia?

  So in other words, the pregnancy may have unmasked something that she was just sort of stoically pushing through before?

• 1:26:08Speaker 01

  It served, it exacerbated it. Yeah.

• 1:26:11Dr. Peter Attia?

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

• 1:26:29Speaker 01

  Yeah.

• 1:26:29Dr. Peter Attia?

  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 the, how does T3 and T4 and TSH interact with, with the, with the system, with the psychiatric system overall?

• 1:26:46Speaker 01

  Sure. Well, just to give an overview of it, TSH is what the pituitary thinks of the thyroid axis. 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 in the average psychiatrist, people with normal range TSH, let's say in the top 50% of that range. So if the normal

• 1:27:28Speaker 01

  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. And thyroid hormone, there are two types. T4, which has two functions, it's a pro-drug and it gets into the central nervous system to be converted centrally. There are two

• 1:28:11Speaker 01

  T3 and it's also a pro-drug in the periphery. So there are two different types of di-enzymes, 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.

• 1:28:46Dr. Peter Attia?

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

• 1:28:52Speaker 01

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

• 1:28:58Dr. Peter Attia?

  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?

• 1:29:22Speaker 01

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

• 1:29:28Dr. Peter Attia?

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

• 1:29:31Speaker 01

  For me, yes.

• 1:29:32Dr. Peter Attia?

  And then tell me, in your experience, where?

• 1:29:39Dr. Peter Attia?

  When this is being missed, right? So if this is being ignored.

• 1:29:42Speaker 01

  Yeah.

• 1:29:44Dr. Peter Attia?

  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?

• 1:29:52Speaker 01

  Yeah. Well, hypothyroidism, low thyroid is showing up as depression. Hyperthyroidism is showing up more typically and rarely.

• 1:30:04Dr. Peter Attia?

  Yeah, rarely.

• 1:30:05Speaker 01

  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?

• 1:30:21Dr. Peter Attia?

  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, like literally zero.

• 1:30:37Speaker 01

  Yeah.

• 1:30:38Dr. Peter Attia?

  Their free T4 was quite elevated, although not so elevated that you would think anything was going on. But they, when unquestioning, they were, they had lots, you know, 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.

• 1:30:58Speaker 01

  Yeah.

• 1:30:58Dr. Peter Attia?

  That hot thyroid nodule.

• 1:31:00Speaker 01

  Yeah, there can be a hypertensive crisis, right?

• 1:31:03Dr. Peter Attia?

  Yeah, that's a good point. He had slight hypertension, but he wasn't in kind of a crisis. He was, it required medication, but it was easy to manage on one drug.

• 1:31:12Speaker 01

  Yeah.

• 1:31:12Dr. Peter Attia?

  Yeah.

• 1:31:12Speaker 01

  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.

• 1:31:46Dr. Peter Attia?

  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? Do you like to use desiccated formulations that combine them in fixed ratios? Or how do you?

• 1:32:08Speaker 01

  Yeah.

• 1:32:08Dr. Peter Attia?

  Choose off the menu?

• 1:32:09Speaker 01

  I like to use a combination of T4 and T3.

• 1:32:12Dr. Peter Attia?

  Okay.

• 1:32:13Speaker 01

  Where I can have more control over the exact dosage.

• 1:32:20Dr. Peter Attia?

  And in the cases where you're prescribing it, presumably it's because of the psychiatric underlying belief or case that you're treating.

• 1:32:30Speaker 01

  Yeah.

• 1:32:30Dr. Peter Attia?

  Are those the symptoms you are titrating the drug to? Or do you look at something else, such as the biomarker?

• 1:32:37Speaker 01

  No, the symptoms.

• 1:32:38Dr. Peter Attia?

  Symptom, yeah.

• 1:32:38Speaker 01

  I checked the labs.

• 1:32:40Dr. Peter Attia?

  Yeah.

• 1:32:41Speaker 01

  I absolutely checked 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.

• 1:32:54Dr. Peter Attia?

  Yeah.

• 1:32:55Speaker 01

  Yeah.

• 1:32:55Dr. Peter Attia?

  Say more about that.

• 1:32:56Speaker 01

  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.

• 1:33:12Dr. Peter Attia?

  And when you say T3 for the listener, can you differentiate between the FDA-approved T3, Cytemel, which is very short-acting, versus the compounded formulations that are more time-released?

• 1:33:27Speaker 01

  Yeah, I avoid the compounded ones. And I usually recommend twice a day, like first thing in the morning, and then six, eight hours later, not too late because it could cause insomnia.

• 1:33:42Dr. Peter Attia?

  Got it. And what doses, I mean, it's, we're talking five micrograms? These are presumably relatively modest doses?

• 1:33:49Speaker 01

  Yeah, I start low.

• 1:33:50Dr. Peter Attia?

  Yeah.

• 1:33:50Speaker 01

  I can even start at 2.5 twice a day. But sometimes it goes high. It can go to 25 twice a day.

• 1:34:02Dr. Peter Attia?

  25 micrograms of immediate-release T3?

• 1:34:06Speaker 01

  Yeah, for someone who's very depressed.

• 1:34:07Dr. Peter Attia?

  That's amazing.

• 1:34:08Speaker 01

  And responds to it.

• 1:34:09Dr. Peter Attia?

  Yes.

• 1:34:10Speaker 01

  And has normal blood pressure and pulse.

• 1:34:12Dr. Peter Attia?

  Yeah, so give me an example of a pa, can you, can you recall a case of a patient that required that much T3?

• 1:34:20Speaker 01

  Yeah.

• 1:34:21Dr. Peter Attia?

  So what had you tried before?

• 1:34:23Speaker 01

  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.

• 1:34:42Dr. Peter Attia?

  But this was not bipolar?

• 1:34:44Speaker 01

  Not bipolar, no. Yeah, unipolar depression.

• 1:34:47Dr. Peter Attia?

  Unipolar depression, and you've, and I assume you're trying monoamine oxidase inhibitors?

• 1:34:52Speaker 01

  No.

• 1:34:53Dr. Peter Attia?

  No, you were all SSRI or SNRI?

• 1:34:55Speaker 01

  Yeah.

• 1:34:55Dr. Peter Attia?

  Okay.

• 1:34:56Speaker 01

  Yeah, or bupropion.

• 1:34:58Dr. Peter Attia?

  Okay, and, which is wellbutrin for the listener. So each of those therapies in monotherapy had not been successful. And then even when you layered on presumably a, not a bipolar dose of lithium, but?

• 1:35:11Speaker 01

  Or any typical antipsychotic, because those are also indicated for treatment-resistant depression. Drugs like Rexulti, there are a number of them that are used now, Abilify.

• 1:35:25Dr. Peter Attia?

  Yep.

• 1:35:26Speaker 01

  Rexulti is Brexproprazole, Aroproprazole, Zyprexa, Alanzapine. Those drugs are often quite effective as augmentation strategies, adding on top of an antidepressant.

• 1:35:41Dr. Peter Attia?

  And despite all of those combinations, he remained depressed?

• 1:35:45Speaker 01

  Suboptimal.

• 1:35:46Dr. Peter Attia?

  Okay, so he got somewhat better, but not?

• 1:35:49Speaker 01

  Yeah. I'm, I think mentally I'm conflating several patients.

• 1:35:54Dr. Peter Attia?

  Understood. And when you used the T3, did you discontinue the other drugs or did you?

• 1:36:02Speaker 01

  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. Yeah, later on, when they're feeling good, is the time where you have the luxury of peeling the layers of the onion.

• 1:36:20Dr. Peter Attia?

  So in that particular example that you've got your mind on, when the T3 brought symptom relief.

• 1:36:28Speaker 01

  Yeah.

• 1:36:28Dr. Peter Attia?

  Do you recall if you were also able to get any of the other agents off?

• 1:36:32Speaker 01

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

• 1:36:46Dr. Peter 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?

• 1:36:52Speaker 01

  The order of efficacy.

• 1:36:53Dr. Peter Attia?

  In the order of efficacy, okay. So we are slave to efficacy first, side effects second?

• 1:36:58Speaker 01

  It's up to the patient.

• 1:36:59Dr. Peter Attia?

  Okay.

• 1:37:00Speaker 01

  It's your decision-making.

• 1:37:01Dr. Peter Attia?

  Because some of those drugs, like Abilify, have unwanted side effects like appetite increase or things like that, correct?

• 1:37:08Speaker 01

  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. Potentially irreversible. Now, there are actual drugs to treat it with.

• 1:37:30Dr. Peter Attia?

  Wow.

• 1:37:31Speaker 01

  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.

• 1:37:45Dr. Peter Attia?

  Yeah, so the stakes are high if you're going down that route.

• 1:37:48Speaker 01

  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.

• 1:38:04Dr. Peter Attia?

  Now, in a patient that ultimately ends up needing that much T3, did their thyroid labs look that dramatic or not necessarily?

• 1:38:13Speaker 01

  Not necessarily.

• 1:38:15Dr. Peter Attia?

  So that is not necessarily a patient that showed up with a TSH of seven?

• 1:38:18Speaker 01

  No. Oh, yeah, those I refer to endocrinology. I wouldn't go near that.

• 1:38:24Dr. Peter Attia?

  Okay. This is remarkable to me. Why do you think, in the case of those few patients that have required, or?

• 1:38:33Speaker 01

  Many patients who are depressed and have low, normal free T4 and/or free T3 seem to respond quite well to thyroid hormone supplementation.

• 1:38:50Dr. Peter Attia?

  And you believe that the reason is primarily through upregulation of metabolism and increased metabolic rate more than it is?

• 1:38:57Speaker 01

  It could be central.

• 1:38:59Dr. Peter Attia?

  Yeah.

• 1:38:59Speaker 01

  I mean, thyroid upregulates catecholamine receptor response.

• 1:39:05Dr. Peter Attia?

  So it could be norepinephrine that's, they're getting more norepinephrine?

• 1:39:07Speaker 01

  And dopamine. It could also be serotonin. Thyroid increases serotonin receptors density, serotonin receptor density. It also increases mitochondrial biogenesis on a genetic level.

• 1:39:25Speaker 01

  See, here we go again.

• 1:39:26Dr. Peter Attia?

  Yeah, the probability is it's doing more than one thing.

• 1:39:29Speaker 01

  Yeah. How deep these hormones go.

• 1:39:30Dr. Peter Attia?

  Yeah.

• 1:39:30Speaker 01

  Right? In terms of the overlap and the co-mingling with neurotransmission and neural circuits.

• 1:39:39Dr. Peter Attia?

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

• 1:39:45Speaker 01

  Yeah.

• 1:39:45Dr. Peter Attia?

  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

• 1:40:04Speaker 01

  Yeah.

• 1:40:05Dr. Peter Attia?

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

• 1:40:12Speaker 01

  You can't treat it directly.

• 1:40:14Dr. Peter Attia?

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

• 1:40:20Speaker 01

  Yeah.

• 1:40:20Dr. Peter Attia?

  Because, you know, it's, there are usually problems of too little, and we know how to fix it.

• 1:40:25Speaker 01

  Yeah.

• 1:40:26Dr. Peter Attia?

  Over here, it's usually too much, and we now know how to fix it.

• 1:40:29Speaker 01

  But it's really a signal.

• 1:40:30Dr. Peter Attia?

  Yeah.

• 1:40:31Speaker 01

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

• 1:40:54Dr. Peter Attia?

  Yep.

• 1:40:54Speaker 01

  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.

• 1:41:06Dr. Peter Attia?

  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. It's hyperarousal

• 1:41:27Speaker 01

  Yeah.

• 1:41:27Dr. Peter Attia?

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

• 1:41:31Speaker 01

  Or an acute.

• 1:41:32Dr. Peter Attia?

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

• 1:41:35Speaker 01

  Yeah.

• 1:41:35Dr. Peter Attia?

  And, as we've just danced around, we don't, we don't have a pill to block it. We don't, we can't say, go and take this pill and it'll make it go away.

• 1:41:43Speaker 01

  And even if we did, that may not really solve the problem.

• 1:41:49Dr. Peter Attia?

  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, psychiatry hat on?

• 1:42:02Speaker 01

  I don't think that way. In other words, I don't see any dichotomy between psychiatry and endocrinology. And so, I, I don't have different hats, just to be, you know, 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

• 1:42:44Speaker 01

  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.

• 1:43:10Dr. Peter Attia?

  And are you discussing it that way with a patient in the same way? Because it's, if you're giving a patient estrogen, you're explaining to them why, right?

• 1:43:18Speaker 01

  Yeah.

• 1:43:18Dr. Peter Attia?

  This is, this is what estrogen is doing, this is why we're replacing it.

• 1:43:21Speaker 01

  I have to.

• 1:43:22Dr. Peter Attia?

  If you're giving a patient levodaroxin, or cytomel, this is, this is why, and this is what it's gonna do.

• 1:43:27Speaker 01

  Yeah.

• 1:43:28Dr. Peter Attia?

  So when the patient, when you suspect that, hey, a big part of what's going on here is hyperarousal.

• 1:43:34Speaker 01

  Yeah.

• 1:43:35Dr. Peter Attia?

  How much

• 1:43:36Speaker 01

  I don't tell the patient that.

• 1:43:37Dr. Peter Attia?

  You don't?

• 1:43:38Speaker 01

  No.

• 1:43:38Dr. Peter Attia?

  Okay.

• 1:43:39Speaker 01

  No, because I don't think, I don't have an endocrine-centric vocabulary.

• 1:43:46Speaker 01

  So I just talk, people talk.

• 1:43:51Speaker 01

  Like, you know, that boss, you and that boss, you know, have you asked for a transfer? Or, 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, you know, live at your house, but you don't have to do all the work. A more common sense approach.

• 1:44:21Dr. Peter 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.

• 1:44:36Speaker 01

  Yeah.

• 1:44:36Dr. Peter Attia?

  Plus some of these endocrine adaptive tools.

• 1:44:39Speaker 01

  Yeah.

• 1:44:40Dr. Peter Attia?

  And 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 few patients merged into one, 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 unlock. Do you have any other cases like that that come to your mind?

• 1:45:04Speaker 01

  Let's say a woman who comes to me, perimenopausal age, who says, 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.

• 1:45:35Speaker 01

  So then, I ask her, 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 twenties and thirties. Oh, okay. And she smiles and says, they were chaotic. I, 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.

• 1:46:15Speaker 01

  And 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.

• 1:47:00Dr. Peter Attia?

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

• 1:47:07Speaker 01

  Yes.

• 1:47:08Dr. Peter Attia?

  Okay.

• 1:47:08Speaker 01

  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 thirties, 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 goes back to what we were talking to earlier. What happened? Well, first it was miraculous, she says. Then, a couple of weeks later, I started having those racing thoughts again, and they

• 1:47:48Speaker 01

  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.

• 1:47:56Dr. Peter Attia?

  She stopped the medication, and what happened?

• 1:48:00Speaker 01

  Back to baseline. The same roller coaster.

• 1:48:02Dr. Peter Attia?

  Hypomania, oh, yeah, okay.

• 1:48:04Speaker 01

  The roller coaster, yeah.

• 1:48:06Dr. Peter Attia?

  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?

• 1:48:16Speaker 01

  No.

• 1:48:19Dr. Peter Attia?

  Isn't that amazing?

• 1:48:20Speaker 01

  Yeah.

• 1:48:21Dr. Peter Attia?

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

• 1:48:32Speaker 01

  Yeah. Well, it's clearly some limbic dysregulation.

• 1:48:37Dr. Peter Attia?

  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?

• 1:48:52Speaker 01

  No.

• 1:48:53Dr. Peter Attia?

  Like, and yet they have to somehow treat this person?

• 1:48:55Speaker 01

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

• 1:49:17Dr. Peter 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.

• 1:49:22Speaker 01

  Oh, tell me your question.

• 1:49:23Dr. Peter Attia?

  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.

• 1:49:31Speaker 01

  Yes.

• 1:49:32Dr. Peter Attia?

  So can you tell me your experience with seeing patients go through ketamine therapy for difficult-to-treat depression? Or just, just, yeah, give me your thoughts on the subject.

• 1:49:45Speaker 01

  Do you want me to tell you how it works?

• 1:49:47Dr. Peter Attia?

  That would be great.

• 1:49:47Speaker 01

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

• 1:49:57Dr. Peter 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, does it have any relationship to MDMA? But it does not.

• 1:50:07Speaker 01

  No, no, what's up? 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 in 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.

• 1:50:49Speaker 01

  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 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.

• 1:51:34Speaker 01

  But 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.

• 1:51:50Dr. Peter Attia?

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

• 1:51:59Speaker 01

  Yeah. I'm not that expert in ketamine, honestly. So I'm not sure. I haven't seen that.

• 1:52:06Dr. Peter Attia?

  And for the patients-

• 1:52:08Speaker 01

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

• 1:52:15Dr. Peter Attia?

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

• 1:52:20Speaker 01

  Yeah, with, with monitoring.

• 1:52:22Dr. Peter Attia?

  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?

• 1:52:35Speaker 01

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

• 1:52:49Dr. Peter Attia?

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

• 1:52:54Speaker 01

  Oh, heterogeneous. For, for some people-

• 1:52:57Dr. Peter Attia?

  Clearly, it can be only days, if that's what you're saying.

• 1:53:00Speaker 01

  Yeah, yeah.

• 1:53:01Dr. Peter Attia?

  Okay.

• 1:53:01Speaker 01

  Yeah.

• 1:53:02Dr. Peter Attia?

  And on the long end of that spectrum?

• 1:53:05Speaker 01

  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. It's, this is an emerging field.

• 1:53:25Dr. Peter Attia?

  And how is it, is it, is the dose given in such a way that it's dissociative to the patient?

• 1:53:30Speaker 01

  Yes. Yes.

• 1:53:33Dr. Peter Attia?

  I see.

• 1:53:33Speaker 01

  I mean, it is a dissociative anesthetic.

• 1:53:36Dr. Peter Attia?

  Yeah, I just didn't know if it was given so, I mean, I didn't realize the patient was completely dissociating, because obviously it could be given at a lower dose, right?

• 1:53:45Speaker 01

  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-

• 1:54:00Dr. Peter Attia?

  Yep.

• 1:54:01Speaker 01

  -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. That's the latest thinking, from my understanding.

• 1:54:23Dr. Peter Attia?

  So do you have any concern about what appears to be a lot of recreational use of ketamine outside of these clinical settings?

• 1:54:31Speaker 01

  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.

• 1:55:00Dr. Peter Attia?

  Have you seen any patients who have had negative experiences and have sought you out as a result of it? You know, something-

• 1:55:07Speaker 01

  No, but I, I have friends who've referred patients like that for addiction treatment.

• 1:55:13Dr. Peter Attia?

  I see. Okay. And, you know, you, 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, you know, therapeutic dose of psilocybin?

• 1:55:34Speaker 01

  Yeah.

• 1:55:34Dr. Peter Attia?

  That had some memory recovery?

• 1:55:36Speaker 01

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

• 1:55:43Dr. Peter Attia?

  Yeah, yeah, yeah. But so interesting.

• 1:55:45Speaker 01

  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.

• 1:56:03Dr. Peter Attia?

  Yeah.

• 1:56:05Speaker 01

  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 beyond that. She couldn't have interactions. And then she took this dose of psilocybin and behaved dramatically differently and became somewhat normal after it.

• 1:56:41Dr. Peter Attia?

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

• 1:56:43Speaker 01

  Well, 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. There are no-

• 1:57:05Speaker 01

  Studies, there are no metrics, there is no neuroimaging, there is no anything with the study, so it's the ultimate N of 1. 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. And 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?

• 1:57:43Dr. Peter Attia?

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

• 1:57:51Speaker 01

  Yeah.

• 1:57:52Dr. Peter Attia?

  But yes, usually if it's so severe that a, well, again, part of it comes down to basically airway protection, you know, I don't, it's unclear how capable she was.

• 1:58:02Speaker 01

  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. I'd be very cautious about generalizing that to neurodegenerative disease.

• 1:58:41Speaker 01

  Now, 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 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

• 1:59:25Speaker 01

  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. And so, the hormones that change the conditions within which neurotransmitters operate are very plastic under the right circumstances. Optimal estradiol levels, for example.

• 2:00:09Speaker 01

  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?

• 2:00:39Dr. Peter 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. It was, I didn't find it to be a positive experience and I will never repeat it.

• 2:01:01Speaker 01

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

• 2:01:06Dr. Peter Attia?

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

• 2:01:23Speaker 01

  Did anything positive come out of that subsequently?

• 2:01:28Dr. Peter Attia?

  Not a single positive thing came out of that.

• 2:01:30Speaker 01

  So you had a profoundly adverse reaction?

• 2:01:33Dr. Peter Attia?

  Perhaps the only positive thing I would say is, it gives me enormous caution when I, when I talk to my patients, who themselves are very curious about these things, I just caution them and say, "Look, you know, you simply don't know how you're going to respond to these things. The therapeutic windows on these things are quite narrow." 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 gonna stop."

• 2:02:11Speaker 01

  You're onto my Russian roulette concept.

• 2:02:12Dr. Peter Attia?

  Yeah, yeah. So I think with these, with these agents, I mean, with the exception of MDMA, I think all of these, these so-called psychedelics, I think are, and again, there are, you know, I've used psilocybin in a therapeutic setting that was incredibly positive. I've also had-

• 2:02:32Speaker 01

  Well, let's, if you want to, let's talk about that.

• 2:02:34Dr. Peter 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, it, 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.

• 2:03:09Speaker 01

  Wow.

• 2:03:10Dr. Peter Attia?

  So that was absolutely awful. Again, nothing positive came of that experience. But I've had, I've had very positive experiences on guided MDMA and with another psilocybin experience. And I think-

• 2:03:25Speaker 01

  What made the positive experience positive?

• 2:03:28Dr. Peter Attia?

  Well, again, I think with MDMA-

• 2:03:32Speaker 01

  No, with the psilocybin?

• 2:03:34Dr. Peter Attia?

  With the psilocybin. It was, I mean, it's hard to describe. I think 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." But what was very powerful about this was, I was not experiencing it through my lived

• 2:04:19Dr. Peter Attia?

  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.

• 2:04:37Speaker 01

  Yes.

• 2:04:38Dr. Peter Attia?

  So that, and the durability of that is, a decade later, that will be lifelong durability. So I think because that was-

• 2:04:46Speaker 01

  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, and they're able to re-assimilate it from certainly a more advanced view, and even have compassion for someone who may have-

• 2:05:18Dr. Peter Attia?

  So this was an interesting experience. 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.

• 2:05:46Speaker 01

  Yeah.

• 2:05:47Dr. Peter Attia?

  But now, all of a sudden, I was able to appreciate their life and how much harder it was than my life. And that's, but in a way that I could never articulate now. I can't describe it now.

• 2:06:00Speaker 01

  I understand.

• 2:06:01Dr. Peter Attia?

  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." And it was-

• 2:06:15Dr. Peter Attia?

  And all of the things that have frustrated me are frustrations of someone who's never fully appreciated.

• 2:06:24Speaker 01

  It's about gratitude.

• 2:06:25Dr. Peter Attia?

  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.

• 2:06:42Speaker 01

  Yeah.

• 2:06:42Dr. Peter Attia?

  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. 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.

• 2:07:12Speaker 01

  I think that's very wise.

• 2:07:14Dr. Peter Attia?

  I've extracted something incredibly valuable.

• 2:07:16Speaker 01

  Yes.

• 2:07:17Dr. Peter Attia?

  I don't want to tarnish it with anything negative.

• 2:07:19Speaker 01

  Well, it's beautiful that you got what you did out of it, and also that you knew when to stop.

• 2:07:25Dr. Peter Attia?

  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. There's nothing I can point to in set and setting and dose and deliver, like, there's nothing I can point to that was different.

• 2:07:46Speaker 01

  There's a certain randomness.

• 2:07:48Dr. Peter Attia?

  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.

• 2:07:59Speaker 01

  Yeah.

• 2:08:00Dr. Peter Attia?

  The amount of journaling. I've never had a greater intention.

• 2:08:04Speaker 01

  Yeah.

• 2:08:04Dr. Peter Attia?

  Going into this, right?

• 2:08:06Speaker 01

  You expected a masterpiece to come out of it.

• 2:08:10Dr. Peter Attia?

  Yes, this was, this was Michelangelo going into the chapel. I mean, it was, this was going to be the final elucidation of the three things, the three questions that still, you know, I deal with.

• 2:08:24Speaker 01

  Yes.

• 2:08:25Dr. Peter Attia?

  And instead, I got put into a Tumblr and ripped into pieces and spit out the back. And I, I just, I mean, it was, it was very, very difficult. It took me, it took me months to recover.

• 2:08:40Speaker 01

  I've, I've always been innately scared of those medications and have avoided them.

• 2:08:48Dr. Peter Attia?

  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, 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

• 2:09:32Dr. Peter Attia?

  you can put into a human body, I just need two to three X what every other person needs to experience in effect.

• 2:09:40Speaker 01

  Yeah.

• 2:09:41Dr. Peter Attia?

  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, we're at a point on the PK of that drug that is just well beyond normal behavior. Every time I have used psilocybin, it has been north of 10 grams, because the standard five grams produces nothing.

• 2:10:25Speaker 01

  Wow.

• 2:10:26Dr. Peter Attia?

  So in other words, I say all of that to say.

• 2:10:29Speaker 01

  Maybe you need more estrogen for the.

• 2:10:30Dr. Peter Attia?

  Yeah, well, I mean, it might just be that my horror stories, my horror stories have to do more with my, with my dose, where I am on the dose response curve.

• 2:10:40Speaker 01

  Yeah, yeah.

• 2:10:40Dr. Peter Attia?

  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 Remidex, which for the listener is a drug that prevents the aromatization of testosterone into estradiol. 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.

• 2:11:05Speaker 01

  Yeah.

• 2:11:09Dr. Peter Attia?

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

• 2:11:19Speaker 01

  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.

• 2:11:34Dr. Peter Attia?

  I'm 100% convinced it will last the rest of my life.

• 2:11:37Speaker 01

  And 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 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, maybe

• 2:12:22Speaker 01

  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 two-way receptor that it has to bind to. That's where the classic psychedelic binds to. So 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 and augments the efficacy and mitigates the risk.

• 2:13:01Dr. Peter Attia?

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

• 2:13:06Speaker 01

  Yeah.

• 2:13:07Dr. Peter Attia?

  The two that, to me, seem the most exciting.

• 2:13:10Speaker 01

  Yeah.

• 2:13:10Dr. Peter Attia?

  Are obviously MDMA in PTSD and psilocybin in end-of-life depression, or frankly, just all end-of-life related therapy.

• 2:13:22Speaker 01

  Yeah.

• 2:13:24Dr. Peter Attia?

  What do you think, do you, how much more evidence do you think the, the, the medical community, I mean, the FDA aside, there's a whole issue with the FDA there. But, but from a, from a medical scientific standpoint, where do you sit on those two indications, which are quite specific?

• 2:13:39Speaker 01

  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, because there aren't many things.

• 2:14:05Dr. Peter Attia?

  But we don't want to, we don't want to make it worse.

• 2:14:06Speaker 01

  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.

• 2:14:27Dr. Peter Attia?

  But then the same would apply to significant PTSD.

• 2:14:30Speaker 01

  Yeah, but, but I suspect that it's not MDMA that's going to be the most effective for that.

• 2:14:39Dr. Peter Attia?

  You think it will be psilocybin?

• 2:14:42Speaker 01

  Perhaps, or certainly other drugs. I think MDMA is a so-called empathogen, it increases empathy. Certain types of PTSD, you know, PTSD, like so many things, is a very heterogeneous category. I 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 am, I do find it exciting that medications can

• 2:15:27Speaker 01

  have such adorable and powerful effects. 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.

• 2:15:46Dr. Peter Attia?

  Yeah, I think I would agree with all of that. 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 they don't hear enough of the bad stories, and I think there's.

• 2:16:03Speaker 01

  I agree with you.

• 2:16:04Dr. Peter Attia?

  I think there's, they are drugs, and every drug has a side effect.

• 2:16:08Speaker 01

  Absolutely, including the ones I prescribe.

• 2:16:13Dr. Peter Attia?

  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.

• 2:16:28Speaker 01

  Thank you so much. It's been an enormous pleasure for me.

• 2:16:32Dr. Peter Attia?

  Thank you for listening to this week's episode of The Drive. Head over to peterattiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Attia MD. You can also leave us a 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.

• 2:17:14Dr. Peter Attia?

  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 from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures.