The Peter Attia Drive - #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.

00:00:00.000 Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:53.420 subscription. If you want to learn more about the benefits of our premium membership, head over to

00:00:58.600 peteratiamd.com forward slash subscribe. My guest this week is Dr. Linus Abrams, a psychiatrist with

00:01:07.680 nearly 35 years of clinical experience specializing in mood disorders and psychopharmacology. After

00:01:13.300 three decades in practice, Linus began rethinking many of the assumptions underlying modern

00:01:17.820 psychiatry, leading him to explore how hormones, metabolism, inflammation, circadian biology,

00:01:23.420 and the endocrine system reshape or shape mental health. Today, his work integrates traditional

00:01:29.720 psychiatry with endocrinology, offering a broader framework for understanding the conditions

00:01:34.740 such as depression, anxiety, bipolar disorder, and the profound effects of hormonal changes

00:01:40.900 throughout life. I wanted to have Linus on because his work challenges some of our assumptions about

00:01:46.120 how we think about mental health. We spent a lot of time talking about neurotransmitters and

00:01:50.260 psychiatric medications, but I wanted to explore whether we're overlooking other important drivers

00:01:55.300 of brain health and what that means for how we diagnose and treat patients. So in this episode,

00:01:59.580 we talk about why psychiatry should focus not only on reducing symptoms, but also on restoring

00:02:05.060 the full human experience, how psychiatric medications work, their limitations, including

00:02:10.040 why correctly diagnosing bipolar disorder versus unipolar depression is very important as one

00:02:15.260 example. The role hormones, including estrogen, progesterone, testosterone, and thyroid hormone

00:02:20.480 play in mood, cognition, and mental health across different stages of life. How sleep, metabolism,

00:02:27.280 inflammation, and chronic stress influences mental health. The promise and risk of ketamine and

00:02:33.140 psychedelic therapies in psychiatric medicine. And why the future of psychiatric care may lie

00:02:38.620 in integrating neuroscience, endocrinology, and whole body physiology. So without further delay,

00:02:43.860 please enjoy my conversation with Dr. Linus Abrams.

00:02:52.060 Linus, thank you for coming to Austin. So wonderful to see you.

00:02:55.400 Same here, Peter. Thanks for having me.

00:02:57.940 You have a very interesting practice in psychiatry, or at least I should say a very

00:03:03.220 unique perspective on the integration of all of the traditional tools and insights of psychiatry

00:03:10.360 along with those of endocrinology. Is that a relatively recent fascination for you?

00:03:16.120 You've been in practice for, what, 30 years?

00:03:18.920 Going on 35.

00:03:20.120 Okay.

00:03:21.060 Yeah. Yeah. I did a pivot after 30 years. I felt like I was in a bit of a rut. Like I was

00:03:32.560 enjoying my practice, but I felt I wasn't learning as much as I wanted to learn.

00:03:40.360 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 some of that comes across in the podcast today.

00:04:07.740 So tell me what it was during the first 30 years of your practice that, A, that gave you satisfaction and that you loved, and, sorry, B, that you were beginning to fatigue of or question or feel was insufficient to help your patients.

00:04:26.940 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.

00:04:45.680 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.

00:05:04.180 that the patient felt it was undesirable

00:05:10.660 even if they had a spectacular reduction in symptoms.

00:05:17.260 And it led me to think about what was contributing to that.

00:05:21.760 What I finally decided was the organizing principle

00:05:28.180 was that psychiatry aims at reduction of symptoms

00:05:32.680 but not restoration of the full human experience that makes life most worthwhile.

00:05:43.920 That's a pretty profound statement. I wouldn't say I'm pushing back on it. I'm only asking out

00:05:49.620 of genuine curiosity. If you were at a dinner with nine other psychiatrists, would they share

00:05:55.920 that view as well? Is that a largely and commonly held view amongst your peers?

00:06:01.100 Probably not.

00:06:02.900 Probably not, but I don't go around asking that question.

00:06:07.180 But it's kind of an important question.

00:06:09.780 It is an important question.

00:06:12.100 I would say they would agree with me that there's an unusual amount of struggle, even

00:06:19.980 in cases where there's a dramatic improvement, where people come with horrible levels of

00:06:27.100 suffering, and a psychopharmacologic intervention results in a dramatic reduction of that suffering,

00:06:38.080 that it's often still a struggle to encourage a patient to continue with an ongoing regimen

00:06:48.580 when it's needed. And there are certain conditions that require chronic treatment,

00:06:54.460 I mentioned bipolar disorder. That's certainly a hallmark case of why that would be necessary.

00:07:06.140 I don't want to undersell psychopharmacology. By the way, I feel blessed to have had such a

00:07:15.280 wonderful career and experience of psychiatry. I love the field of psychiatry. I don't mean to

00:07:22.960 criticize psychiatry per se. This is more about adding an additional lens of perspective

00:07:31.980 than detracting anything in any way from psychiatry, because psychiatry is a remarkable

00:07:38.700 field. I was lucky to have been not so dumb to make the choice to become a psychiatrist and

00:07:46.260 to have taken advantage of the wonderful opportunities to get to know human beings

00:07:53.720 on a deeper level, which you asked me before what's been fulfilling. I would say that's been

00:08:00.340 probably the most fulfilling aspect of my career, is to really get to know people in depth who

00:08:08.580 are remarkable human beings. And that's what inspired me to go into psychiatry in the first

00:08:17.280 place, because understanding the patient is always greater than my ability or any provider,

00:08:25.180 to use that word, any provider's ability to understand them, because the nature of a human

00:08:33.000 being is so unique and remarkable. So it's progressive layers of insight and progressive

00:08:42.800 attempts to understand and reinterpret our misinterpretations, if you will.

00:08:51.740 I mean, one of the things about psychiatry that is quite unique to medicine, when you consider

00:08:57.920 all of the medical subspecialties and the surgical subspecialties is the lack of measurable

00:09:05.660 biomarkers or objective findings that could be measured on imaging, for example.

00:09:11.520 So when you think through presumably the spectrum of conditions that a psychiatrist would be

00:09:19.640 treating from anxiety to depression, to hypomania, bipolar disorder, all of the different

00:09:25.960 clustered, all of these things. There's nothing that's going to show up on a CT scan or an MRI

00:09:30.920 of the brain that makes that diagnosis. There isn't a blood-based biomarker that's going to

00:09:35.560 say, oh, this person has high ferritin, or this person has low this or low that.

00:09:39.420 Not yet.

00:09:40.080 Yep. So yet, in other words, something you said a moment ago rings very important, which is,

00:09:46.500 even though you've used the term psychopharmacologist several times already,

00:09:51.160 implying that the tool, the main tool you use is a pharmacologic tool. The human story piece of it

00:09:59.280 is the diagnosis, right? I mean, presumably part of the diagnosis is ratified through

00:10:04.740 a hypothesis of, hey, I think if I'm right on the diagnosis, this medication should make things a

00:10:10.680 little bit better. But you have to have a very good hypothesis based on your subjective interaction

00:10:15.720 with that patient. Yes and no. Yes and no. On both counts. First of all, I do a lot of psychotherapy

00:10:22.660 too, because I'm one of those rare people, not in a special way, but in a self-directed way,

00:10:32.960 who chose a residency program at Harvard that trained both psychotherapy and psychopharmacology.

00:10:39.840 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 led to my curiosity and the psychotherapeutic aspect of it.

00:10:59.340 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 –

00:11:17.500 Harvard is a very heterogeneous institution, and it really depends on which area of which

00:11:28.780 particular hospital, which training program, because there are a number of different training

00:11:33.000 programs.

00:11:33.960 Even within psychiatry?

00:11:35.200 Yeah, within psychiatry.

00:11:36.220 Got it.

00:11:36.660 Yeah.

00:11:36.840 Okay.

00:11:36.960 Now, getting to the other aspect of your question, diagnosis and psychopharmacology

00:11:47.880 don't always go that hand in hand. One would think that they would, but not necessarily.

00:11:56.440 There's a certain art of psychopharmacology that's somewhat intuitive and somewhat

00:12:02.960 evidence-based. And I find that part interesting. And all the information that one gets from a

00:12:12.520 trial of a psychotropic medication is useful information. So it isn't categorical. This is

00:12:20.260 a good drug or a bad drug. Well, of course, that can be true on a certain level. But an adverse

00:12:29.760 response gives us potentially actionable information going forward and should be

00:12:35.920 part of the record permanently to advise any future physician about how to best help that

00:12:44.100 individual. Let's maybe talk a little bit about some of the, I hate the term, but kind of the

00:12:49.940 bread and butter tools of the psychiatrist in the pharmaco tool bucket. So everybody listening

00:12:58.260 to us right now, Linus, has heard of an SSRI, right? There's nobody that hasn't heard of them.

00:13:03.180 And if they haven't heard that term, they've certainly heard the drugs within that class.

00:13:07.560 Your career is such that you've seen the, if not the birth of that class of drugs,

00:13:14.780 certainly the proliferation of that class of drugs.

00:13:16.900 Yeah. Presumably during your training, we were dealing with MAOIs, we were dealing with

00:13:23.460 tricyclics, we were dealing with drugs that actually still probably have great efficacy,

00:13:27.760 provided the indication is understood. What is the best way to help get our listeners up to speed

00:13:33.760 on these different classes of drugs without clobbering them with too much of the mechanistic

00:13:40.220 stuff? But I think enough that they'll understand, because I think we have to understand serotonin

00:13:44.240 if we're going to talk about the endocrine system and how estradiol and serotonin factor in. So I

00:13:49.520 want to make sure we get everybody up to a certain level of understanding. And I think the drugs help

00:13:53.080 us do that. Sure. Well, on a foundational level, psychotropics historically have worked at the

00:14:02.600 level of intervening on neurotransmitter modulation, and particularly the monoamines,

00:14:09.960 serotonin, dopamine, and norepinephrine. And SSRIs are drugs that selectively,

00:14:18.040 for the most part, target serotonin and modulating serotonin neurotransmission

00:14:28.100 through signal. They have mechanisms, one particular mechanism, glad to mention it if

00:14:37.540 you'd like me to, but one particular mechanism to kind of amplify the signal. And that's how it

00:14:46.200 works for that drug. Now, there are also probably familiar to many of the audience a newer class

00:14:55.180 called SNRIs, serotonin and norepinephrine reuptake inhibitors. And that gives a certain

00:15:04.180 balance because raising serotonin can decrease dopamine. So someone, let's say, with attention

00:15:11.980 deficit disorder who has slow dopamine as part of the problem of their attention issues,

00:15:20.720 if they go on an SSRI, they could exacerbate it. And people often talk in terms of side effects

00:15:28.160 about SSRIs. Now, again, I love all medications that help people, and SSRIs have helped millions

00:15:35.700 of people. But raising serotonin can decrease dopamine, and taking an SSRI alone can often

00:15:45.700 make people feel a little bit blunted, not fully vital to the extent that they're

00:15:57.460 desiring. Now, that seems a little counterintuitive, given at least at the sort of...

00:16:04.880 It's a paradox.

00:16:05.960 It's a paradox.

00:16:06.640 So let's make sure the listener understands why.

00:16:08.620 So we, well, there's so much I want to unpack on this, but if we buy the idea that more

00:16:14.180 serotonin is better, and therefore a drug that inhibits the reuptake of serotonin will

00:16:18.860 leave-

00:16:19.600 Some serotonin is better.

00:16:21.520 Yeah, yeah, yeah.

00:16:22.840 Serotonin syndrome is when there's-

00:16:25.200 Devastating.

00:16:25.840 Yeah, yeah.

00:16:26.280 But in the case of, if the hypothesis is that this person is suffering from depression because

00:16:32.460 they don't have enough serotonin around their neurotransmitters. We're going to give this drug,

00:16:37.120 we're going to inhibit the reuptake of it, we're going to leave more serotonin around.

00:16:41.420 But then you're saying, yeah, but you know what? That also reduces dopamine,

00:16:44.920 and we should maybe talk about why that's the case.

00:16:47.180 And norepinephrine.

00:16:48.720 And norepinephrine, because presumably it's competing for the substrate of the...

00:16:53.400 I mean, they're all monoamines, as you said. So is there a feedback loop? Is that why serotonin...

00:16:58.940 Well, I think there's receptor upregulation, downregulation.

00:17:03.400 It's a multifactorial process.

00:17:06.440 So if you have less dopamine and less norepinephrine, you're going to feel the exact types of symptoms

00:17:13.260 that you might have been seeking the drug in the first place?

00:17:16.800 Not necessarily, but you'll experience the typical patient might experience, if the trial

00:17:24.700 as successful, an alleviation of the target symptoms, let's say anxiety, depression,

00:17:32.360 they might feel less symptomatic and better, but they might feel at the same time, despite

00:17:40.400 feeling better, God, I feel better.

00:17:42.960 I'm glad I'm taking the drug, but I wish I felt a little more oomph.

00:17:48.500 okay so they and of course we didn't even talk about sexual side effects appetitive

00:17:55.940 side effects which are probably very common and we should we should discuss those and

00:18:00.520 you also mentioned anxiety right so a lot of people might not associate ssris with treatment

00:18:08.500 of anxiety do you think that the that the term antidepressant is a bad marketing term for an ssri

00:18:16.080 given the breadth of conditions that it can be useful for?

00:18:19.820 Absolutely.

00:18:21.920 Yeah.

00:18:22.800 And it's actually a class of drugs that is more effective for anxiety than it is for depression.

00:18:30.680 Not to say that it's not effective for a lot of depression.

00:18:34.460 It was actually a sort of—the first SSRI fluoxetine was a—

00:18:41.180 Which is Prozac?

00:18:42.220 Yes, exactly.

00:18:43.160 generic Prozac, developed by Eli Lilly in a targeted way to block the serotonin reuptake

00:18:49.840 pump. And they succeeded, and it's very targeted at that. Not all SSRIs are pure SSRIs. For example,

00:19:01.540 sertraline, generic Zoloft, also blocks dopamine. It's also a mild dopamine reuptake inhibitor.

00:19:11.160 So they have some so-called secondary pharmacologic properties in certain cases.

00:19:18.680 So when you think about then the differences between a drug that gets formally labeled

00:19:23.300 an SSRI versus a drug that gets formally labeled an SNRI, it's really just a continuum because

00:19:30.640 they can, it's basically saying like, I mean, I'm being a little bit cheeky, but if on a scale of

00:19:36.480 1 to 10, you're a 10 out of 10 on serotonin and a 3 out of 10 on norepinephrine and a 4 out of 10

00:19:42.940 on norepinephrine. At some point we just say, oh, well, we're going to start classifying you as an

00:19:46.360 SNRI. That's true. I think it's underappreciated. There are certain more pure SSRIs. So it sounds

00:19:53.780 like Prozac was a very pure SSRI. Perhaps. Generic Lexapro,

00:20:00.240 So escitalopram might be the best example, from my understanding right now, of a pure SSRI.

00:20:08.880 Serotonin reuptake blocker without any secondary pharmacologic properties to my knowledge.

00:20:15.320 Well, I'd like to ask you a little bit about that because Lexapro seems to be a drug that

00:20:20.020 I've seen a lot of use.

00:20:23.940 It's a drug that a lot of non-psychiatrists are very comfortable prescribing, which I

00:20:28.380 thing speaks to its relative safety and ease of use. It's a drug that, as far as I can tell,

00:20:34.540 really is administered at only two doses typically, 10 and 20 milligrams. Although I guess you could

00:20:39.040 cut the 10 in half and start at five, but those seem to be the two doses. The other thing I've

00:20:43.320 noticed is it seems to be a drug that's often prescribed not for depression, but rather for

00:20:50.220 almost like rumination or... OCD? Yeah. Yeah. A little bit of OCD. That's an anxiety disorder.

00:21:00.080 Yes. So you're saying it's more in the anxiety cluster than depressive?

00:21:03.460 No. No. It works for both. So it was developed really for what we now call dysthymic disorder,

00:21:10.060 which is different. Which really I do think of as depressive. I mean, dysthymia and anhedonia

00:21:14.140 seem to be really core parts of depression, right? They're different though. Yes.

00:21:19.500 Dysthymia is a chronic low-grade depressive tendency, as opposed to a major depressive

00:21:29.220 episode. So major depression has a bigger amplitude, but typically a lower frequency.

00:21:38.920 Dysthymia is a chronic tendency, if you were to draw a graph of it, where the mood would be below

00:21:45.700 the baseline to a degree that takes a toll on the quality of life of the person who has it.

00:21:52.140 And the goal of the medication is to elevate that toward the mean.

00:21:59.620 And it's interesting that something as describable as dysthymia responds to purely more serotonin

00:22:09.420 without necessarily more, and if anything, less dopamine and norepinephrine if presumably

00:22:15.080 there's a compensation and they go down? Not necessarily, but the side effect profile

00:22:20.540 tends to be better. So remember, when fluoxetine came out, the first SSRI, really the first of

00:22:28.620 the next generation of anti-anxiety, antidepressants, to call them dual intended

00:22:37.540 targets. So it isn't that SSRIs are unique in helping dysthymia, but when they were invented,

00:22:49.260 the existing medications on the market, the tricyclic antidepressants, had typically much

00:22:57.180 more severe side effects, much more severe, and were dangerous in overdose. So they were potentially

00:23:03.960 lethal in overdose. And they had side effects like anticholinergic side effects, but to a

00:23:11.960 severe degree that affected, that gave people terrible constipation, dry mouth, orthostatic

00:23:19.080 hypotension, a host of symptoms that was problematic. And so that class was problematic.

00:23:27.140 like MAO inhibitors, another potentially dangerous drug, if combined with a food containing

00:23:35.080 tyramine, the so-called like the cheese reaction. So people had to be on diets,

00:23:43.540 monitoring their intake of tyramine-containing foods. And it was very anxiety-provoking for

00:23:50.880 those patients. Ironically, let's say someone with anxiety or panic disorder, who's taking

00:23:55.940 medication that they know can give them a hypertensive crisis. So that was the backdrop

00:24:01.720 from which SSRIs came. And SSRIs are really remarkably benign from a side effect profile

00:24:09.600 compared to those older classes of drugs. And then the SNRIs, which I was starting to allude to,

00:24:17.760 if you want me to pivot to that, they're balanced between serotonin and norepinephrine. And the

00:24:25.520 major ones are venlafaxine and desvenlafaxine, Cymbalta and Pristique. Yeah. And those can be

00:24:37.220 very effective and potentially less likely to cause the cognitive dulling or affective blunting

00:24:45.640 that people sometimes get with SSRIs or the cognitive exacerbation, let's say, of an underlying

00:24:54.240 subclinical or full-blown clinical diagnosis of ADHD.

00:25:01.200 So when would an SNRI, which again, you always think the newer the drug, the better it is,

00:25:08.440 but when would you turn to an SSRI over an SNRI?

00:25:14.040 I would turn to an SSRI if I wanted to max out the serotonergic component.

00:25:21.120 And, for example, OCD is a condition that responds better to aggressive serotonergic

00:25:30.160 modulation, or I shouldn't use that word because later I'm going to use a different vocabulary to

00:25:38.500 describe it, but signal amplification. You really want to turn up that serotonin signal

00:25:45.020 with OCD, and also with PTSD. You want to turn it up. And these are generalizations.

00:25:54.440 You know, every one is different. But as a generalization, I would say that's the case

00:26:00.120 from my experience. So help me think about how you evaluate a patient that's coming to you

00:26:08.480 for a given condition. And we can even just broadly pick several conditions. We could start

00:26:13.800 with bipolar because that's obviously very complicated and it's something that I know

00:26:17.340 you have a lot of experience with. So how often is it that a person is coming to you for the first

00:26:22.500 presentation of bipolar disorder rather than someone who's coming to you because they've

00:26:28.100 been recalcitrant to lots of therapy and they're sort of winding up seeing you as sort of a last

00:26:33.940 resort hope? The interesting thing, Peter, if they're coming to me for bipolar, most of the

00:26:40.460 time they don't know they have bipolar. Okay. So you're the one that's sort of

00:26:44.100 creating the framework around this. Yeah. I'm the one who's throwing out that hypothesis.

00:26:51.320 Okay. So tell me about what a person, again, it's hard to pick an average, but pick, you know,

00:26:59.140 sort of use your experience. Well, let me put it a different way, if that's okay. Typically,

00:27:05.180 unless I have a patient in crisis where I'm worried about their safety or self-harm or harm

00:27:12.500 to others, someone who's in an extreme radical situation where I have to focus on safety and

00:27:20.660 protection, I really don't approach a consultation that differently for all patients. It all starts

00:27:30.680 with how can I be of help? What are you thinking about in terms of talking with me and trying to

00:27:39.220 feel better? And that's always the starting point. And I let the patient lead me to the problem.

00:27:48.820 So a person with undiagnosed bipolar will typically voice what concerns? Are they more

00:27:56.660 troubled by the manic symptoms? Are they more troubled by the depressive symptoms?

00:28:00.460 Well, in the population I see, they're more troubled by depression. And the type of bipolar

00:28:10.060 we're alluding to is so-called bipolar 2. Bipolar, much more common form of it, where the manic part

00:28:21.520 is not a true full-blown mania. It's so-called hypomania. And that can be very adaptive.

00:28:27.000 As a matter of fact, I would say maybe over the course of my career, maybe a third

00:28:33.260 of my patient population have been incredibly successful people who've used their hypomanic

00:28:42.040 drive to achieve remarkable things. And so it can be very adaptive.

00:28:48.700 But when they get depressed, they respond differently to antidepressants than someone

00:28:56.140 who has non-bipolar depression. So unipolar depression, which is non-bipolar depression,

00:29:04.100 and bipolar depression have different pharmacologic response profiles.

00:29:12.820 Can you say more about how they differ and what the implication is?

00:29:15.700 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.

00:29:35.260 They could become hypomanic in an unpleasant way, agitated, have trouble sleeping, have racing thoughts, a variety of symptoms, or they could have a mixed state, a combination of depression.

00:29:51.080 That's very common. A combination of depressive symptoms, feeling sad, potentially hopeless,

00:30:01.560 but also having feelings of agitation, physically feeling agitated and disconcerted.

00:30:10.860 And you're saying that if you fail to make the diagnosis of unipolar versus bipolar,

00:30:17.280 and you prescribe the same drug, and the first line might be an SSRI.

00:30:23.260 Well, there are ways to circumvent that. If you ask the right questions,

00:30:29.020 you're less likely to prescribe the wrong drug.

00:30:32.920 And what would be the wrong drug for the bipolar that might be the right drug for the unipolar?

00:30:39.420 Sure. The wrong drug would be, I would say, any antidepressant instead of a mood stabilizer.

00:30:47.280 like lamotrigine. I see. Because lamotrigine, sorry to interrupt, lamotrigine can be very

00:30:54.360 effective about treating depression. People think of bipolar drugs as treating the elevated moods,

00:31:03.860 but lithium and lamotrigine, for example, can be very effective at treating depression with

00:31:12.960 monotherapy for many patients. And that's lamictal, I assume?

00:31:18.540 Yeah. Yeah.

00:31:19.380 What's the mechanism of that drug?

00:31:21.820 I think it changes sodium channels.

00:31:25.120 Okay. And do we know why lithium works?

00:31:28.700 I don't believe so.

00:31:31.180 Okay. So lithium monotherapy or lamictal in monotherapy is not just given to manage

00:31:39.420 the mania, but you're saying it can also improve the depression.

00:31:44.060 Well, it's the correct way to initiate pharmacotherapy with someone with bipolar depression.

00:31:50.940 So sometimes it proves to be successful as monotherapy. Sometimes combination pharmacotherapy

00:31:59.660 is required, and you have to consider adding on, for example, an antidepressant. But they have the...

00:32:07.500 But you have to stabilize them first.

00:32:08.880 Exactly. And it has the ceiling effects for certain drugs and the floor effects. So it's less likely that adding an antidepressant will make them more depressed or hypomanic or put them into a mixed state.

00:32:25.320 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?

00:32:39.580 Well, irritability is such a huge category.

00:32:45.880 And a lot of people with depression have a lot of irritability.

00:32:51.700 So irritability can be part of a classic dysthymic disorder presentation.

00:32:58.420 Irritability, pessimism, sadness, a lack of optimism, a lack of planning forward.

00:33:12.300 Those can all be part of dyslemic disorder.

00:33:16.640 So irritability can exist in that context.

00:33:20.080 In a bipolar context, it can be more dramatic.

00:33:23.600 I would say the word would be volatility.

00:33:27.420 as opposed to irritability, that might be more descriptive of a typical

00:33:33.860 patient with untreated or poorly treated bipolar disorder.

00:33:41.280 When you think about the world we live in today, and you imagine a time machine that were to take

00:33:46.100 you back in time 10,000 years, do you think we would still see the same prevalence of depression?

00:33:53.860 I'm not going to focus on anxiety because I think the answer is we'd see a lot less anxiety.

00:33:58.880 I don't have enough insight into bipolar to comment, but I want to focus specifically on

00:34:03.020 depression. How much of depression do you think is purely biological and how much of it do you

00:34:08.160 think is environmental? Well, it's hard to know. I would say there are probably evolutionary reasons

00:34:17.680 that the genes have survived. And so if you think of diurnal variation, change of mood over the

00:34:26.260 course of the day, and hypersomnia, excessive sleep, that might have been conserved evolutionarily

00:34:34.560 because people stayed in their caves longer hours and only came out during the fewer daylight hours

00:34:43.560 where there was more opportunity for mating, for acquisition of resources, food, obviously,

00:34:51.640 and whatever other resources were sought for, and sought refuge in their caves or dwellings

00:35:02.020 in a protective way so that their survival was likely to be enhanced.

00:35:09.120 so where do you think from an evolutionary perspective depression specifically or let's

00:35:21.120 just say dysthymia or anhedonia where do you think those would have been evolutionarily

00:35:27.120 protective because i can sort of see anxiety having an evolutionary benefit for sure that

00:35:32.120 makes a ton of sense yeah i can clearly see why hypomania could have an enormous evolutionary

00:35:36.740 benefit. I'm not saying I don't agree that the others could. I'm trying to think through the

00:35:41.960 cases. Yeah. Well, it's very interesting. Specifically, I alluded to the theory of

00:35:53.620 depression as being protective. Anxiety can be protective, but it can also be disadvantageous.

00:36:03.620 people's judgment can be impaired when they're anxious or when they're panicked, let's say.

00:36:09.400 If someone is having a panic attack, instead of undergoing a life-protective behavior,

00:36:17.920 they could be undergoing a foolish, impulsive behavior driven by their anxiety rather than

00:36:24.720 a more objectively based appraisal of the dangers of the environment that they might

00:36:31.360 be unnecessarily encountering.

00:36:33.620 So yeah, I guess what I'm trying to understand is there are so many things that we can clearly

00:36:44.620 say are pathology, even if natural selection had no point of view on them. So I'll give you an

00:36:50.220 example. So atherosclerosis. I don't think natural selection and evolution care to lick about it

00:36:55.920 because it's a disease that doesn't really take hold until you're long past your reproductive age.

00:37:02.020 and it just wasn't within the purview of it. So we've sort of created a luxury problem for

00:37:08.760 ourselves, which is we've... Or that might have even been adaptive.

00:37:13.920 Well, so that's an interesting question, right? How would it... I mean, I will tell you what part

00:37:17.860 of atherosclerosis was adaptive. The fact that we are humans and we are one of the few species

00:37:23.700 that can experience atherosclerosis, I will tell you the adaptive part of that is we are the ones

00:37:29.600 that carry the ApoB lipoprotein. And that's the thing that's causing atherosclerosis. But that's

00:37:35.380 the thing that allowed us to have so much cholesterol to feed our huge brains in an

00:37:41.280 environment where nutrients were scarce. So I can make the case that having LDL particles allowed

00:37:48.740 us to have tons of cholesterol, even if we were starving. And that allowed us to never compromise

00:37:54.240 our growth, including our brains. But now that we live in an environment where nutrients are

00:38:01.140 plentiful, it's not serving us so well anymore and we get atherosclerosis.

00:38:06.180 Is there kind of a case that can be made that says either we are pathologizing depression

00:38:12.540 and in reality, again, I can't imagine any person likes feeling, I've experienced anhedonia,

00:38:20.560 I've experienced dysthymia, I know what those things feel like. They feel horrible.

00:38:24.120 But is that, I hate to ask the dumb question, is that a bad thing?

00:38:28.440 Is there a time and a place for experiencing those things so we can appreciate it when

00:38:32.560 we don't feel those things?

00:38:33.640 Let's take anhedonia out of it because that's a misunderstood concept.

00:38:40.640 But I would say depression is bad.

00:38:43.720 It takes a huge toll on people.

00:38:46.160 It can be lethal.

00:38:47.360 it can it definitely increases the risk factors for a lot of medical problems and

00:38:56.180 in that sense it's very adaptive from a psychological point of view it can lead to

00:39:01.740 a radical reappraisal of one's priorities and priors to get to a probabilistic model of thinking

00:39:12.060 It can serve almost as a giant shakeup of one's previous model of the world and their place in it.

00:39:23.960 So it can ultimately serve a purpose.

00:39:28.060 But I wouldn't want someone to have to suffer like that to achieve that goal.

00:39:33.700 There are better ways of getting there than getting there through depression.

00:39:38.620 Depression is not a good thing.

00:39:40.800 We're talking about clinical depression.

00:39:42.420 We're not talking about the depression of everyday life.

00:39:46.000 That's a good thing.

00:39:47.660 Okay.

00:39:47.900 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?

00:39:59.720 That's one of those questions I could speculate about.

00:40:03.380 But, you know, Peter, when I look at our world today and our children and the kind of world they're facing, they're facing enormous challenges existentially.

00:40:22.940 What role am I going to have?

00:40:24.900 Artificial intelligence is evolving.

00:40:27.160 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 it in certain areas, then how can I flourish?

00:40:49.140 But let's go back in time 10 years when nobody was thinking about that other than a few people.

00:40:53.560 Okay.

00:40:53.780 Wasn't the prevalence of major depression a decade ago comparable to today?

00:40:58.420 And would that still have been significantly higher than it was thousands of years ago?

00:41:01.760 I think it's going up because there are multiple simultaneous challenges.

00:41:08.440 There's a lot of environmental anxiety.

00:41:13.120 We see a lot of increased challenges to the environment, fires in the summer, fires even

00:41:22.600 in the winter.

00:41:23.780 in certain places in the cold. But again, when I think about those things,

00:41:28.080 and I'm not disputing that those things are happening, but contrast that with how miserable

00:41:33.340 it must have been. Just imagine what it was like to be alive 1,000 years ago. Wouldn't you rather

00:41:39.380 be the least wealthy person in the United States today than the King of England 1,000 years ago?

00:41:47.140 You know, it's very complicated. I'm just saying, for as lousy,

00:41:53.060 and we can talk about all the things that make the world a lousy place today. It's still

00:41:57.360 infinitely better than it was just a thousand years ago. From a bourgeois point of view,

00:42:02.160 yes. But from a relational point of view- Well, so that's exactly where I'm trying to go with

00:42:08.220 this, which is what are the factors? The word environmental trigger, I think, is preventing

00:42:16.780 me from really getting at the question. Yeah, I think I was premature.

00:42:19.320 Well, no, no, no. I'm just saying I'm genuinely curious as to what do we think is the causal relationship between mental health deteriorating and the world we inhabit?

00:42:34.240 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.

00:43:04.240 and therefore isolated as a result. And people are having less sex. People are having fewer

00:43:12.880 romantic relationships. People are using online pornography more in the absence of

00:43:19.420 relationships. Fertility rates are going down. Reproductive rates are going down.

00:43:26.060 there's this great divide socioeconomically that i think is having an outsized role too

00:43:34.260 so when the king was the king of england 10 000 years ago well you know whatever time frame

00:43:43.420 you were alluding to one thousand one thousand that's a more historically accurate but thank

00:43:49.800 you. Thanks for correcting that. Probably everybody else didn't know anything different.

00:44:00.600 And if there was better, they just accepted that's how it was. They weren't going to be

00:44:07.060 kings. They lived in the moment more. They accepted the realities such as they were,

00:44:15.560 perhaps. Again, this is all hypothetical. And so that enabled them to live more in the moment,

00:44:24.380 just like older people, people who are close to the end of life without being ill, are able to

00:44:31.500 enjoy the moment more, appreciate the moment more. So I think that the great divide socioeconomically

00:44:41.280 has created a lot of anxiety and demoralization. And when people have low

00:44:48.320 adaptive capacity and low vulnerability thresholds for mental illness, that's when it starts to

00:44:55.900 emerge. Yeah, that makes sense to me. It makes sense to me that the relational component,

00:45:04.940 the comparing component, the digital component, these things must be contributing.

00:45:12.260 And in addition to everything you've said, and I've brought this up before on the podcast,

00:45:16.520 I had a guest on many years ago. His name is Tom Katena. He's a physician who's a missionary in

00:45:23.120 the Nuba Mountains of Sudan. And so he takes care of 1 million people there that are without any

00:45:29.080 healthcare. And these are people that are particularly being targeted by their government.

00:45:32.580 So they're literally being killed by their own government. And so they're being bombed and he's

00:45:38.460 taking shrapnel out of their wounds in this hospital by himself with a couple of nurses.

00:45:43.660 Remarkable.

00:45:44.660 Unbelievable. And I asked him, and I can't remember if I asked him this on the podcast or just when we

00:45:50.200 were together having dinner at some point, but I said, you know, Tom, what's the prevalence of

00:45:54.000 depression there? And he said, like, none. Like, there is no depression. You know, tight-knit

00:46:01.560 families, common purpose. Yes, it's scary. When the airplanes come over, they all have to dive

00:46:07.740 into a ditch. But basically, other than that, they're farming, they're doing their thing,

00:46:13.820 and they don't know better is part of what it is. I'm not suggesting that we want that,

00:46:21.880 that that needs to stop. But there's a price we pay for modernity, and I wonder if this is the

00:46:29.180 price. Very complicated. War seems to improve people's mental health, ironically, with obviously

00:46:36.880 dramatic exceptions for PTSD and other laws. But to say it's the price we pay for modernity,

00:46:47.300 if you want to accept modernity as it is without challenging it, yes. But a lot of people are

00:46:59.220 challenging modernity in, let's say, looking for alternative approaches such as living more

00:47:09.580 in nature would be a great example of that. And getting off the grid would be an example.

00:47:15.480 When I say this is the price you pay for modernity, I think what I would say after that is

00:47:23.840 unless you start to take individual measures to control some of this. So again, we have to make

00:47:30.480 a greater effort to be outdoors today. I think there's tremendous benefit to our mental and

00:47:35.160 emotional health in being outdoors, but it's no longer the default. You see, we used to live

00:47:39.720 outdoors. Now we don't. So if you want to be outdoors anymore, you have to actually take the

00:47:43.760 steps and do it. It's much easier to live in isolation today. 10,000 years ago, it was

00:47:49.240 metaphysically impossible to live in isolation. You would have died very quickly. Today,

00:47:53.840 You could live in isolation all you wanted.

00:47:56.160 So if your tendency is to isolate,

00:47:57.980 you actually have to work to overcome that.

00:48:00.580 Similarly, it's very easy today to see everything,

00:48:04.260 to be overrun by information.

00:48:06.720 If that's contributing to your mental health,

00:48:09.480 you actually now have to take a deliberate step

00:48:11.500 to pull away from media if that's part of the problem

00:48:14.920 or whatever it is.

00:48:15.840 So I'll give you an example.

00:48:18.620 I did a podcast recently on sleep.

00:48:20.960 And the way I sort of framed it was,

00:48:23.840 Without having great evidence for this, but looking at sort of some of the literature on

00:48:28.040 hunter-gatherers, there's no evidence that hunter-gatherers suffered from insomnia.

00:48:32.800 They didn't necessarily sleep eight hours a night. There's some evidence that they slept in

00:48:36.800 sort of shorter windows. But the point is, they weren't walking around, struggling to fall asleep,

00:48:42.960 waking up, ruminating, and suffering from a lot of the things that people suffer from today.

00:48:47.920 And without rehashing the entirety of the podcast, I basically made the case that, look,

00:48:52.180 it was really down to the things that drive sleep, circadian rhythm, adenosine, cortisol,

00:48:58.020 all of these things have to be in sync for you to sleep. And the world back then allowed those

00:49:04.020 things to be in sync. Fast forward to today, we've engineered a world that works against those

00:49:10.480 things. It works against the rise and fall of cortisol, the rise and fall of adenosine,

00:49:16.200 the rise and fall of melatonin, all of those things are being countered by our environment.

00:49:22.540 Agreed.

00:49:23.020 And so if you want to be able to sleep really, really well in the modern world,

00:49:27.820 you have to do things that might feel unnatural, meaning you have to disconnect from your phone.

00:49:33.160 You have to auto-correct the light in your environment. You have to force yourself-

00:49:38.040 They're anti-normative.

00:49:39.020 Exactly. They're anti-normative. That's a great way to say it. So all of that is to say,

00:49:42.860 It seems to me that the entire field of psychiatry, or at least part of it, could be viewed as an anti-normative response to a modern world, at least when it comes to certain things like anxiety and depression.

00:49:54.500 Yeah. And it's interesting, you bring up sleep. I think all the foundational biological factors,

00:50:02.560 so in my model of endocrinology, certainly hormones and the endocrine system are part of it,

00:50:12.000 but also inflammation, metabolism, and stress circuitry, in addition to circadian biology

00:50:21.580 and sleep architecture, all those factors are challenged by modernity. If we want to look at

00:50:28.320 metabolism, diets and people weren't needing to go on GLP-1s a thousand years ago, maybe unless

00:50:37.660 they were the king. That's right. We know the king had gout, but we don't know if anybody else

00:50:42.360 did. You raise a great point, and I've discussed this also on the podcast in the past, this mental

00:50:49.020 model of distress tolerance. And I wrote about this actually in my book, which was,

00:50:54.400 this is the model that I use. It's how I think about my life. So when I'm irritable, which let's

00:51:00.300 be honest, I can be quite irritable. I'm imagining kind of a window in which I occupy. And the window

00:51:08.620 is my distress tolerance window. When that window is wide open, I can tolerate a lot. I can take a

00:51:15.340 lot of bullets and I'm fine. Yeah. When that window is narrow, even the littlest thing will

00:51:21.400 sort of irk me. If my kid does this or if my wife says this or an employee says this, I'll be

00:51:27.200 irritable. Okay. So then I ask the question, what determines the width of my window? And what's

00:51:34.500 amazing but obvious is what you just said. Your biology plays such a role in that window. Yeah.

00:51:42.900 If I exercised or didn't exercise, that's an enormous contributor to the width of my window.

00:51:48.620 Oh, yeah.

00:51:49.280 If I had a good night's sleep versus a bad night's sleep, huge contributor.

00:51:54.060 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.

00:52:05.100 Death by a thousand cuts.

00:52:06.540 And I didn't think anything of it, but as I found myself irritable two weeks into this,

00:52:11.460 someone said, untreated pain is going to make you irritable. I could rattle off all the things

00:52:18.160 that do it. But everybody, I think, has to kind of discover what creates, what lengthens their

00:52:23.320 window. And do you get the impression- Yes and no. I mean, it's part of the human condition

00:52:28.380 that we all have these foundational biological factors and we have an adaptive capacity.

00:52:36.540 and that's always changing over time how much of that is part of psychiatry like you obviously you

00:52:42.060 as a psychiatrist are attuned to that but do you do you get the impression that that should be part

00:52:46.780 of the foundational treatment which is yes i know that you're depressed i know that your anxiety is

00:52:51.020 this way or the other way i know that you're irritable but are we looking at your nutrition

00:52:55.660 are we looking at how much you exercise are we trying to regulate your sleep and are we actually

00:52:59.660 treating some of those underlying foundations as well well i think a lot of psychiatrists are

00:53:04.700 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.

00:53:24.640 And I think most psychiatrists try hard to touch upon those things.

00:53:31.900 So I'd be careful to say anybody wasn't doing it adequately to generalize.

00:53:40.840 But I think we have to have a framework about how to think about it, that the brain doesn't operate in isolation.

00:53:50.420 And it's part of this larger system with bidirectional feedback.

00:53:54.020 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.

00:54:15.600 You're producing less BDNF, which is critical for neuroplasticity.

00:54:22.120 So on many different levels, there are these continuous bi-directional interactions between what happens on a neurotransmitter level and what happens with the foundational biological factors.

00:54:37.760 I just chose endocrinology as the one I wanted to focus on because it fascinated me particularly.

00:54:45.480 Well, that's great because that's exactly where I kind of wanted to go.

00:54:48.620 let's go back in time five years ago when this interest of yours started. Why did you pick

00:54:55.300 endocrinology and how did you dip your toe in that water? Yeah. Well, I was always interested

00:55:00.140 in endocrinology and I have some friends, colleagues who are endocrinologists, but I was

00:55:06.440 really struck by the impact of the interpretation and the reinterpretation of the Women's Health

00:55:14.720 Initiative and how that changed prescribing practices so profoundly in general medicine,

00:55:21.600 it led me to think, well, if that happened in general medicine, how is it affecting the

00:55:26.840 appreciation of endocrinology in psychiatry? And I concluded that endocrinology, from my

00:55:36.320 perspective tends to be, at least by me, previous to that, was significantly underappreciated in

00:55:46.180 psychiatry. And that there are a number of reasons for that. But that was something I wanted to

00:55:54.900 roll my sleeves up and get into. So I sort of went back to school, so to speak. I took

00:56:01.920 a course in bioidentical hormone replacement therapy. I got certified as an advanced practitioner

00:56:08.660 of BHRT, which just opened a window, and I did a number of other educational activities

00:56:15.440 to learn more about it. And I found it to be fascinating, particularly how I feel the

00:56:25.820 neural circuits and neurotransmitters are really inseparable from the endocrine system.

00:56:34.440 So I want to go back to something you said. You've talked about the WHI.

00:56:37.640 Your career has spanned pre and post-WHI. So 25 years ago, you got to witness the complete

00:56:45.640 reduction in the prescription of estrogen for women during menopause. What was the impact you

00:56:53.800 saw in your practice as you saw women go from receiving hormones at the time of menopause to

00:57:01.840 women being deprived of hormones? Variable. Variable. And it was so long ago and I was so

00:57:13.420 relatively ignorant as to where I am now that I'd be hesitant to make any generalizations about it.

00:57:21.380 But you brought it up as, hey, five years ago, which means you're 20 years post-WHI. It was still kind of clearly there was still something there that made you think about it.

00:57:31.320 impact on me. I had the impression that people, again, getting back to adaptive capacity, that

00:57:38.460 women whose adaptive capacities were higher, their ability to self-regulate and adjust to

00:57:44.760 internal and external threats and changes was being eroded off of estradiol.

00:57:54.400 And similarly, for both sexes, that men who needed testosterone weren't getting it,

00:58:04.820 were being told it wasn't safe, similarly had an erosion of their function across multiple domains.

00:58:15.200 So I don't think there's a way that we can dive into this, Linus,

00:58:19.400 without you explaining some of the biology of how estradiol and testosterone and maybe even

00:58:25.660 progesterone or levofibroxine, like all of these things. Yeah. Let's start with estradiol. I mean,

00:58:31.900 I share your point of view. I feel very strongly that estradiol is one of the most important

00:58:38.900 hormones in the brain, both for men and women. So maybe walk us through kind of some of the

00:58:47.560 reasons why that's the case? Because it probably isn't intuitive to everybody.

00:58:51.560 Definitely not. It wasn't to me. So in preparing for the podcast, I came up with a mouthful,

00:58:57.500 but estradiol is a constitutive, pleiotropic, multi-system regulator of neurotransmitters

00:59:07.700 and neural circuits. So constitutive, what does that mean? It means part of the architecture

00:59:15.140 evolved. Hormones were evolved by the brain for the brain. So there's no separation of

00:59:22.800 the endocrine system and the brain at that level. Pleotropic, it has multiple actions

00:59:30.360 at multiple levels throughout neurotransmission. So for example, estradiol modulates not only

00:59:40.480 serotonergic transmission profoundly, but also the dopamine system, the GABA system,

00:59:47.960 acetylcholine, NMDA, and glutamate. So it's really profound. And it serves a regulatory

00:59:58.900 function. While psychotropics are signal amplifiers, estradiol, for example,

01:00:07.740 is a system modulator. It creates the conditions within which neurotransmission occurs.

01:00:19.020 Do we know how these hormones are regulated in the brain? We have a pretty good sense of how

01:00:24.520 they're regulated in the periphery. We understand the feedback loops. It's actually hard to

01:00:30.580 disentangle them because, quite frankly, it's the pituitary gland that does so much of the

01:00:34.520 regulation in the periphery through luteinizing hormone and follicle-simulating hormone.

01:00:39.500 How is that happening in the brain?

01:00:40.720 Well, it's the HPG axis, the hypothalamic-pituitary-gonadal axis,

01:00:46.940 and all the bidirectional feedback that occurs within that framework.

01:00:54.060 In other words, is there actual estradiol in a synapse, or is it removed from that given its

01:01:00.520 size and it's regulating upstream of the actual synaptic contents between where the actual

01:01:08.480 neurotransmitters live? No. There are receptors for it on the membranes of neurons. So they're

01:01:17.820 well-characterized. There's membrane estrogen receptor alpha and membrane estrogen receptor

01:01:24.580 beta. And there are also transcriptional binding sites, estrogen response elements within our

01:01:33.280 genomes. So estrogen is penetrating to the deepest level of our central nervous system

01:01:40.960 where transcription is regulated. And that, for example, is how serotonin synthesis is upgraded

01:01:50.360 through tryptophan hydroxylase. There are specific estrogen response elements that bind to promoting

01:01:58.200 factors for tryptophan hydroxylase, therefore increasing serotonin. The same thing for dopamine

01:02:06.020 through tyrosine hydroxylase. The same thing for acetylcholine through choline acetyltransferase.

01:02:14.580 So it's right there. It's at ground zero of neuronal activity, which is fascinating.

01:02:23.520 And that's part of why I find the whole thing just so remarkable, that it's embedded within the brain.

01:02:32.940 I had another term that I was searching for, imbued with and embedded within the brain is how I think about it.

01:02:41.900 And so let's now talk about the removal of that. So everything you said kind of explains

01:02:50.300 the biology of what estrogen is doing. But now let's characterize the phenotype.

01:02:55.720 So if estrogen is reduced, all other things being equal, how does the brain experience that?

01:03:05.520 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.

01:03:34.020 So therefore, this pleiotropic role has been evolutionarily very adaptive, that one hormone has these multi-system effects.

01:03:48.460 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.

01:04:05.900 And why do you think it is so variable, Linus?

01:04:08.780 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, and there are other women who barely notice it.

01:04:29.360 Is it receptor density?

01:04:32.280 Is there some other sensitivity?

01:04:34.080 It's a combination of genetics for receptor morphology and function. But rather than absolute

01:04:44.560 levels being determinative of psychopathology or emotional variability in response to

01:04:54.260 change in estradiol levels, it's more the actual change and fluctuations and oscillations

01:05:02.940 of those levels themselves. That's why PMDD is what it is, because allopregnanolone levels,

01:05:12.640 a derivative of progesterone, go down significantly toward the end of the luteal phase.

01:05:21.200 And therefore, there are some women, due to a variety of reasons, it's all biological. It has

01:05:28.520 to do with receptor morphology, genetic influences, possible environment influences

01:05:35.760 that have degraded their receptor modulation and responsivity. Some women are susceptible

01:05:43.640 to a much greater degree. You know, you use the example of, I have a toothache and I have an

01:05:53.020 exercise and I'm feeling, you know, irritable as hell. Well, the same thing applies to all of us.

01:05:59.100 We have different adaptive capacities. So a woman who's sleeping well, who has good social supports,

01:06:07.000 who doesn't have huge caregiving burdens that are overwhelming, who doesn't have occupational

01:06:13.000 stressors that are overwhelming, who has meaning and purpose in her life, she's more likely to have

01:06:19.760 a higher adaptive capacity in general to menopausal changes. I'm not talking about

01:06:26.360 PMDD now, going back to menopause. She's likely to have the bandwidth to withstand it than a woman

01:06:34.960 who's incredibly burdened at work with terrible stress, who has huge caregiving burdens, let's say

01:06:42.880 for a parent with Alzheimer's or the primary caregiver and that parent is living at home,

01:06:49.720 someone who's metabolically challenged, overweight, not exercising. So all these

01:06:56.500 factors play a role as well as medical illness as a generalization. And then, of course, it's

01:07:02.980 complicated because a lot of times the loss of hormone makes it difficult to regulate

01:07:08.460 metabolic health makes it difficult to have the motivation. It's a very vicious cycle and it

01:07:13.740 amplifies the problem. Absolutely. Can you say anything about this in men? Because again,

01:07:18.560 I think this is counterintuitive, but I don't think men are particularly less susceptible to

01:07:24.440 this, both testosterone and estradiol. Yeah. Well, let's start. Let me just say

01:07:29.180 men get their estradiol from testosterone, from the aromatization of testosterone. So testosterone

01:07:37.660 is a pro-drug for estradiol as well as, of course, being a primary drug for all the obvious reasons.

01:07:44.780 But as a primary hormone, testosterone modulates—there's a lot of system redundancy. So

01:07:55.220 testosterone modulates dopamine, in particular, to a high degree. So losses in testosterone in men

01:08:04.940 are much more typically, not always, typically andropause, which is the male version of

01:08:12.700 menopause that some of the audience may not be familiar with the terminology. Andropause is more

01:08:19.800 gradual and insidious and less likely as a result to be identified. But it can present with a sense

01:08:27.620 of dulling, a loss of the dopamine-mediated functions. So the mesolimbic and mesocortical

01:08:37.460 functions, those are two pathways of the dopamine system. The mesolimbic has to do with reward

01:08:43.760 salience, what goals are worth pursuing, and reward prediction. If I pursue this, how likely

01:08:52.120 am I to get it? And the mesocortical system has to do with executive function, working memory,

01:09:01.680 all the symptoms that are impaired in someone who has ADHD. So you can have like so-called

01:09:09.020 subclinical syndromes of cognitive dysfunction and ADHD-like symptoms in men with declining

01:09:18.560 testosterone in addition to the androgen-based, generally more vital, physically active

01:09:27.560 and libido-enhancing effects of testosterone. And how much of that do you think women are also

01:09:35.660 dependent on in terms of their testosterone? Yeah. Well, I think libido is a huge one.

01:09:41.600 that women are almost entirely dependent on testosterone for libido.

01:09:50.980 What about mood, sleep, or some of the other things where men receive a benefit?

01:09:56.720 Less so.

01:09:57.500 Men are more vulnerable in that department.

01:10:01.380 Why do you think that is?

01:10:02.620 To testosterone.

01:10:03.640 Yeah.

01:10:03.900 Why do you think women are less responsive to and or dependent on testosterone for some of those other things?

01:10:09.840 Is it because estrogen over-

01:10:11.000 Evolution.

01:10:11.040 because they make so much less of it.

01:10:13.280 Got it.

01:10:13.940 Although they still make 10 times as much.

01:10:17.340 I was about to say, they still make much more testosterone than estradiol.

01:10:20.180 But compared to men.

01:10:21.260 Yeah.

01:10:21.620 Yeah.

01:10:23.000 Which for the audience, that might be worth your reiterating.

01:10:28.720 Yeah.

01:10:29.340 I think what's always misleading when you look at a laboratory report is the number for estradiol

01:10:35.180 is so much bigger than the number for testosterone in women.

01:10:39.040 Right.

01:10:39.220 But that's because testosterone is reported-

01:10:41.380 In picograms per deciliter, right?

01:10:44.440 Testosterone is reported in nanograms per deciliter.

01:10:46.900 Estradiol is reported in picograms per deciliter.

01:10:49.020 So you have to normalize those because they're off by a factor of 1,000.

01:10:52.600 And when you do that, you realize that a woman's testosterone level is about 10 times higher

01:10:57.840 than her estradiol level, although it's about one-tenth the level of a man.

01:11:02.380 Yeah, yeah.

01:11:03.280 As you no doubt know, there are various ways to increase testosterone in men. The most obvious

01:11:11.680 and direct way is to give a man exogenous testosterone. That's a very safe and effective

01:11:17.460 way to do it. It's also the easiest way to do it. But not all men want to receive testosterone that

01:11:24.620 way. Sometimes they want to indirectly receive testosterone by taking hormones that will tell

01:11:31.820 their body to make more endogenous testosterone. And the two most common ways to do that are

01:11:36.360 giving HCG, which is giving effectively luteinizing hormone, telling the body to make

01:11:42.160 testosterone. And then the other would be using drugs like Clomid or...

01:11:47.200 Clomiphene.

01:11:47.740 Yeah, Clomiphene or Enclomiphene, which basically trick the brain by blocking at the hypothalamus

01:11:54.760 the receptors for estradiol and testosterone such that the pituitary says, oh gosh, we're...

01:12:01.220 We've got to make more of this. We're going to make more LH and FSH. Is there any reason to

01:12:07.840 believe that that approach robs the brain of the very estrogen and testosterone that you're trying

01:12:14.860 to give it? Well, I would say just empirically, men who take chromiphene tend to be dissatisfied.

01:12:26.880 Even though their numbers are high in the periphery, that's been our experience as well.

01:12:33.000 There's a symptom laboratory mismatch.

01:12:34.560 Yes.

01:12:35.240 And I have no data to suggest why, but this has always been the question I've thought.

01:12:41.800 Which is unfortunate because-

01:12:43.520 It's an otherwise very convenient way to replace testosterone.

01:12:46.280 Absolutely.

01:12:47.080 Yeah.

01:12:47.360 Yeah.

01:12:48.100 So, okay.

01:12:48.920 I wondered if that was your experience.

01:12:50.360 Let's mention the primary reason why clomiphene is typically prescribed.

01:12:56.880 And as well as HCG. No, the rationale.

01:13:00.900 Okay. So I think there's three rationales for clomiphene and n-clomiphene.

01:13:05.520 But I think where you're going is you preserve endogenous production when you use either-

01:13:12.400 Well, fertility.

01:13:13.500 Yes. Which of course comes with it. Yeah.

01:13:16.200 So that's a huge part of it. I think even when you consider HCG, which I think is a superior drug

01:13:23.520 to clomiphene and end clomiphene because it's administered peripherally, it acts peripherally,

01:13:29.820 and it doesn't have a central block. But let's be honest, it's injectable. It's a very,

01:13:35.680 very delicate peptide. It's very expensive. It's inconvenient. It's got all those problems.

01:13:41.340 Clomid's cheap. It's oral. And by the way, a lot of people don't know this, it's not regulated.

01:13:46.960 So testosterone and HCG are schedule four. Clomid and clomiphene are not regulated.

01:13:52.840 For now.

01:13:53.700 Yeah. So you don't have to go and see a doctor formally to do it. It can be kind of a jack-in-the-box

01:14:00.080 online thing that can give it to you. But you're correct. The few times we have used it for

01:14:05.960 patients who want to preserve fertility, want to rely on endogenous function, don't want to deal

01:14:11.020 with needles, it really fixes the numbers. It just doesn't seem to fix the symptoms.

01:14:16.560 Yeah. That seems to be the case. Not always. There are some people who take it and

01:14:22.240 do well. But compared to exogenous testosterone, testosterone cypionate injection, for example,

01:14:32.260 dramatically better responses. Yeah. Let's talk a little bit about progesterone.

01:14:38.860 Sure. You've already alluded to it in one very important capacity, which is in the case of a

01:14:44.900 woman who is experiencing a somewhat regular menstrual cycle, you already mentioned that

01:14:49.960 in the second half of the luteal phase. And I guess it's worth... It's sometimes easier if

01:14:54.860 people can picture how the hormones cycle during a woman's cycle. But progesterone is the easiest

01:15:00.520 one, I think, to draw. Because for the first 14 days during the follicular phase, from the moment

01:15:06.880 she has her period until she ovulates, there's nothing. It's flatline. And then it rises as it

01:15:12.100 prepares for implantation. It hits a peak, assuming there is no implantation. And it's important to

01:15:18.580 mention why that is. Because it comes from the corpus luteum, the follicle that is broken,

01:15:26.940 and the lining of that follicle, I believe, is what secretes the progesterone.

01:15:32.380 Right. In preparation for the follicle to be implanted. But once it's not implanted,

01:15:38.020 the lining sheds, which is what the period is. But the point that you're making is,

01:15:43.200 but it's that progesterone that is crashing down. And what I find very interesting is that

01:15:50.260 the woman didn't feel bad when her progesterone level was low, right? Because she felt fine

01:15:58.300 during the follicular phase. No oscillation. Exactly. It's the fall back to low from high

01:16:04.140 that causes the symptoms. This is incredibly fascinating.

01:16:07.420 It is. And one of the most fascinating paradigms in human biology is postpartum,

01:16:14.440 where progesterone goes from all-time highs, and so does estradiol. Estradiol goes from

01:16:21.000 30,000 to, let's say, 30. Progesterone goes from several hundred to less than one

01:16:30.440 within 24 to 48 hours, it's amazing that women do as well as they do. I'm in awe of-

01:16:39.000 In other words, yeah. I just want to make sure the listener knows what you're saying.

01:16:41.640 The more I learn about hormones, the more in awe of women I am.

01:16:44.420 Yeah. You're in awe that more women don't experience postpartum depression.

01:16:48.940 Yeah. But I'm in awe of all women for having to deal with these issues that

01:16:54.800 guys don't have to deal with and how profound they are and how challenging they are.

01:17:00.720 So do you think we understand why, and I know you've talked about it in terms of genetics,

01:17:08.240 receptor density, is there anything else we know about why some women will experience that drop

01:17:13.940 in progesterone over the course of a week and the last part of their cycle and be really debilitated

01:17:20.160 by it, and while some will not notice it. How genetic is it? I assume there's a strong

01:17:26.180 concordance between mother-daughter? I believe it's highly genetic, yes.

01:17:31.260 Do you know how predictive that is of postpartum depression or how predictive that is of cognitive

01:17:38.500 or depressive symptoms during menopause when there's a depletion of both progesterone and

01:17:45.100 estrogen? I'm not sure. I'm not sure. There is a correlation. I'm not sure how high a correlation

01:17:51.840 there is. But I would think there would be a very high prevalence of women who have severe

01:18:03.900 postpartum depression or psychosis who also have PMDD, but not the converse.

01:18:10.840 Yeah, let's talk about postpartum depression. Do you see any women for that in your practice?

01:18:17.620 Yes, only because postpartum depression is a very heterogeneous condition.

01:18:24.740 The most dramatic example of severe postpartum depression and psychosis happens within a week

01:18:32.600 of childbirth. And it usually unfolds in a hospital where a woman goes from a normal

01:18:42.700 frame of mind. And with estradiol levels and progesterone at their peaks, these women are,

01:18:49.860 you know, women in general at the end of pregnancy are primed to be in wonderful moods.

01:18:55.320 And they go from there to having the ones who are afflicted by severe cases of postpartum depression and psychosis start to become suspicious of the hospital personnel, become hypervigilant about where the baby is and have very intense separation anxiety,

01:19:17.700 can have intrusive ideation about harming their own children themselves without wanting to,

01:19:26.020 but having some fear. It's an OCD-like phenomenon that they can have a fear that they can

01:19:32.440 do something that they would never do. And we don't know why this happens to some

01:19:37.280 women. And fortunately, few women- It's being researched. Hopkins has a big program in that.

01:19:43.900 Do you know the prevalence of that severe a level of postpartum depression?

01:19:49.440 Fortunately, less than 1%, much less.

01:19:52.960 So those aren't the women you see, because presumably those are the women that are under

01:19:56.100 care of a psychiatrist within the hospital. You're seeing women who go home, everything seems fine,

01:20:01.380 and presumably over the next few weeks or even months, they just don't get back to themselves?

01:20:06.140 Yeah.

01:20:06.720 Okay. So when a woman like that comes to you, and let's assume she's never seen

01:20:10.540 any psychiatrist before. How do you do the evaluation and how do you think about treating

01:20:14.960 her? I do the evaluation the same way. I ask her what's troubling her. And I have a third year for

01:20:25.400 issues around the existential shift in identity of becoming a mother, either for the first time

01:20:35.700 or subsequent times. It's a profound identity transition, and it affects different women

01:20:42.300 differently. Different women have different levels of support from their spouses, if they have one,

01:20:48.700 from their families, different levels of socioeconomic, really economic support.

01:20:55.540 But what if there's been no change? So what if you have a case where a woman,

01:20:59.180 it's not her first child. So the identity piece hasn't changed. There's nothing obvious you can

01:21:06.320 point to in her personal life from a support network or attention. In other words, does it

01:21:13.280 sometimes just occur almost randomly? Yes, de novo. It does.

01:21:20.220 Okay, let's say you make the diagnosis, which I assume is not impossible to make.

01:21:23.840 Like, what are the treatment?

01:21:26.000 Even for a psychiatrist.

01:21:28.220 What are you thinking about as you start to lay out treatment options?

01:21:33.920 How much do you, and again, maybe I'll just make it a little straightforward and say,

01:21:38.620 let's assume there are no other comorbid conditions that would make the, yeah.

01:21:42.060 Pretty similar to non-postpartum depression.

01:21:47.280 It's only the acute type where there's a synthetic analog of that chemical that the body makes, the hormone, allopregnanolone, called xeranolone, which is now in a pill form.

01:22:03.420 It used to be brexanolone, which was an intravenous infusion given in an ambulatory center where a woman had to stay there for a protracted period of time.

01:22:17.280 think about a woman who's having all these issues and has to be separated from her family and her

01:22:23.040 baby, you know. So fortunately, they came out with an oral form of it. The generic name is

01:22:29.960 xeranolone. And it's a synthetic version of the neurosteroid allopregnanolone, which is the

01:22:38.060 breakdown product of progesterone via five alpha reductase and three alpha hydroxy steroid

01:22:46.980 hydrogenase. So would you give that as monotherapy or do you give that in combination with, for

01:22:53.080 example, an SSRI? Oh, well, that's the one in the hospital that starts in the hospital.

01:22:58.580 Okay. But when she's- When she goes home. When she goes home, what do you-

01:23:01.480 No. All other things being equal, you just give that.

01:23:05.780 You just give that.

01:23:06.560 Yeah. If someone is on an SSRI, I wouldn't take them off of it, but you wouldn't start an SSRI

01:23:14.960 then. And in your experience for that woman in the case we've described, who's presenting to you

01:23:23.120 in the weeks or months following her pregnancy, how long does she typically require treatment

01:23:31.040 before depression. Okay, but we're talking about a different category than the synthetic

01:23:36.460 neurosteroid category, which is that acute immediate. Yes, I'm talking about the woman

01:23:43.000 who presents to you outside. Yeah, that's a very heterogeneous population. If they had

01:23:48.800 so-called premorbid history of depression, history of depression before their pregnancy,

01:23:57.600 for example, or if they have bipolar disorder. Let's say they didn't have either.

01:24:02.900 Then I was going to say they're at higher risk. If they had neither, then you would treat them

01:24:09.820 pretty much like any other patient with suppression. And when you're talking to that

01:24:14.740 patient and setting expectations, and they say to you, doctor, how long am I going to

01:24:19.600 need this medication until I'm back to myself? What would you say?

01:24:25.200 When people ask me questions like that, which I get all the time, I go back to what their

01:24:32.060 previous baseline is.

01:24:34.300 So if they were well for 34 years, and then they have this one episode, I would say, oh,

01:24:44.500 evidence-based medicine would suggest that you stay on this medication for somewhere

01:24:49.960 on the order of 8 to 12 months. And then we could, depending on if you respond well,

01:24:57.400 we could taper you off of it slowly and see how you do. But I wouldn't think at all that you have

01:25:05.180 to be on this medication indefinitely. But if they said that they went into it and they had

01:25:12.620 dysthymic tendencies that weren't diagnosed, like pessimism, constant irritability,

01:25:20.960 just sadness, and they felt that their mood was beneath baseline for most of it, then I would say,

01:25:30.400 well, let's see what you want. It isn't what you need. It's more a quality of life issue.

01:25:35.940 Because often what happens in a situation like that is a woman goes on a medication for an acute depression and she finds her new baseline is better than her premorbid baseline.

01:25:50.620 So 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.

01:26:01.240 So in other words, the pregnancy may have unmasked something that she was just sort of stoically pushing through before?

01:26:08.480 It served, it exacerbated it. Yeah.

01:26:12.100 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?

01:26:20.360 So everybody's heard of TSH and everybody kind of understands more or less the thyroid.

01:26:26.260 We did a great podcast on it recently.

01:26:28.800 I think it's kind of intuitive to people that, well, maybe it's not, actually. Maybe it's not.

01:26:36.060 So let's just take it away with how does T3 and T4 and TSH interact with the psychiatric system

01:26:45.840 overall? Sure. Well, just to give an overview of it, TSH is what the pituitary thinks of the

01:26:56.220 thyroid axis. And what I find is that a lot of people with quote-unquote normal values of TSH,

01:27:07.900 which is often what the average internist measures in the average psychiatrist, people with

01:27:19.220 normal range TSH, let's say in the top 50% of that range. So if the normal range is 0.8 to 5.0,

01:27:32.820 people, let's say in the range of 2.5 to 5, are often considered normal and dismissed.

01:27:40.760 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.

01:27:56.520 In thyroid hormone, there are two types. T4, which has two functions. It's a prodrug and it

01:28:05.780 gets into the central nervous system to be converted centrally there to T3. And it's also

01:28:14.240 a prodrug in the periphery. So there are two different types of diaginases, enzymes that

01:28:22.240 convert them. So free T4 is a very, very important value. And if free T4 is suboptimal in a patient

01:28:34.140 with depression, it's a signal to me that that person should have an endocrine consult or I

01:28:42.680 myself should directly prescribe them thyroid supplementation. So do you rely more on the

01:28:49.260 TSH level or the free T4 level? Yeah, free T4 and free T3. Yeah, but primarily free T4.

01:28:59.380 And if the TSH level is in the middle or low end of the range, but the free T4 is low,

01:29:10.280 how do you act versus if the TSH is in the higher end of the range, but the free T4

01:29:18.240 is also in the higher end of the range? How do you act in those two settings?

01:29:22.580 Well, I'm not concerned about the TSH. I'm concerned about the free T4.

01:29:29.000 So that's the biomarker that's more of interest.

01:29:31.440 For me, yes.

01:29:32.180 And then tell me in your experience where, when this is being missed, right? So if this is being

01:29:42.220 ignored, where is it most showing up? Is it showing up more on the depressive side of the

01:29:48.240 axis? Is it showing up more in the anxiety side or the OCD side? Yeah. Well, hypothyroidism,

01:29:55.740 low thyroid, is showing up as depression. Hyperthyroidism is showing up more typically

01:30:03.560 and rarely. Yeah, rarely. I see very little of that. But that's more likely to manifest with

01:30:10.080 anxiety. And there's a dramatic example of that called thyroid storm where someone, I know you're

01:30:16.760 familiar with that, but for the audience, how would you describe it? I've only seen one case

01:30:23.080 of it, believe it or not. But of course, in my practice, it wouldn't be common. But it was a

01:30:26.740 patient that had a nodule in their thyroid that was making so much thyroid hormone that they

01:30:32.300 showed up. And on their first evaluation, their TSH was zero, like literally zero.

01:30:37.440 Their free T4 was quite elevated, although not so elevated that you would think anything was going

01:30:43.080 on. But on questioning, they had palpitations of their heart. Their resting heart rate was quite

01:30:49.900 high. They were sweating quite a bit. And so that was a patient that we very quickly got into an

01:30:54.900 endocrinologist for the appropriate medical management of that hot thyroid nodule.

01:31:00.400 Yeah. There can be a hypertensive crisis, right?

01:31:03.400 Yeah. That's a good point. He had slight hypertension, but he wasn't in kind of a

01:31:07.600 crisis. It required medication, but it was easy to manage on one drug.

01:31:12.180 Yeah. So I've actually never seen it in my practice. But less dramatic hyperthyroidism

01:31:19.900 I have seen, and that can absolutely manifest in anxiety. And it's very physiologic. So

01:31:26.440 it's less the cognitive anxiety, worry, rumination, social anxiety, and whatnot.

01:31:33.140 And it's somatic anxiety, anxiety in the body, racing heart, restlessness, agitation, insomnia.

01:31:42.180 that sort of anxiety is what's manifesting. And so focusing on the hypo, because that's the

01:31:49.860 far, far more common one that you see, and we would all see, of course, is your approach to

01:31:55.500 treating this with monotherapy, T4 monotherapy? Do you like to use T4 and T3 together? Do you

01:32:02.260 like to use desiccated formulations that combine them in fixed ratios? Or how do you

01:32:08.100 Yeah. I like to use a combination of T4 and T3 where I can have more control over the exact

01:32:17.920 dosage. And in the cases where you're prescribing it, presumably it's because of the psychiatric

01:32:26.780 underlying belief or case that you're treating. Are those the symptoms you are titrating the drug

01:32:33.280 to? Or do you look at something else, such as the biomarker? No, the symptoms. I check the labs.

01:32:41.000 I absolutely check the labs. But I'm focusing mainly on symptoms. And by the way, there are

01:32:47.840 exceptions where I sometimes only prescribe T3 for treatment-resistant depression.

01:32:55.300 Say more about that. It seems to, for whatever reason, there's been research done on it for

01:33:01.380 many years. It's a longstanding treatment for treatment-resistant depression because it boosts

01:33:09.140 metabolism and energy. And when you say T3 for the listener, can you differentiate between

01:33:16.940 the FDA-approved T3 cytomel, which is very short-acting, versus the compounded formulations

01:33:24.300 that are more time-released. Yeah. I avoid the compounded ones. And I usually recommend

01:33:32.560 twice a day, like first thing in the morning, and then six to eight hours later, not too late

01:33:40.320 because it could cause insomnia. Got it. And what doses? I mean, we're talking five

01:33:47.080 micrograms. These are presumably relatively modest doses. Yeah, I start low. I can even

01:33:52.240 started 2.5 twice a day, but sometimes it goes high. It can go to 25 twice a day.

01:34:02.800 25 micrograms of immediate release T3.

01:34:06.380 For someone who's very depressed and responds to it and has normal blood pressure and pulse.

01:34:12.640 Yeah. So give me an example of a patient. Can you recall a case of a patient that required that

01:34:18.880 much T3? Yeah. So what had you tried before? I tried a series of monotherapies with

01:34:28.040 antidepressants in combination therapies with antidepressants and mood stabilizers and let's

01:34:37.400 say lithium, which is a so-called augmentation strategy. But this was not bipolar, this was

01:34:44.540 depression. No. Yeah. Unipolar depression. Unipolar depression. And I assume you're trying

01:34:50.340 monoamine oxidase inhibitors. No. No. You were all SSRI or SNRI? Yeah. Yeah. Okay. Yeah. Or

01:34:57.280 bupropan. Okay. And which is Welbutrin for the listener. So each of those therapies in monotherapy

01:35:03.320 had not been successful. And then even when you layered on presumably not a bipolar dose of

01:35:10.900 lithium. Or an atypical antipsychotic, because those are also indicated for treatment-resistant

01:35:17.760 depression. Drugs like Rixalti, there are a number of them that are used now. Abilify,

01:35:26.120 Rixalti is brexpiprazole, aripiprazole, zyprexa, olanzapine. Those drugs are often quite effective

01:35:34.900 as augmentation strategies, adding on top of an antidepressant.

01:35:40.620 And despite all those combinations, he remained depressed?

01:35:45.600 Suboptimal.

01:35:46.780 Okay. So he got somewhat better, but not-

01:35:49.140 Yeah. I think mentally I'm conflating several patients.

01:35:54.660 Understood. And when you used the T3, did you discontinue the other drugs or did you-

01:36:02.160 I always try to be as minimalistic as possible, but when someone is depressed and has a partial

01:36:09.640 response, I'm not going to take them off.

01:36:12.660 You can't remove.

01:36:13.240 Yeah.

01:36:13.780 Later on, when they're feeling good is the time where you have the luxury of peeling

01:36:18.380 the layers of the onion.

01:36:19.880 So in that particular example that you've got your mind on, when the T3 brought symptom

01:36:27.300 relief, do you recall if you were also able to get any of the other agents off?

01:36:32.160 Well, I know in the long run, I tend to try to taper someone off if their regimen looks

01:36:43.740 ungainly.

01:36:46.680 And presumably there's an order in, I mean, do you try to remove drugs in the order of

01:36:50.780 side effects?

01:36:51.400 So for example-

01:36:52.220 The order of efficacy.

01:36:53.420 In the order of efficacy.

01:36:54.280 Okay.

01:36:54.540 So we are a slave to efficacy first, side effects second.

01:36:58.280 It's up to the patient.

01:36:59.680 Okay.

01:37:00.240 It's shared decision-making.

01:37:01.740 Because some of those drugs like Abilify have unwanted side effects like appetite increase

01:37:07.060 or things like that, correct?

01:37:08.260 Well, much potentially worse than that.

01:37:10.400 They can have delayed neurotoxic side effects.

01:37:14.420 So what I mean by that is they can cause tardive dyskinesia, tardive dystonia.

01:37:20.080 Tardive dyskinesia is a particularly disturbing side effect for someone to have.

01:37:25.300 Potentially irreversible.

01:37:27.100 You know, there are actual drugs to treat it with.

01:37:30.560 Wow.

01:37:30.880 But it's an uncontrollable movement of the mouth, tongue, and throat muscles that can be really disturbing and even dangerous.

01:37:42.420 It can interfere with eating.

01:37:45.360 Yeah, so the stakes are high if you're going down that route.

01:37:48.480 Well, yes, they are.

01:37:50.640 And I always let the patient know. And that's a rare side effect. And it has to do with

01:37:56.640 dose and length of exposure really over years.

01:38:04.220 Now, in a patient that ultimately ends up needing that much T3,

01:38:08.640 did their thyroid labs look that dramatic or not necessarily?

01:38:13.880 Not necessarily.

01:38:14.900 So that is not necessarily a patient that showed up with a TSH of seven.

01:38:18.640 No. Oh, yeah. Those I refer to endocrinology. I wouldn't go near that.

01:38:24.340 Okay. This is remarkable to me. Why do you think in the case of those few patients that have

01:38:31.560 required or who's- Many patients who are depressed and have

01:38:38.160 low normal free T4 and or free T3 seem to respond quite well to thyroid hormone supplementation.

01:38:50.500 And you believe that the reason is primarily through upregulation of metabolism and increased

01:38:55.380 metabolic rate more than it is- It could be central. I mean, thyroid upregulates

01:39:01.960 catecholamine receptor response. So it could be norepinephrine. They're getting more norepinephrine.

01:39:07.600 And dopamine. It could also be serotonin. Thyroid increases serotonin receptors,

01:39:15.000 density, serotonin receptor density. It also increases mitochondrial biogenesis

01:39:20.240 on a genetic level. See, here we go again.

01:39:26.540 Yeah, the probability is it's doing more than one thing.

01:39:28.660 How deep these hormones go, right? In terms of the overlap and the commingling with

01:39:36.200 neurotransmission and neural circuits? So when I talk to patients about hormones,

01:39:41.960 I usually say, I think of them as four axes. Okay. So I think of the thyroid axis,

01:39:48.440 the androgen axis, the adrenal cortical axis, and the fuel partitioning axis. So your insulin,

01:39:55.780 glucagon, et cetera. I think the one that is most challenging is the third one in that list I gave,

01:40:01.300 which is the cortisol pathway. Because most people are experiencing too much and not too

01:40:08.620 little. And we don't have a pill that is an antidote. You can't treat it directly.

01:40:14.060 Right. So you have every one of those other systems we can treat directly. We have so

01:40:18.020 many amazing ways to treat. Because there are usually problems of too little and we know how

01:40:25.000 to fix it. Over here, it's usually too much and we now know how to fix it.

01:40:29.360 it's really a signal. It's a signal that that person is under enormous stress because

01:40:36.160 evolutionarily, the cortisol system, the HPA axis evolved for survival, for threat detection,

01:40:46.300 hypervigilance, diverting resources to the moment, away from the immune system even,

01:40:55.480 fragmented sleep architecture to maintain safety. All those things are adaptive in an acute context,

01:41:02.260 but when they become chronic, it becomes very maladaptive.

01:41:07.060 Yeah. And yet, I would bet that amongst the people listening to us today, and perhaps even

01:41:13.480 the people that come into your office, that would be the most common underlying endocrine condition

01:41:18.700 that is underpinning whatever other psychiatric or mental health condition we have. It's hyper

01:41:26.400 arousal that should be reserved for an acute state that is instead in a chronic state.

01:41:35.220 And as we've just danced around, we don't have a pill to block it. We can't say,

01:41:41.740 go and take this pill and it'll make it go away. And even if we did, that may not really solve the

01:41:47.480 problem. So how do you, with your endocrinology hat on, not your psychiatry hat on, think about

01:41:57.020 that? Or do you just say, I can only solve this with my psychiatry hat on? I don't think that way.

01:42:04.040 In other words, I don't see any dichotomy between psychiatry and endocrinology.

01:42:10.160 And so I don't have different hats, just to be transparent about it.

01:42:19.380 But I think I solve it.

01:42:21.460 I don't solve it.

01:42:22.460 I collaborate with a patient if that patient is willing to attack it at its source.

01:42:29.040 So if whatever the source of the hyperarousal that's maladaptive, whether it's a caregiving burden,

01:42:37.400 whether that person at work is taking on way too much, which I see a lot of, whether it's

01:42:44.920 medical illness that they're not paying sufficient attention to that's causing

01:42:49.460 hyperarousal, to address it at the source. The cortisol is a signal, as far as I'm concerned.

01:42:58.100 It's not really the primary problem. It's a secondary manifestation of a primary stress

01:43:04.840 problem that isn't being managed adaptively. And are you discussing it that way with a patient

01:43:12.600 in the same way? Because if you're giving a patient estrogen, you're explaining to them why,

01:43:18.240 right? This is what estrogen is doing. This is why we're replacing it. I have to. If you're

01:43:22.520 giving a patient levothyroxine or Cytomel, this is why and this is what it's going to do. So when

01:43:28.600 And the patient, when you suspect that, hey, a big part of what's going on here is hyperarousal.

01:43:34.660 Yeah.

01:43:35.660 I don't tell the patient that.

01:43:37.680 You don't?

01:43:38.220 No.

01:43:38.660 Okay.

01:43:39.100 No.

01:43:39.640 Because I don't think, I don't have an endocrine-centric vocabulary.

01:43:45.760 So I just talk, people talk.

01:43:48.340 like you know that boss you and that boss you know have you asked for a transfer or

01:43:59.020 you know i know you're a very dedicated daughter but you know your father with alzheimer's

01:44:06.720 he's very wealthy you could hire nurses around the clock you could still have him you know live

01:44:15.220 at your house, but you don't have to do all the work, a more common sense approach.

01:44:22.020 So let's think about a couple of ways to illustrate this for folks and tie it all together,

01:44:28.960 right? Which is thinking about the psychic pharmacology of the modern tools that you have,

01:44:36.580 plus some of these endocrine adaptive tools. And is there a case or two that come to your mind

01:44:43.240 where, I mean, we've already discussed one, right? And it was potentially a few patients

01:44:48.480 merged into one. But this case of recalcitrant depression that responded to what in my world

01:44:56.260 would have been a very high dose of T3, and yet that was the unlock. Do you have any other cases

01:45:03.200 like that that come to your mind? Let's say a woman who comes to me,

01:45:07.200 perimenopausal age, who said, doctor, I need hormones. And I say, what's going on?

01:45:18.500 And she says, well, I've always been the strongest person handling my emotions as far back as I can

01:45:29.540 remember, but menopause is overwhelming me. So then I asked her, well, you've always been

01:45:38.820 the strongest, had the strongest emotions. What does that mean? Well, I'm just a high-energy

01:45:47.060 person. I said, well, tell me about your 20s and 30s. Oh, okay. And she smiles and says,

01:45:54.080 they were chaotic. I started several companies. I traveled. I spent a lot of money. I had a lot

01:46:04.780 of ideas. Sometimes thoughts would race through my mind faster than I could write them down.

01:46:11.360 And I would ask more questions. And in this particular example, menopause was really

01:46:20.680 happening. I investigated the hormones and the gonadotropins, and it lines up, as well as the

01:46:27.980 symptomatology. But menopause was a clue to longstanding neglected bipolar disorder.

01:46:35.660 So I started her on Lamotrigine, and that was a road to restitution of her life's narrative.

01:46:45.480 She didn't know what was happening to her, her entire adult life.

01:46:49.600 And with that organizing hypothesis, she understood all the difficulties she had sustained.

01:46:56.580 And now looking forward, she had reason to believe things would be a lot different.

01:47:00.960 Now, in the case of that woman, did she talk about any of the depressive?

01:47:07.480 Yes.

01:47:08.160 Okay.

01:47:08.420 Yes.

01:47:08.640 And she had gone to a previous psychiatrist for a, I would call it a bipolar depression, an episode of depression that happened in her 30s after she had a extended hypomanic period of incredible productivity.

01:47:27.860 She crashed and could barely get out of bed and went to the psychiatrist.

01:47:32.720 He prescribed an antidepressant.

01:47:34.500 This gets back to what we were talking to earlier.

01:47:36.900 What happened?

01:47:37.800 Well, first it was miraculous, she says. Then a couple of weeks later, I started having those

01:47:47.280 racing thoughts again and they were the worst I'd ever had and I couldn't sleep at all. So I stopped

01:47:53.640 it and never went back to that doctor. She stopped the medication and what happened?

01:47:59.740 Back to baseline, the same rollercoaster. Baseline hypomania. Oh yeah. Okay.

01:48:04.100 The roller coaster. Yeah. By the way, do we know how much of what's happening in her brain is,

01:48:10.640 like, do we know biologically, receptor-wise, what's happening in her brain that is causing

01:48:15.780 the hypomania? No. Isn't that amazing? Yeah. I mean, I can't imagine for you how amazing that

01:48:23.840 is. Like, for me, it's amazing, and I don't treat these patients, and yet you're looking at this

01:48:29.240 person and you're watching their experience. Yeah. Well, it's clearly some limbic dysregulation.

01:48:37.060 But it's, I mean, this is why I think psychiatry is such an incredible field and such a challenging

01:48:43.000 field is like, can you imagine a diabetologist not understanding that there's a beta cell that

01:48:51.380 makes insulin? No. And yet they have to somehow treat this person. Yeah. Yeah. Well-

01:48:59.240 On a molecular level, it's probably understood better than I'm describing in terms of ion channel function and whatnot.

01:49:10.420 But it's very abstruse, and I don't think it's helpful for our audience to go there.

01:49:17.340 So I want to ask you, well, do you have another case you want to talk about?

01:49:20.500 Because I have another question that goes back to kind of depression.

01:49:22.640 Oh, tell me your question.

01:49:23.820 Okay.

01:49:24.140 So you talked about recalcitrant depression.

01:49:26.420 Yeah.

01:49:26.540 One drug we haven't talked about that's getting a lot of interest these days is ketamine.

01:49:31.380 Yes.

01:49:32.160 So can you tell me your experience with seeing patients go through ketamine therapy for

01:49:40.380 difficult-to-treat depression or just, yeah, give me your thoughts on the subject.

01:49:45.520 Do you want me to tell you how it works?

01:49:47.260 That would be great.

01:49:47.980 Sure.

01:49:48.980 So ketamine is a so-called NMDA receptor antagonist.

01:49:56.340 So when-

01:49:57.760 And we should just make sure people listening, that is not the same as MDMA.

01:50:01.580 This is totally, totally unrelated.

01:50:03.480 But I know people hear it and they think, oh, is that the same?

01:50:05.720 Is that, has any relationship to MDMA?

01:50:07.200 But it does not.

01:50:07.740 No, no whatsoever.

01:50:08.560 So it antagonizes, it blocks those receptors, which are actually normally inhibiting GABA

01:50:17.360 interneurons that attach to glutamate.

01:50:20.880 So what it does is it results in this massive release of glutamate and the excitatory response as well as the mTOR pathway and protein synthesis and synaptic remodeling.

01:50:38.100 So sudden, dramatic, epic neuroplasticity.

01:50:42.840 So it happens remarkably fast, and it stops remarkably fast.

01:50:48.780 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 dramatically, dramatically better.

01:51:11.100 the depression doesn't necessarily. So basically, in my experience, I've used it sort of as a bridge

01:51:20.120 to finding the solution for that patient, rather than it being the solution. Occasionally,

01:51:26.440 it is the solution. And the patient goes for ketamine treatments and goes into remission

01:51:32.820 from their depression. But more often than not, in my experience, they don't. And you have to

01:51:40.360 find the right drug or the right other approach to definitively treat their depression on a longer

01:51:48.340 time basis. Do patients become resistant to the effect over time? Is there a

01:51:57.140 tachyphylaxis that develops? Yeah. I'm not that expert in ketamine, honestly,

01:52:03.220 so I'm not sure. I haven't seen that. Because practically, it's very time-consuming,

01:52:12.220 expensive, and inconvenient. The patients that you would send for this treatment,

01:52:18.020 how is it administered? Is it administered intravenously?

01:52:20.860 Yeah, with monitoring.

01:52:22.920 Yep. And in the most severe cases, what is the frequency with which they would need those

01:52:29.580 treatments if you are relying on that treatment solely to ameliorate symptoms.

01:52:35.300 Yeah. Well, that depends on the infusion center and the practitioner. I mean,

01:52:44.100 some people might be willing to give it three or more times a week.

01:52:49.840 Oh, I was asking it more through the lens of how long the relief can last.

01:52:54.060 Oh, heterogeneous. For some people-

01:52:57.940 Clearly, it can be only days, if that's what you're saying.

01:53:00.520 Yeah, yeah, yeah.

01:53:01.200 Okay. And on the long end of that spectrum?

01:53:04.940 People go into remission for all kinds of reasons, that are unknowable in any given individual.

01:53:14.380 It could be spontaneous remission. It could be a placebo. It could be a true drug effect.

01:53:20.220 um you know it's hard to know it's this is an emerging field and how is it is it is the dose

01:53:27.660 given in such a way that it's dissociative to the patient yes yes i see i mean it it is a

01:53:34.580 dissociative anesthetic so yeah i just didn't know if it was given so i mean i didn't realize

01:53:41.260 the patient was completely dissociating because obviously you could be given at a lower dose

01:53:44.640 I wouldn't say completely dissociating. I would say typically, from what I hear,

01:53:50.940 because I don't administer it, they're partially dissociated, sometimes profoundly.

01:53:59.060 But fully doesn't really apply, I don't think. But I think there's a spectrum.

01:54:06.000 And I'm not sure if there's a correlation like there is for psychedelic medicine,

01:54:10.140 where the degree of the experiential effects of the psychedelic correlate to the therapeutic

01:54:18.260 effects, supposedly. That's the latest thinking from my understanding.

01:54:23.340 So do you have any concern about what appears to be a lot of recreational use of ketamine

01:54:29.520 outside of these clinical settings? Absolutely. I mean, as we've established,

01:54:35.260 It's a dissociative anesthetic. So people who take it and dissociate from it have reactions

01:54:43.800 from that. Plus, it can have its well-established mood-changing effects. That could go good or bad.

01:54:51.960 It absolutely needs to be controlled and supervised. If taken randomly,

01:54:57.520 it's playing Russian roulette as far as I'm concerned.

01:55:00.200 Have you seen any patients who have had negative experiences and have sought you out as a result

01:55:06.880 of it? You know, something- No, but I have friends who've referred

01:55:10.360 patients like that for addiction treatment. I see. Okay. And, you know, you've sort of

01:55:18.260 opened the door to psychedelics. Did you see that study probably in the last few months

01:55:25.540 about a patient with Alzheimer's disease who was given five grams, which is a full therapeutic dose

01:55:33.100 of psilocybin that had some memory recovery? Well, it was more than that. It was that Japanese

01:55:38.340 woman who, and this is the ultimate N of one study, by the way. Yes. Yeah, yeah, yeah. But

01:55:44.620 That's so interesting.

01:55:46.020 Yeah.

01:55:46.760 Well, so, yes.

01:55:51.600 So she got the five grams of psilocybin.

01:55:55.820 But she supposedly had a diagnosis of severe Alzheimer's for a decade, which strikes me as unusual, to say the least.

01:56:08.880 And she had no urinary function.

01:56:13.520 She was completely incontinent. She spoke at most monosyllabically. She couldn't talk

01:56:21.360 beyond that. She couldn't have interactions. And then she took this dose of psilocybin

01:56:30.000 and behaved dramatically differently and became somewhat normal after it.

01:56:41.080 and how long did it last? I don't recall. Well, it was a very confusing case report

01:56:47.380 because all it says is something to the effect of it lasted until the second

01:56:53.880 administration of three grams of psilocybin. And it doesn't say anything more than that.

01:57:03.000 There were no studies. There were no metrics. There was no neuroimaging. There was no

01:57:09.860 anything with the study. So it's the ultimate end of one. I have an alternative hypothesis

01:57:16.640 as to what the etiology was of the problem. Some people with post-traumatic stress disorder,

01:57:27.540 particularly if they have mild cognitive impairment or mild Alzheimer's, can regress.

01:57:32.540 And let me just preface to say, someone having severe Alzheimer's and surviving 10 years don't go together, in my experience.

01:57:42.300 What do you think about that?

01:57:44.520 I don't think I have enough experience to say, but yeah.

01:57:48.100 Again, it's a bit of a subjective title, right?

01:57:51.140 Yeah, yeah.

01:57:52.280 But yes, usually if it's so severe that a – well, again, part of it comes down to basically airway protection.

01:57:59.540 It's unclear how capable she was.

01:58:02.540 So this N of 1 study is something I can't draw any conclusion from, but I find it theoretically

01:58:11.880 interesting that so much adaptive capacity could be restored. So if PTSD was the etiology and she

01:58:21.140 would regress and this interfered and turned around the regression, that's wonderful. Whatever

01:58:29.920 it is, if it helped this patient, it's a wonderful initial response. I'd be very cautious about

01:58:37.300 generalizing that neurodegenerative disease. You know, the Robin Carhart-Harris rebus model,

01:58:46.120 relaxed belief under psychedelics, is about neuroplasticity for adjusting maladaptive

01:58:53.900 priors, people who have beliefs that are problematic for them and the underpinnings

01:59:01.740 of a lot of depressive and anxiety disorders. And administering classic psychedelics

01:59:10.140 provides a therapeutic window within which a lot of neuroplasticity occurs and with the right

01:59:19.920 response either within the individual or between the individual and family or formal therapists,

01:59:29.660 change can occur in that critical window. And I find that of interest because, of course,

01:59:38.200 estradiol creates a lot of neuroplasticity because it acts through BDNF and NMD and glutamate.

01:59:48.060 And so the hormones that change the conditions within which neurotransmitters operate are very plastic under the right circumstances, optimal estradiol levels, for example.

02:00:09.180 And administering a psychedelic medication can also alter neuroplasticity, is intended really, to alter neuroplasticity in the studies of psychedelics for the most part.

02:00:25.200 Not all, but a lot of them are thinking of that set and setting model, which is based on a concept of neuroplasticity.

02:00:33.200 Now, what's your experience been of psychedelics?

02:00:40.460 I have tried in as clinical a setting as I think possible several of these psychedelic agents.

02:00:50.020 So I have tried ketamine under therapeutic conditions once.

02:00:57.020 I didn't find it to be a positive experience and I will never repeat it.

02:01:01.320 do you want to elaborate about the negative aspects of it um i you know i described it to

02:01:10.060 a friend after as guantanamo bay for my soul and my psyche i mean absolutely devastating

02:01:18.840 so just a endless spiral of death did anything positive come out of that subsequently not a

02:01:28.520 single positive thing came out of that. So you had a profoundly adverse reaction?

02:01:33.080 Perhaps the only positive thing I would say is it gives me enormous caution when I talk to my

02:01:39.960 patients who themselves are very curious about these things. I just caution them and say, look,

02:01:46.100 you simply don't know how you're going to respond to these things. The therapeutic

02:01:51.360 windows on these things are quite narrow. And they're just not well understood. It's not like,

02:01:57.500 hey, if we're going to give you Prozac, we sort of know that most people respond at this dose.

02:02:05.540 Some people need it to be at this dose. Some people need it to be at this dose. These are

02:02:09.000 the side effects. If this happens, we're going to- You're on to my Russian roulette concept.

02:02:13.380 Yeah. Yeah. So I think with these agents, I mean, with the exception of MDMA, I think all of these

02:02:19.480 these so-called psychedelics, I think are, and again, there are, you know, I've used psilocybin

02:02:27.440 in a therapeutic setting that was incredibly positive. I've also had, but I've had experiences

02:02:35.140 on psilocybin that were brutal. I mean, I had one experience on psilocybin where I, you know,

02:02:42.460 it's hard to know exactly how much time was was was passing but but certainly for hours it it um i

02:02:50.140 had a reoccurring experience of being in a guillotine where the blade was dropping and so

02:02:56.940 what i was experiencing was the sound of the blade as it's getting closer to the back of my neck but

02:03:01.820 it would always stop just before it hit my neck so that would provide a modicum of relief but then

02:03:07.420 the blade would go back up and it would happen again wow so that was absolutely awful again

02:03:12.480 nothing positive came of that experience but i've had i've had very positive experiences

02:03:17.640 on guided mdma and and with uh with with with another psilocybin experience um and i think

02:03:24.640 what made the positive experience positive um well again i think with mdma no with the psilocybin

02:03:34.340 Um, it was, I mean, it's hard to describe. I think it's, it's, this is over 10 years. This

02:03:40.780 is about 10 years ago. It was an out of body experience, meaning I was only witnessing myself

02:03:47.560 from outside of myself, but at different places in my life. But they were very vivid. These were

02:03:55.060 not vague images. This was, you are back in this room at this moment in your life when you were 12

02:04:05.720 years old. And this is exactly what's happening. But what was very powerful about this was I was

02:04:15.520 not experiencing it through my lived experience, but through the other person in the room,

02:04:22.700 in this case a parent and for me that gave incredible empathy to what was going on with

02:04:32.980 the other person during an experience in my life yes so that and the durability of that is

02:04:40.900 a decade later that that will be lifelong durability so i think because that's a fascinating

02:04:47.280 description beautifully expressed about something fundamental about people

02:04:57.100 maybe in a different category who revisit a traumatic experience from a more developed

02:05:04.540 perspective in their lives and they're able to re-assimilate it from certainly a more advanced

02:05:14.320 view and even have compassion for someone who may have. So this was an interesting experience.

02:05:20.120 This was not a traumatic experience in my life at all. And so therefore it's very unclear to me

02:05:26.460 in this particular instance, why I went to that place, but instead what it gave me was,

02:05:37.040 and it might've been that I was at the exact same age as my parent at the, in other words,

02:05:43.380 in my life, I was the same age as my parent in this vision. But now all of a sudden I was able

02:05:49.660 to appreciate their life and how much harder it was than my life. But in a way that I could never

02:05:58.440 articulate now, I can't describe it now. It was the feeling of, wow, their life was so much harder

02:06:06.000 than my life. And everything I have is because of them and their sacrifice. And all of the things

02:06:16.260 that have frustrated me are frustrations of someone who's never fully appreciated.

02:06:24.480 It's about gratitude.

02:06:26.120 Yes. So it was, I think, one of the most beautiful experiences I've ever had in my life.

02:06:31.680 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. 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.

02:06:57.120 And so I made a decision about two years ago that I was probably never going to do that again.

02:07:04.380 I was sort of, and I won't describe the litany of things I've tried, but I will never, I just don't.

02:07:12.300 I think that's very wise.

02:07:14.520 I've extracted something incredibly valuable.

02:07:16.600 Yes.

02:07:17.100 I don't want to tarnish it with anything negative.

02:07:19.200 Well, it's beautiful that you got what you did out of it and also that you knew when to stop.

02:07:25.240 Well, I wish I could say I did. I went back to the well a couple of times and paid a very heavy

02:07:31.820 price for it. But that's also the intellectual part of me, the scientist, right, is completely

02:07:39.100 interested in why. There's nothing I can point to in set and setting and dose and delivery. There's

02:07:44.840 nothing I can point to that was different. There's a certain randomness.

02:07:48.260 No, yes, exactly. And that's what makes it so terrifying. In fact, the last time I did this

02:07:52.840 was the most prepared I've ever been. The amount of work I did with the therapist ahead of time,

02:08:00.140 the amount of journaling. I've never had a greater intention going into this, right?

02:08:06.860 You expected a masterpiece to come out of it. Yes, this was Michelangelo going into the chapel.

02:08:13.880 I mean, this was going to be the final elucidation of the three things, the three

02:08:20.620 questions that still you know yeah i deal with yes and instead i got put into a a tumbler and

02:08:31.080 ripped into pieces and spit out the back and i i just i mean it was it was very very difficult

02:08:38.240 it took me it took me months to recover i've i've always been innately scared of those medications

02:08:46.240 and have avoided them.

02:08:49.620 Yeah, I think there's a part of me that still remains optimistic

02:08:54.540 that as more and more research is being done,

02:08:58.140 the benefits of these things will outweigh the harms.

02:09:00.920 I think there's one point I should make just for listeners

02:09:03.820 who are wondering who would say,

02:09:05.520 wow, Peter, that's crazy that you would have those experiences.

02:09:07.900 There is an issue with me that has been an issue

02:09:10.900 when it comes to any medication or drug or anything

02:09:14.800 that would alter consciousness or frankly any drug i am highly resistant to every medication

02:09:22.160 for which there's variability in dose so whether we're talking about caffeine whether we're talking

02:09:28.800 about alcohol any medication you can put into a human body i just need two to three x what every

02:09:38.500 other person needs to experience in effect. So I could drink four drinks and I wouldn't feel a

02:09:46.500 buzz. I can drink four cups of coffee and I don't feel anything. So the doses of these agents that

02:09:56.680 I require to feel anything are much higher than other people. And so maybe the reason my experiences

02:10:04.720 have been so different is we're at a point on the PK of that drug that is just well beyond

02:10:15.080 normal behavior. Every time I have used psilocybin, it has been north of 10 grams

02:10:21.260 because the standard five grams produces nothing. So in other words, I say all of that to say-

02:10:28.980 Maybe you need more estrogen for the-

02:10:30.680 Yeah. Well, I mean, it might just be that my horror stories have to do more with where I am

02:10:39.000 on the dose response group. It's interesting. I had a discussion yesterday with a patient about

02:10:43.260 estradiol. He had been under the care of a doctor before he came into our practice that was trying

02:10:48.460 to give him a Remedex, which for the listener is a drug that prevents the aromatization of

02:10:53.900 testosterone into estradiol. And he had been taught, so to speak, that estrogen was bad and

02:10:59.020 you want high testosterone and low estrogen. So needless to say, we had a great discussion about

02:11:03.640 why that was a very bad idea. Yeah. What hope do you hold out for the utilization,

02:11:14.080 the proper utilization of psychedelics in psychiatric medicine over the next 10 to 20

02:11:19.580 years? Well, part of it relates to your positive experience. It's extraordinary that a single

02:11:26.920 administration of a drug can produce a durable effect that you're projecting will last a lifetime.

02:11:34.560 I'm 100% convinced it will last the rest of my life.

02:11:36.840 And I'm 100% convinced by you of the power of that experience and how transformative it is.

02:11:45.980 So I find it remarkably exciting and promising, but I also appreciate the dangers and unpredictability.

02:11:55.120 So I'm hoping that they'll find a strategy, they meaning the researchers in that field, will find either a molecule that preserves the risk-benefit ratio shifting much more favorably or a set-in-setting strategy that modifies or some other strategy, maybe combination pharmacotherapy.

02:12:24.120 pharmacotherapy, because it is a pharmacotherapy. It's the use of a psychotropic medication. Maybe

02:12:29.760 concurrent use of other medications that don't block the serotonin 2A receptor that it has to

02:12:37.800 bind to. That's where the classic psychedelic binds to. So if you block that receptor with

02:12:43.820 another drug, instead of needing twice as much, you may need 20 times as much. So that's not

02:12:49.560 reasonable, but finding an appropriate pharmacologic strategy that augments the efficacy and mitigates

02:13:01.120 the risk. Of all of the indications that are being talked about for these drugs, the two that,

02:13:07.900 to me, seem the most exciting are obviously MDMA and PTSD and psilocybin in end-of-life

02:13:17.680 depression or frankly, just all end of life related therapy. What do you think, how much

02:13:26.680 more evidence do you think the medical community, I mean, the FDA aside, there's a whole issue with

02:13:32.460 the FDA there, but from a medical scientific standpoint, where do you sit on those two

02:13:38.100 indications, which are quite specific? Yeah. Well, end of life treatment, the risk reward

02:13:44.600 shifts a little bit. If someone is struggling with existential anxiety on an absolute order,

02:13:54.720 I think if there's something that could help them with that, they deserve the option of exercising

02:14:02.480 that. Because there aren't many things- But we don't want to make it worse.

02:14:06.720 We don't want to, but it's pretty bad to begin with. So the risk-reward may shift. It depends

02:14:15.820 on your medical ethical model. If the baseline would shift the risk-reward calculus about that,

02:14:23.980 I'm not sure. Something worth thinking about. But then the same would apply to significant PTSD.

02:14:30.260 Yeah, but I suspect that it's not MDMA that's going to be the most effective for that.

02:14:40.340 Do you think it will be psilocybin?

02:14:44.040 Perhaps, or certainly other drugs.

02:14:47.900 I think MDMA is a so-called empathogen.

02:14:52.400 It increases empathy.

02:14:54.080 certain types of PTSD. PTSD, like so many things, is a very heterogeneous category.

02:15:02.840 I think when empathy is called for related to reconciliation of relationships or traumatic

02:15:14.340 experiences, it might have a very strong role. So much remains to be determined. But I do find

02:15:23.900 it exciting that medications can have such a durable and powerful effect. And I find it

02:15:31.960 intimidating and disturbing that it can also go in the other direction. But I'm very optimistic

02:15:40.720 that something positive will be found to reconcile that discrepancy.

02:15:46.500 yeah i think i would agree with all of that um but i do i do always feel the need to caution

02:15:56.320 people i think it's one of those things where people hear a lot of the good stories i think

02:16:00.880 they don't hear enough of the bad stories and i i think there's i agree with you i think there's

02:16:05.120 they are drugs and uh every drug has a side effect absolutely and including the ones i prescribe yeah

02:16:14.180 Yeah. Well, Linus, this has been a really fascinating discussion. I've learned a lot.

02:16:20.340 And so I'm hoping by extension, everybody listening has learned a lot as well.

02:16:24.180 So thank you very much for your visit and for more importantly, sharing your wisdom.

02:16:29.260 Thank you so much. It's been an enormous pleasure for me.

02:16:33.720 Thank you for listening to this week's episode of The Drive. Head over to

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The Peter Attia Drive - August 17, 2026

#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.

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