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

Key Takeaway

Today, widen your “distress-tolerance window” before trying to solve every feeling with willpower. Take a 10-minute walk outdoors, protect tonight’s sleep routine, move your body, and identify one avoidable source of chronic stress—an overcommitment, unresolved conversation, or constant digital input. These actions will not replace professional care, but they can improve the biological foundations that shape irritability, mood, resilience, and your capacity to respond rather than react.

Episode Overview

Peter Attia speaks with psychiatrist Lionus about expanding psychiatry beyond neurotransmitters to include hormones, thyroid function, metabolism, inflammation, stress physiology, sleep, and circadian biology. They discuss antidepressant classes, bipolar diagnosis, menopause and andropause, postpartum depression, thyroid augmentation for treatment-resistant depression, and the promise and risks of ketamine and psychedelic therapies.

Full Transcript

Transcript of 404 ‒ Mental health beyond neurotransmitters: hormones in psychiatry, psychedelic therapies, & more from The Peter Attia Drive Podcast. Auto-generated from episode audio; may contain minor errors.

Hey everyone, welcome to the drive podcast. I'm your host Peter Aia. Lionus, thank you for coming to Austin. So wonderful to see you. Same here, Peter. Thanks for having me. you have a very interesting practice in psychiatry or at least I should say a very um unique perspective on the integration of all of the traditional tools and insights of psychiatry along with those of endocrinology. Um is that a relatively recent fascination for you? You've been in practice for [clears throat] what 30 years going on 35.

Okay. Yeah. Yeah. I did a pivot after 30 years. I felt like I was in a bit of a rut, like I was um en enjoying my practice, but I felt I wasn't learning as much as I wanted to learn. And there are a number of factors that we can talk about that drove me in this direction, but um the pivot is quite recent and I'm learning about endocrinology as we speak. It 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.

So tell me what it was during the first 30 years of your practice that a that gave you satisfaction and that you loved or a and sorry b that you were beginning to fatigue of or question or feel was insufficient to help your patients. I see myself basically as a kind of humanistic existential oriented psychiatrist who happens to be practicing psychopharmarmacology as a way to make a living and having an expertise in bipolar spectrum disorders. Um but I found that psychopharmarmacology was perceived ambivalently for the most part even in very successful cases from an objective point of view in terms of symptom reduction that the patient felt it was undesirable even if they had a spectacular reduction in symptoms.

And it led me to think about what was contributing to that. And what I finally um decided was the organizing principle was that psychiatry aims at reduction of symptoms but not restoration of the full human experience that makes life most worthwhile. That's a pretty profound statement. Um I I don't I wouldn't say I'm pushing back on it. I'm only asking out of genuine curiosity. If you were at a dinner with nine other psychiatrists, do you would they share that view as well? Is that is that a largely commonly held view amongst your peers?

Probably not. Probably not. But I don't go around asking that question. But it's kind of an important question. It is an important question. Um but I I would say they would agree with me that there's an unusual amount of struggle even in cases where there's a dramatic improvement where people come with horrible levels of suffering and a psychopharmarmacologic intervention results in a dramatic reduction of that suffering. that it's often still a struggle to encourage a patient to continue with an ongoing regimen when it's needed. And there there are certain conditions that require chronic treatment and I mentioned bipolar disorder.

That's, you know, a certainly a chief among them. Yeah. A hallmark case of why that would be necessary. So I don't want to under sell psychopharmarmacology and by the way I've had I feel blessed to have had such a wonderful career and experience of psychiatry. I love the field of psychiatry and I don't mean to um criticize psychiatry per se. This is more about adding an additional lens of perspective than detracting anything in any way from psychiatry because psychiatry is a remarkable field. Um I w I was lucky to have been not so dumb to make the choice to become a psychiatrist and to have um taken advantage of the wonderful opportunities to get to know human beings on a deeper level which you asked me before what's been fulfilling.

I would say that's been probably the most fulfilling aspect of my career is to really get to know people in depth who are remarkable human beings. And that's what inspired me to go into psychiatry in the first place because understanding the patient is always greater than my ability or any um provider to use that word any provider's ability to understand them because the nature of a human being is so unique and remarkable. So, it's progressive layers of insight and progressive attempts to understand and reinterpret our misinterpretations, if you will.

I mean, one of the things about psychiatry that is quite unique to medicine when you consider all of the medical subsp specialties and the surgical subsp specialties is the lack of measurable biomarkers or objective findings that could be measured on imaging for example. Sure. So when you think through presumably the spectrum of conditions that a psychiatrist would be uh treating from anxiety to depression to hypomomania, bipolar disorder, all of the different clustered all of these things, there's nothing that's going to show up on a CT scan or an MRI of the brain that makes that diagnosis.

There isn't a blood-based biioarker that's going to say, "Oh, this, you know, this person has high feritin or this person has low this or low that." Not yet. Yep. So, so yet in other words, something you said a moment ago rings very important, which is even though you you've used the term psychopharmarmacologist several times already, implying that the tool, the main tool you use is a pharmacologic tool, the human [snorts] story piece of it is the diagnosis, right? I mean, presumably part of the diagnosis is ratified through a hypothesis of, hey, I think if if my if I'm right on the diagnosis, this medication should make things a little bit better, but you have to have a very good hypothesis based on your subjective interaction with that patient.

Yes and no. Um, on both counts. Um first of all I do a lot of psychotherapy too because I'm one of those rare people not in in a special way but um in a selfdirected way who chose a residency program at Harvard that trained both psychotherapy and psychopharmarmacology and I did that quite intentionally because I wanted to have a lot of cases where I was doing both as opposed to um dividing and partitioning a patient's care because that led to my curiosity and the psycho therapeutic aspect of it.

Yeah. Do you think that that's um I know I know from other friends who have done psychiatry residencies at Harvard that at least according to them and and I'm asking you for that to clarify is is Harvard unique in that in that it still preserves that legacy of Harvard is a very heterogeneous institution and it really depends on which area of which particular hospital which training program because there are a number of different training programs even within psychiatry. Yeah, within psychiatry. Got it. Yeah. Okay. Now getting to the other aspect of your question.

Um diagnosis and psychopharmarmacology don't always go that hand in hand. One would think that they would, but not necessarily. There's a certain art of psychopharmarmacology that's somewhat intuitive and somewhat evidence-based and I find that part interesting and all the information that one gets from a trial of a psychotropic medication is useful information. So it isn't categorical this is a good drug for this per or a bad drug. Well, of course that can be true on a certain level, but um a an adverse response gives us potentially actionable information going forward and should be part of the record permanently to advise any future physician about how to best help that individual.

Let's maybe talk a little bit about some of the I hate the term, but kind of the breadandbut tools of the uh of the of the psychiatrist in the in the pharmarmacco um tool bucket. So, everybody listening to us right now, Lionus, has heard of an SSRI. Yeah. Right. There's nobody that hasn't heard of them. And if they if they haven't heard that term, they've certainly heard the drugs within that class. Um your career is such that you've seen the if not the birth of that class of drugs certainly the proliferation of that class of drug.

Yeah. Um presumably during your training we were dealing with MAIs. We were dealing with tricyclic. We were dealing with drugs that actually still probably have great efficacy provided the indication is is understood. um what is the best way to help get our listeners up to speed on these different classes of drugs without clobbering them with uh with with too much of the mechanistic stuff but I think enough that they'll understand because I think we have to understand serotonin if we're going to talk about the endocrine system and and how estradiol and serotonin factors like so so I want to make sure we get everybody up to a certain level of understanding and I think the drugs help us do that on a foundational level um psychotropics historically have worked at the level of intervening on neurotransmitter modulation and particularly the monoamines serotonin, dopamine and norepinephrine and SSRIs are drugs that selectively for the most part target serotonin and modulating serotonin neurotransmission.

through signal. They h have mechanisms. One particular mechanism, glad to mention it if you'd like me to, but one particular mechanism to kind of amplify the signal and that that's how it works for that drug. Now there are also probably familiar to many of the audience a a newer class called SNRIs, serotonin and norepinephrine reuptake inhibitors and that gives a certain balance because raising serotonin can decrease dopamine. So someone let's say with attention deficit disorder who has slow dopamine as part of the problem of their attention issues if they go on an SSRI that could exacerbate it.

And people often talk in terms of side effects about SSRIs. Now again, I love all medications that help people and SSRIs have helped millions of people, but um raising serotonin can decrease dopamine and taking an SSRI alone can often make people feel a little bit blunted. um not fully vital to the extent that they're desiring. Now that that seems a little counterintuitive given at least at the sort of it's a paradox. It's a paradox. So let's make sure the listener understands why. So we well there's so much I want to unpack on this but but if we buy the idea that more serotonin is better and therefore a drug that inhibits the reuptake of serotonin will leave some serotonin is better.

Yeah. Yeah. Yeah. Serotonin syndrome Yes. is when there's devastating. Yeah. Yeah. But but in the case of if the hypothesis is that this person is suffering from depression because they don't have enough serotonin around their neurotransmitters, we're going to give this drug. we're going to inhibit the re-uptake of it. We're going to leave more serotonin around. But then you're saying, "Yeah, but you know what? That also reduces dopamine." And we should maybe talk about why that's the case. And norepinephrine and norepinephrine because presumably it's competing for the substrate of the the I mean they're they're all monoamines as you said.

So yeah. Is there a feedback loop? Is that why serotonin? Well, I think there's receptor [clears throat] upregulation down regulation. It's a multiffactorial process. So if you have less dopamine and less norepinephrine, you're going to feel the exact types of symptoms that you might have been seeking the drug in the first place. Not necessarily, but you'll experience um the typical patient might experience um if if the trial is successful um an alleviation of the target symptoms. let's say anxiety, depression, they they might feel less symptomatic and better, but they might feel at the same time despite feeling better.

God, I feel better. I'm glad I'm taking the drug, but I I wish I felt a little more. And of course, we didn't even talk about sexual side effects, appetitive side effects, which are probably very common, and we should we should discuss those. Um, and you also mentioned anxiety, right? So, a lot of people might not associate SSRIs with treatment of anxiety. Do you think that the that the term anti-depressant is a bad marketing term for an SSRI given the breadth of conditions that it can be useful for?

Absolutely. And it's actually a class of drugs that is more effective for anxiety than it is for depression. Not to say that it's not effective for a lot of depression. It was actually a sort the first um SSRI fluoxitine was a which is Prozac. Exactly. generic prozac developed by Eli Liy in a targeted way to block this um serotonin reuptake pump and they succeeded um and it's very targeted at that um not all SSRI are pure SSRI for example um certuline generic zoloft also blocks dopamine it's also a mild dopamine reuptake inhibitor.

So, um they have some so-called secondary pharmacologic properties in certain cases. So, when you think about then the differences between a drug that's get that gets formally labeled an SSRI versus a drug that gets formally labeled an SNRI. Yeah. It's really just a continuum because they can it's basically saying like I mean I'm being a little bit cheeky but if on a scale of 1 to 10 you're a 10 out of 10 on serotonin and a three out of 10 on norepinephrine and a a four out of 10 on norepinephrine at some point we just say oh well we're going to start classifying you as an SNRI.

That's true. Yeah. I think it's underappreciated. Now there are certain more pure SSRIs. So it sounds like Prozac was a very pure SSRI per perhaps um generic Lexapro Satalopreg might be the best example. Got it. From my understanding right now of a pure SSRI. Um a serotonin reuptake blocker without any secondary pharmacologic properties to my knowledge. Well, I'd like to ask you a little bit about that because Lexapro seems to be a drug that I've seen a lot of use. Yeah. Um, it's a drug that a lot of non- psychiatrists are very comfortable prescribing, which I think speaks to its relative safety um, and ease of use.

Um, it's a drug that, as far as I can tell, really is administered at only two doses, typically, 10 and 20 milligrams, although I guess you could cut the 10 in half and start at five, but those seem to be the two doses. Um, the other thing I've noticed is it seems to be a drug that's often prescribed not for depression, but rather for almost like rumination or um OCD. Yeah. Yeah. A little bit of OCD anxiety disorder. Yes. So, so you're saying it's more in the anxiety cluster than depressive?

No. No, it works for both. So, it was developed really for what we now call dysicate disorder. So which is which really I do think of as depressive. I mean dyia and anidonia seem to be really core parts of depression, right? They're different though. Yes, dyia is a chronic low-grade depressive tendency and um as opposed to a major depressive episode. So major depression is more has a bigger amplitude but typically a lower frequency. Dimeia is a chronic tendency if you were to draw a graph of it where the mood would be below the baseline to a degree that takes a toll on the quality of life of the person who has it.

And the goal of the medication is to elevate that toward the mean. And it's interesting that something as describable as dthyamia responds to a to purely more serotonin without necessarily more and if anything less dopamine and norepinephrine if presumably there's a compensation and they go down not necessarily but the side effect profile tends to be better. So remember when um fluoxitine came out the the first SSRI um really the first of the next generation of anti-anxiety anti-depressants to call them dual um intended targets. It isn't that SSRI are unique in helping dysia but when they were invented the existing medications on the market the triccyclic anti-depressants had typically much more severe side effects much more severe and were dangerous in overdose.

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

Ironically, let's say someone with anxiety or panic disorder who's taking a medication that they know can give them a hypertensive crisis. Um, so that was the backdrop from which SSRIs came. And SSRIs are really remarkably benign from a side effect profile compared to those older classes of drugs. And then the SNRIs, which I was starting to allude to, if you want me to pivot to that. Um, They're balanced between serotonin and norepinephrine. And the major ones are um venlaxine and desenlaxine um symbola and prestique. Yeah.

And um those can be very effective and potentially less likely to cause the cognitive dulling or a effective blunting that people sometimes get with SSRIs or the cognitive exacerbation, let's say, of an underlying subclinical or full-blown clinical diagnosis of ADHD. When would an SNRI, which again, you always think the newer the drug, the better it is, but when would you turn to an SSRI over an SNRI? I would turn to an SSRI if I wanted to max out the serotonin component. And for example, OCD is a condition that responds better to aggressive serotonin modulation.

or I I shouldn't use that word because later I'm going to um use a different vocabulary to describe it, but signal amplification, you really want to turn up that serotonin signal with with OCD. And also with PTSD, you you want to turn it up. And these are generalizations. Yep. you know, everyone is different, but as a generalization, I would say that's the case from from my experience. Help me think about how you evaluate a patient um that's coming to you for a given condition and we can even just broadly pick several conditions.

We could start with bipolar because that's obviously very complicated and it's something that I know you have a lot of experience with. So it how often is it that a person is coming to you for the first presentation of bipolar disorder rather than someone who's coming to you because they've had, you know, they've been recalcitrant to lots of therapy and they're sort of winding up uh as a seeing you as as sort of a last resort hope. The interesting thing, Peter, if they're coming to me for bipolar, most of the time they don't know they have bipolar.

Okay. So you're the one that's sort of creating the framework around this. Yeah. I'm the one who's um throwing out that hypothesis. Okay. So tell me about what a person again it's hard to pick an average but pick you know sort of use your experience. Let me put it a different way if if that's okay. Yeah. I don't typically unless I have a patient in crisis where I'm worried about their safety or um self harm or harm to others, someone who's in an extreme radical situation where I have to focus on safety and protection.

I really don't approach a consultation that differently for all patients. It's all it all starts with how how can I be of help? Um what are you thinking about um in terms of talking with me and trying to feel better and that that's always the starting point and I let the patient lead me to the problem. So a person with undiagnosed bipolar will typically voice what concerns? Are they more troubled by the manic symptoms? Are they more troubled by the depressive symptoms? Well, in the population I see, they're more troubled by depression.

And the um type of bipolar we're alluding to is so-called bipolar too. Like bipolar much more common form of it where the manic part is not a true full-blown mania. It's so-called hypomomania. And that can be very adaptive. Yeah. As a matter of fact, I tr I would say maybe over the course of my career, maybe a third of my patient population have been incredibly successful people who've used their hypomomanic drive to achieve remarkable things. And so it can be very adaptive. But when they get depressed, they respond differently to anti-dopressants than someone who has nonbipolar depression.

So unipolar depression, which is nonbipolar depression, and bipolar depression have different pharmacologic response profiles. Can you say more about how they differ and what the implications? Absolutely. Well, someone with unipolar depression will typically have a, if the trial succeeds, a favorable response. They'll feel better. Someone with bipolar depression could either have an a negative response. It could trigger so-called mood cycling. They could become hypomomanic in an unpleasant way like a agitated, have trouble sleeping, have racing thoughts, um a variety of symptoms or they could have a mixed state, a combination of depression that's very common.

a combination of depressive symptoms, feeling sad, um potentially um hopeless, but also having feelings of agitation, physically feeling agitated and disconcerted. And you're saying that if the if you if you fail to make the diagnosis of unipolar versus bipolar and you prescribe the same drug and first line might be an SSRI. Well, there are ways to circumvent that. If you ask the right questions, you're less likely to prescribe the wrong drug. And what would be the wrong drug for the bipolar that might be the right drug for the unipolar?

The wrong drug would be I would say any anti-depressant instead of a mood stabilizer like lamotrogene. I see. So because lamotrogene, sorry to interrupt, lamotrogene can be very effective about treating depression. People think of bipolar drugs as treating the elevated moods, but um lithium and lamotrogene for example can be very effective at treating depression with monotherapy for many patients. That's lamed I assume. Yeah. Yeah. What's the mechanism of that drug? I think it changes sodium channels. Okay. And do we know why lithium works? I don't believe so.

So lithium monotherapy or lamedalin monotherapy is not just given to manage the mania but you're saying it can also improve the depression. Well it's the correct way to initiate pharmicotherapy with someone with bipolar depression. So sometimes it proves to be successful as monotherapy. Sometimes combination pharmicotherapy is required and you have to consider adding on for example an anti-depressant but they have the but you have to stabilize them first. Exactly. And it has the um sealing effects for certain drugs and the floor effects. Um, so, so it's it's less likely that adding an anti-depressant will make them more depressed or hypomomanic or put them into a mixed state.

Now, in an individual who you do not believe has bipolar disorder but still has irritability and mood swings, can SSRI or SNR stabilize mood? Well, irritability is such a huge category and a lot of people with depression have a lot of irritability. So, irritability can be part of a classic dysthic disorder presentation. um irritability, pessimism, sadness, um a lack of optimism, a lack of planning forward. Those can all be part of dysmic disorder. But so irritability can exist in that context. In a bipolar context, it's it can be more dramatic.

It can be I would say the word would be volatility as opposed to irritability that might be more descriptive of a typical patient with untreated or poorly treated bipolar disorder. When you think about the world we live in today and you imagine a time machine that were to take you back in time 10,000 years, do you think we would still see the same prevalence of depression? I'm not going to focus on anxiety because I I think the answer is we'd see a lot less anxiety. I don't have enough insight into bipolar to comment, but I I want to focus specifically on depression.

How much of depression do you think is purely biological and how much of it do you think is environmental? It's hard to know. I would say there are probably evolutionary reasons that the genes have survived. And so if you think of dal variation, change of mood over the course of the day and hyperomnia, excessive sleep, that might have been conserved evolutionarily because people stayed in their caves longer hours and only came out during the fewer daylight hours where there was more opportunity for mating, for acquisition of resources, food obviously.

ly and whatever other resources were sought for and sought um refuge in their caves or dwellings in a protective way so that their survival was likely to be enhanced. Where do you think from an evolutionary perspective depression specifically or let's just say dimeia or anodonia where do you think those would have been evolutionarily protective because I can sort of see anxiety having an evolutionary benefit for sure that makes a ton of sense I can clearly see why hypomomania could have an enormous evolutionary benefit um and I'm not saying I don't agree that the others could I just I'm trying to think through the cases.

Yeah. Well, you know, you know, it's very interesting. Um, specifically, I alluded to the theory of depression as being protective. Um, anxiety um can be protective, but it can also be disadvantageous. people's judgment can be impaired when they're anxious or when they're panicked. Let's say if someone is having a panic attack, instead of doing um undergoing a life protective behavior, they could be undergoing a foolish impulsive behavior driven by their anxiety rather than a more objectively based appraisal of the dangers of the environment that they might be unnecessarily encountering.

Yeah. I I I guess what I'm trying to understand is um there are so many things that we can clearly say are pathology even if natural selection had no point of view on them. So I'll give you an example. So atherosclerosis, I don't think natural selection and evolution cared a lick about it because it's a disease that doesn't really take hold until you're long past your reproductive age and it's just it just wasn't within the purview of it. So we've we've sort of created a luxury problem for ourselves which is we've we've even been adaptive.

Well, so that's an interesting question, right? How would it I mean I will tell you what part of aththerosclerosis was adaptive. The fact that we are humans and we are one of the few species that can experience atherosclerosis. I will tell you the adaptive part of that is we are the ones that carry the apo lipoprotein and that's the thing that's causing atherosclerosis but that's the thing that allowed us to have so much cholesterol to feed our huge brains in an environment where nutrients were scarce.

So, I can make the case that having LDL particles allowed us to have tons of cholesterol even if we were starving and that allowed us to never compromise our our growth, including our brains. But now that we live in an environment where nutrients are plentiful, it's not serving us so well anymore and we get aththerosclerosis. Um is there is there kind of a case that can be made that says either we are pathizing depression and in reality uh again I I can't imagine any person likes feeling I've I've experienced anonia I've experienced I know what those things feel like they feel horrible but but is that I hate to ask the dumb question is that a bad thing is there a time and a place for experiencing those things so that we so we can appreciate it when we don't feel those things.

Let's take anhidonia out of it because that that's a misunderstood concept. But I would say depression is bad. It um it takes a huge toll on people. It can be lethal. Um it can it it definitely increases the risk factors for a lot of medical problems. And um in that sense it's very adaptive from a psychological point of view. It can lead to a radical reappraisal of one's priorities and priors to get to a probabilistic model of thinking. um it can serve almost a as a giant shakeup of one's previous model of the world and their place in it.

So it can ultimately serve a purpose but I wouldn't want someone to have to suffer like that to achieve that goal. There are better ways of getting there than getting there through depression. Depression is not a good thing. We're talking about clinical depression. We're not talking about the depression of everyday life. Yeah, that's a good thing. Okay. So, that's what I'm sort of getting at, right? Is do you believe that there is a much higher incidence of clinical depression today than there would have been 10,000 years ago?

That's one of those questions I could speculate about. But you know, Peter, when I look at our world today and our children and the kind of world they're facing, they're facing enormous challenges existentially. What role am I going to have? Artificial intelligence is evolving. If we if our primary identity is our intellectual function and we're creating machines that are going to surpass our own intellectual function or in certain examples have surpassed it in certain areas then how can I flourish but but let's go back in time 10 years when nobody was thinking about that other [clears throat] than a few people okay wouldn't the wasn't the prevalence of major depression a decade ago so comparable to today and would that still have been significantly higher than it was thousands I think it's going up because there are mult multiple simultaneous challenges there's a lot of environmental anxiety that we see a lot of increase um challenges to the environment fires in the summer fires even in the winter in certain places in the cold but again I I I when I think about those things, and I'm not disputing that those things are happening, but contrast that with how miserable it must have been.

Like just imagine what it was like to be alive a thousand years ago. Yeah. Like wouldn't you rather be the least wealthy person in the United States today than the king of England a thousand years ago? You know, it's very complicated. I'm just saying like is for as lousy and we can talk about all the things that make the world a lousy place today. Yeah. It's still infinitely better than it was just a thousand years ago. From a bourgeoa point of view, yes. But from a relational point of view, well, so that's that's a that's that's exactly where I'm trying to go with this, which is what are the factors?

What are the I don't the word environmental trigger I think is is is is preventing me from really getting at the I think I was premature. Well, no, no, no. I I I'm just saying like I'm genuinely curious as to what what do we think is the causal relationship between mental health deteriorating um and the world we inhabit. I think a lot of it has to do with things that are spoken about social media. Um, people being on digital devices, being isolated, and having a distorted view of the world created by commerce to be kind of sucked into their algorithms and therefore isolated as a result.

And people are having less sex. People are having fewer romantic relationships. People are using online pornography more in in the absence of relationships. Fertility rates are going down. Reproductive rates are going down. There's this great divide socioeconomically that I think is having an outsized role too. So when the king was the king of England 10,000 years ago, well, you know, what whatever time frame you were alluding to? Yeah, 10,000. 10,000. That's a more historically accurate one. Thank you. Thanks for correcting that. um probably everybody else didn't know anything different and if there was better they just accepted that was the that's how it was.

They weren't going to be kings. Um they lived in the moment more. they accepted the realities such as they were perhaps you again this is all hypothetical um the and so that enabled them to live more in the moment just like older people people who are close to the end of life um wi without being ill um are able to enjoy the moment more appreciate the moment more um so I think that the great divide socioeconomically has created a lot of anxiety and demoralization. And when people have low adaptive capacity and low vulnerability thresholds for mental illness, that's when it starts to emerge.

Yeah. I I I that that makes sense to me. makes sense to me that the relational component, the comparing component, the digital component, these things must be contributing. Um, and in addition to everything you've said, and I've brought this up before on the podcast, I I had a a guest on many years ago. His name is Tom Katana. He's a a physician who's a missionary in um uh the Nuba Mountains of Sudan. And so he takes care of 1 million people there that are without any health care.

And these are people that are particularly being targeted by their government. So they're they're literally being killed by their own government. And so, you know, they're being bombed and he's taking shrapnel out of their wounds in this hospital by himself with a couple of nurses. Remarkable. Unbelievable. Um, and I asked him, um, and I can't remember if I asked him this on the podcast or just when we were together having dinner at some point, but I said, um, you know, Tom, what what's the prevalence of depression there?

And he said, like, none. Like there is no depression, you know. Um, tight-knit families, common purpose. Uh, yes, it's scary when the when the airplanes come over. They all have to dive into a ditch, but basically other than that, they're they're farming. They're doing their thing. And um they don't know better is is part of the part of part of what it is. I'm not suggesting that we should that we want that that that's we that needs to stop. But but but there's a there's a there's a price we pay for modernity.

Yes. And I wonder if this is the price. Um, very complicated. War seems to improve people's mental health, ironically. Yes. With obviously dramatic exceptions for PTSD and other loss. Um, but to to say it's the price we pay for maternity. Um, if you want to accept modernity as it is without challenging it, yes. But a lot of people are challenging modernity and let's say looking for alternative approaches such as living more in nature. Y would be a great example of that and getting off the grid.

Yeah. And I when I say that the the the the um you know this is the price you pay for modernity. I think what I what I would say after that is unless you start to take individual measures to control some of this. So again we have to make a greater effort to be outdoors today. I think there's tremendous benefit to our mental and emotional health in being outdoors but the but it's no longer the default. You see, we used to live outdoors. Now, we don't.

So, if you want to be outdoors now, you have to actually take the steps and do it. Um, it's much easier to live in isolation today. 10,000 years ago, it was metaphysically impossible to live in isolation. You would have died very quickly. Today, you could live in isolation all you wanted. So, if your tendency is to isolate, you actually have to work to overcome that. Uh, similarly, it's very easy today to see everything to be overrun by information. Mhm. If if that's contributing to your mental health, you actually now have to take a deliberate step to pull away from media if that's part of the problem or whatever it is.

So, um I I'll give you an example. Um, I I did a podcast recently on sleep and the way I sort of framed it was without having great evidence for this, but looking at sort of some of the literature on hunter gatherers, there's no evidence that hunter gatherers suffered from insomnia. Um, they didn't necessarily sleep 8 hours a night. They they they there's some evidence that they slept in in sort of shorter windows, but the point is they weren't walking around struggling to fall asleep, waking up ruminating and and suffering from a lot of the things that people suffer from today.

Um, and without rehashing the entirety of the podcast, I basically made the case that look, it was really down to the things that drive sleep. Circadian rhythm, adenosine, cortisol, all of these things have to be in sync for you to sleep. And the world back then allowed those things to be in sync. Fast forward to today, we've engineered a world that works against those things. It works against the rise and fall of cortisol, the rise and fall of adenosine, the rise and fall of melatonin. All of those things are being countered by our environment.

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

Yeah. And it's interesting you bring up sleep. Um I think all the foundational biological factors. So in my model of endocrinology c certainly hormones and the endocrine system are part of it but also inflammation, metabolism and stress circuitry in addition to circadian biology and sleep architecture. All those factors are challenged by modernity. Um if we want to look at metabolism diets and you know um people weren't needing to go on GLP1s a thousand years ago maybe unless they were the king. That's right. We know the king had gout but we don't know if anybody else did.

Um you know you raise a great point and um I' I've discussed this also on the podcast in the past. this uh this mental model of distress tolerance. So I I sort of and I wrote about this actually in my book which was um I this is the model that I use. It's how I think about my life. So when I'm irritable, which let's be honest, I can be quite irritable. I'm imagining I'm imagining kind of um a a window in which I occupy. And if the window is my distress tolerance window, when that window is wide open, Yeah.

I can tolerate a lot. I can take a lot of bullets and I'm fine. When that window is narrow, even the littlest thing will sort of irk me. If my kid does this or if my wife says this or an employee says this, I'll be irritable. Okay. So then I ask the question, what determines the width of my window? And and what's amazing but obvious is what you just said. Your biology plays such a role in that window. Yeah. Yeah. If I exercised or didn't exercise, that's an enormous contributor to the width of my window.

Oh, yeah. If I had a good night's sleep versus a bad night's sleep, huge contributor. If I'm in pain, you know, I had a dental issue a year or two ago and it just lingered for weeks. Like a lowgrade six out of 10 pain. Death. Death by a thousand guts. And I didn't think anything of it. But as I found myself irritable 2 weeks into this, you know, someone said like untreated pain is going to make you irritable. Um, if I could I could rattle off all the things that do it, but but everybody I think has to kind of discover what creates what lengthens their window.

Yeah. And do you get the impression? Yes and no. I mean it's part of the human condition that we all have these foundational biological factors and we we have an adaptive capacity and that's always changing over time. Um but how much of that is part of psychiatry? Like you obviously you as a psychiatrist are attuned to that but do you do you get the impression that that should be part of the foundational treatment which is yes I know that you're depressed. I know that your anxiety is this way or the other way.

I know that you're irritable, but are we looking at your nutrition? Are we looking at how much you exercise? Are we trying to regulate your sleep? And are we actually treating some of those underlying foundations as well? Yeah. Well, I think a lot of psychiatrists are um and there are specialists like for example um in nutrition and psychiatry um sleep and psychiatry um there's a lot of research being done on the pathophysiology of metabolism and its role in psychiatric illness and I think most psychiatrists just try hard to touch upon those things.

So, I'd be careful um to say anybody wasn't doing it adequately to generalize, but I think we have to have a framework about how to think about it that the brain doesn't operate in isolation and it it's part of this larger system with birectional feedback. Mhm. And so when you have a toothache, that's um obviously tapping into your stress circuitry that's affecting your cortisol levels that that's affecting potentially if it's going on that's affecting your memory because it's toxic to the hippocampus. You're producing less BTNF which is critical for neuroplasticity.

So on many different levels um there are these continuous birectional interactions between what what happens on a neurotransmitter level and what happens with the foundational biological factors. I just chose endocrinology as the one I wanted to focus on because it fascinated me particularly. Well that's that's that's great because that's exactly where I kind of wanted to go. So let's go back in time five years ago when this interest of you of yours started. Yeah. Why did you pick endocrinology and how did you dip your toe in that water?

Yeah. Well, I was always interested in endocrinology and I have some friends, colleagues who are endocrinologists, but I I was really struck by the impact of the interpretation and the reinterpretation of the women's health initiative and how that changed prescribing practices so profoundly in general medicine. It led me to think, well, if that happened in general medicine, how is it affecting the appreciation of endocrinology in psychiatry? And I concluded that endocrinology from my perspective tends to be at least by me previous to that was significantly underappreciated in psychiatry.

and that there are a number of reasons for that, but that that was something I wanted to roll my sleeves up and get into. So, I sort of went back to school, so to speak. I took a course in bioididentical hormone replacement therapy. I got certified as an advanced practitioner of BHRT which just opened a window and I did a number of other educational activities to learn more about it and I found it to be fascinating particularly how I feel the um neural circuits and neurotransmitters are really inseparable from the endocrine system.

So, I want to go back to something you said. You talked about the WHI. Um, your career has spanned pre and postw. So, so 25 years ago, you got to witness the complete reduction in the prescription of estrogen um for women during menopause. Correct. What was the impact you saw in your practice as you saw women go from receiving hormones at the time of menopause to women being deprived of hormones? Variable. And it was so long ago and I was so relatively ignorant as to where I am now that I'd be hesitant to make any generalizations about it.

But you brought it up as hey five years ago which means you're 20 years post WHI. It was still kind of clearly there was still something there that made you think it made an impact on me. I had the impression that it people, you know, again getting back to adaptive capacity, that um women whose adaptive capacities were higher, their ability to self-regulate and adjust to internal and external threats and changes was being eroded off of estradile. And similarly for both sexes that um men who needed testosterone, weren't getting it, were being told it wasn't safe, um similarly had an erosion of their function across multiple domains.

I don't think there's a way that we can dive into this Lionus without you explaining some of the biology of how estradiol and testosterone and maybe even progesterone or uh leoparoxy like all of these things. Yeah. Like let's start with estradiol. I mean I I I share your point of view. I feel very strongly that estradiol is one of the most important hormones in the brain both for men and women. Um, so, um, maybe walk us through kind of some of the reasons why that's the case and because it it probably isn't intuitive to everybody.

Definitely not. It wasn't to me. Um, so in preparing for the podcast, I came up with a mouthful, but um, estradile is a constitutive pleotropic multi-system regulator of neurotransmitters and neural circuits. So constitutive what does that mean? It means um part of the architecture um evolved hormones were evolved by the brain for the brain. So there's no separation of the endocrine system and the brain at that level. Pleotropic it has multiple actions um at multiple levels throughout neurotransmission. So for example, estradiol mod modulates not only serotoninergic transmission profoundly but also the dopamine system, the GABA system, acetylcholine, NMDA and glutamate.

Um so it's really profound. Um and it's it serves a regulatory function. Well, psychotropics are signal amplifiers. Um, estradiol for example is a system modulator. It um creates the conditions within which neurotransmission occurs. Do we know how these hormones are regulated in the brain? We have a pretty good sense of how they're regulated in the periphery. We understand the feedback loops. We it's it's actually hard to disentangle them because quite frankly it's the pituitary gland that does so much of the regulation uh in in the periphery through luteinizing hormone and follical stimulating hormone.

How is that happening in the brain? Well, it's the HPG axis, the hypothalamic pituitary gonatal axis and all the birectional feedback that occurs w within that um framework. In other words, is there actual estradiol in a syninnapse or is it removed from that given its size and it's regulating it? It's it's it's regulating upstream of the of the actual synaptic uh contents between you know where the actual neurotransmitters live. Um no um it there are receptors for it on the membranes of neurons. So they're they're well characterized.

There's um membrane estrogen receptor alpha and membrane estrogen receptor beta. And they're also transcriptional binding sites, estrogen response elements within our genomes. So estrogen is penetrating to the deepest level of our central nervous system where transcription is regulated. And that for example is how serotonin synthesis is upgraded through tryptophan hydroxilase. There are specific estrogen response elements that bind to promoting factors for tryptophan hydroxilase therefore increasing serotonin. The same thing for dopamine through tyrrosine hydroxilase. um the same thing for acetylcholine through choline acetal transferase. So it's right there.

It's you know at ground zero of neuronal activity which is fascinating and that's part of why I find the whole thing just so remarkable that it's embedded um with with embedded w within the brain. And I I I I had another term for that that I was searching for. Um you know, imbued with and embedded within the the brain is how I think about it. Let's now talk about the removal of that. So everything you said kind of explains the biology of what estrogen is doing.

Yeah. But now let's characterize the phenotype. So if estrogen is reduced, all other things being equal, how does that how does the brain experience that? Well, let's think of evolution. Um estradiol evolved to be not only a sex hormone but this pleotropic regulator of other systems because for successful reproduction it's not only conception that's required. It's nurturing. It's forming social bonds. It's acquiring resources. So therefore this pleotropic role has been evolutionarily very adaptive that one hormone has these multi-system effects and that's why you see women with low estrogen having multiple domain challenges from cognition to mood regulation to anxiety to um you know a number of other challenges and why do you think it is so variable Lionus there are I I I can't imagine you haven't seen what any doctor has seen in this situation which is there are some women whose cognitive symptoms in the presence of estrogen withdrawal are incompatible with normal life and there are other women who barely notice it is Is it receptor density?

Is there some other sensitivity? It's a combination of genetics for receptor morphology um and function rather than absolute levels being determinative of psychopathology or emotional variability in response to change in estradiol levels. It's more the actual change and fluctuations and oscillations of those levels themselves. That's why PMDD is what it is because alopreganolone levels a derivative of progesterone go down significantly toward the end of the ludal phase. And therefore there there are some women due to a variety of reasons. It's all biological. It has to do with receptor morphology, genetic influences, possible environment influences that have degraded their receptor modulation and responsivity.

Um some some women are are susceptible to a much greater degree. You know, you use the example of, you know, I I have a toothache and I haven't exercised and I'm feeling, you know, irritable as hell. Well, the the same thing applies to all of us. We have different adaptive capacities. So, a woman who's sleeping well, who has good social supports, who doesn't have huge caregiving burdens that are overwhelming, who doesn't have occupational stressors that are overwhelming, who has meaning and purpose in her life, she's more likely to have a higher adaptive capacity in general to menopausal changes.

I'm not talking about PMDZ. going back to menopause, she's likely to have the bandwidth to withstand it than a woman who's incredibly burdened at work with with with terrible stress who has huge caregiving burdens, let's say for a parent with Alzheimer's or the primary caregiver and that parent is living at home, someone who's um metabolically challenged, overweight, not exercising, Um so all these factors play a role as well as medical illness as a generalization and then of course it's it's complicated because a lot of times the loss of hormone makes it difficult to regulate metabolic health makes it difficult to have the motivation.

It's it's a very vicious cycle and it amplifies the problem. Absolutely. Um can you say anything about this in men because again I think this is counterintuitive but but I don't think men are particularly less susceptible to this both testosterone and estradiol. Let let me just say men get their estradiol from testosterone from the aromatization of testosterone. So testosterone is a prod drug for estragile as well as as of course being a primary drug for all the obvious reasons but as a primary hormone um testosterone modulates there there's a lot of system redundancy.

So um testosterone modulates dopamine in particular to a high degree. So um losses in testosterone in men are much more typically not always typically andropause which is the male version of menopause that some of the audience may not be familiar with the terminology. Um andropause is more gradual and insidious and less likely as a result to be identified. um but it can present with a sense of dulling a loss of um the dopamine mediated functions. So the miso liyic and misoccortical functions those are two path pathways of the dopamine system.

The misolyic has to do with reward salience. What what goals are worth pursuing and reward prediction? I if I pursue this, how how likely am I to get it? Um and the the misoccortical system has to do with executive function, um working memory, um all the symptoms that are impaired in someone who has ADHD. So you can have like so-called subclinical um syndromes of cognitive dysfunction and ADHD like um symptoms in men with declining testosterone in addition to the androgenbased um generally more um vital physically active and libido enhancing effects of testosterone.

And how much of that do you think women are also dependent on in terms of their testosterone? Yeah. Well, I think li libido is a huge one that women are almost entirely dependent on testosterone for libido. And um what about mood, sleep or some of the other things that where men receive a benefit? Men men are more vulnerable in that department. Yeah. Why do you think that is to testosterone? Yeah. Yeah. Why do you why do you think women are less responsive to andor dependent on testosterone for some of those other things?

Is it because estrogen evolution? Because they make so much less of it. Got it. Although um they they still make 10 times as I was about to say they still make much more testosterone than compared to men. Yeah. Yeah. for the audience that might be worth your reiter reiterating. Yeah. I think what's always misleading when you look at a laboratory report is the number for estradiol is so much bigger than the number for testosterone in women, right? Um but that's because testosterone is reported pog per mill per deciliter, right?

Testosterone is reported in nanogs per deciliter. Estradile is reported in pograms per deciliter. So you have to normalize those because they're off by a factor of a thousand. And when you do that, you realize that a woman's testosterone level is about 10 times higher than her estradile level, although it's about onetenth the level of a man. Yeah. Yeah. Um, as you no doubt know, there are various ways to increase testosterone in men. Um, the most obvious and direct way is to give a man exogenous testosterone.

That's a very safe and effective way to do it. It's also the easiest way to do it. But not all men want to receive testosterone that way. Sometimes they want to indirectly receive testosterone by taking hormones that will tell their body to make more endogenous testosterone. And the two most common ways to do that are giving hCG, which is giving effectively luteinizing hormone, telling the body to make testosterone. And then the other would be using uh drugs like Clomid or Pomophin. Yeah. Clomophene or enclomophene. Yeah.

Which basically trick the brain by blocking at the hypothalamus the receptors for estradile and testosterone such that the pituitary says, "Oh gosh, we're we're let's we got to make more of this. We're going to make more LH and FSH." Is there any reason to believe that that approach robs the brain of the the very estrogen and testosterone that you're trying to give it? I would say just empirically men who t take chromophane tend to be dissatisfied even though their numbers are high. Yes. In the periphery.

Yes. Yeah. That's been our experience. Laboratory mismatch. Yes. That that and I and I I have I have no data to suggest why, but this has always been the question I've thought is which is unfortunate because it's an otherwise very convenient way to replace testosterone. Absolutely. Yeah. Yeah. So, okay. I wondered if that if that was your Let's mention the primary reason why clomophene is typically prescribed and as well as HCG. No, no. The rale. Okay. So, there's I think there's three rationes for clomophene and enlomophene.

But I think where you're going is you preserve endogenous production when you use either well fertility. Yes. Which of course comes with it. Yeah. Yeah. Um so that's a huge part of it. Um I think even when you consider hcg which I think is a superior drug to clomophene and enclomophene because it's administered peripherally. It acts peripherilally and it doesn't have a central block. Yeah. But it let's be honest it's injectable. It's a very very delicate peptide. It's very expensive. It's inconvenient. It's got all those problems.

Clomid's cheap. It's oral. And by the way, a lot of people don't know this. It's not regulated. So, right, testosterone and hcg are schedule 4. Clomid and clomophene are not regulated for now. Yeah. So, any you don't have to go and see a doctor formally to do it. It can be kind of a jack in the box online thing that can give it to you. Um, but you're correct. The few times we have used it for patients who want to preserve fertility, want to rely on endogenous function, don't want to deal with needles, it really fixes the numbers.

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

But progesterone is the easiest one I think to draw because for the first 14 days during the Yeah. During the follicular phase from the moment she has her period until she ovulates there's nothing flat lines and then it rises as it prepares for implantation. Yeah. It hits a peak assuming there is no implantation. And it's important to mention why that is because it comes from the corpus ludium. The follicle that is broken and the lining of that follicle I believe is what secretes the progesterone. Right.

In preparation for the follicle to be implanted. Yeah. But once it's not implanted the lining sheds, which is what the period is. But the point that you're making is but it's that progesterone that is crashing down. Yeah. Yeah. And what I find very interesting is that it's it's the woman didn't feel bad when her progesterone level was low. Right. Cuz she she felt fine during the follicular. No oscillation. Exactly. It's the fall back to low from high that causes the symptoms. This is this is incredibly fascinating.

It is. And one of the most fascinating paradigms in human biology is postpartum where progesterone goes from all-time highs and so does estradiol. Estradile goes from 30,000 to let's say 30. Yeah. Um progesterone goes from several hundred to less than one within 24 to 48 hours. It's amazing that women do as well as they do. I'm in awe of You're in other words. Yeah. I just want to make sure the listener knows what hormones the more in awe of women I am. Yeah. You're you're in awe that more women don't experience postpartum depression.

Yeah. But of all women for having to deal with these issues that guys don't have to deal with and how profound they are and how challenging they are. So, do you think we understand why, and I know you've talked about it in terms of genetics, receptor density? Is there anything else we know about why some women will experience that drop in progesterone over the course of a week in the last part of their cycle and be really debilitated by it and well, some will not notice it.

Um, there's a lot of research. How genetic is it? I I assume it's quite there's a strong concordance between mother daughter. I believe it's highly genetic. Yes. Do you know how predictive that is of postpartum depression or how predictive that is of cognitive or depressive symptoms during menopause when there is a depletion of both progesterone progesterone and estrogen? Um I'm not sure. There is a correlation. And I'm not sure h how how high a correlation there is, but I would think there would be a very high prevalence of women who have post severe postpartum depression or psychosis who also have PMDD.

Let's talk about not the converse. Yeah, let's talk about postpartum depression. Um, yeah. Do you see any women for that in your practice? Yes, because only because postpartum depression is a very heterogeneous condition. The most dramatic example of severe postpartum depression and psychosis happens within a week of childbirth. And it usually unfolds in a hospital where a woman goes from a normal frame of mind. And with estradiol levels and progesterone at their peaks, these women are, you know, women in general at the end of pregnancy are primed to be in wonderful moods.

Yeah. And they go from there to having um the ones who are afflicted by severe um cases of postpartum depression and psychosis start to become suspicious of um the hospital personnel become hypervigilant about where the baby is and have very intense separation anxiety. can have intrusive ideiation about their harming their own children themselves without wanting to but having some fear. It's an OCD like phenomenon that they can have a fear that they can do something that they would never do and we don't know why this happens to some women and fortunately few women it's being researched um Hopkins has a big program in that what do you know the prevalence of that severe a level of postpartum depression um fortunately less than 1% much less so those aren't the women you see because presumably those are the women that are under care of a psychiatrist within the hospital, you're seeing women who go home, everything seems fine and presumably over the next few weeks or even months.

Yeah. They just don't get back to themselves. Yeah. Okay. So, when a woman like that comes to you and let's assume she's never seen any psychiatrist before. Yeah. How do you do the evaluation and how do you think about treating her? Um, I do the evaluation the same way. Okay. Um I asked her um what's troubling her and I um h have a third year for um issues around um the existential shift in identity of becoming a mother um either for the first time or subsequent times.

It's a profound identity transition and it affects different women differently. Different women have different levels of support from their spouses if they have one, from their families. Um, different levels of socioeconomic really. What if there's been no change? So, what if you have a case where a woman, it's not her first child, so the identity piece hasn't changed. There's nothing obvious you can point to in her personal life from a support network or attention in other in other words like does it sometimes just occur almost yes random yeah and and and so how do you okay let's say you make the diagnosis which I assume is not impossible to make what what are the even for a psychiatrist what are the um what are you thinking about as you start to lay out treatment options how How much do you and again maybe I'll just make it a little straightforward and say let's assume there are no other comorbid conditions that would make the Yeah.

pretty similar to non-postpartum depression. It's only the acute type where so there's a synthetic analog of that chemical that the body makes the hormone alopanolone called seranalone um which is now in a pill form. It used to be Brexanolone which was an intravenous infusion given in a ambulatory center where a woman had to stay there for you know a protracted period of time. Think about a woman who's having all these issues and has to be separated from her family and her baby you know so for fortunately they came out with an oral form of it.

Um the generic name is zeranolone and it's a synthetic version of the neuroststereroid alop pregnanolone which is the breakdown product of progesterone via five alpha reductase and three alpha hydroxy steroid hydrogenase. So would you give that as monotherapy or do you give that in combination with for example an SSRI? Oh, well that's the one in the hospital that starts in the hospital. Okay. But when she's when she goes home when she goes home, what do you No. Um, all other things being equal, you you just give that.

You just give that. Yeah. Okay. Yeah. If someone is on an SSRI, I I wouldn't take them off of it, but you wouldn't start an SSRI then. Okay. No. And in your experience for that woman in the case we've described who's presenting to you in the weeks or months following her pregnancy. Yeah. How long does she typically require treatment before the depression? We're talking about a different category than the synthetic neurosteroid category which is that acute immediate. Yes. I'm talking about the woman who presents to you outside.

That's a very heterogeneous population. Um, if they had so-called pre preorbid history of depression, a depress history of depression before their pregnancy, for example, or if they have bipolar disorder, let's say they didn't have either, then I was going to say they're at higher risk. Yeah. um if they had neither um then you would treat them pretty much like any other patient with depression. And when you're talking to that patient and setting expectations and they say to you, uh doctor, how long am I going to need this medication until I'm back to myself?

What what would what would you say? When people ask me questions like that, which I get all the time, um I go back to what their previous baseline is. So if if they were well for 34 years and then they have this one episode, I would say, "Oh, um um evidence-based medicine would suggest that you stay on this medication for somewhere on the order of 8 to 12 months and then we could depending if you respond well, we could taper you off of it slowly and see see how you do, but I wouldn't think at all that you have to be on this medication indefinitely.

But if they said that they went into it and they they had dysmic um tendencies that weren't diagnosed like pessimism, constant irritability, um [clears throat] just sadness and they felt that their mood was um beneath baseline for most of it. Then I would say, well, let's see what you want. it isn't what you need. It's more a quality of life issue. Um because often what happens in a situation like that is a woman goes on a medication and for an acute depression and she finds her new baseline is better than her preorbid baseline.

So she's she feels better than she did before she ever started taking the psychotropic or had the certainly better than before she had the major depression. So in other words, the pregnancy may have unmasked something that she was just sort of stoically pushing through before. Um it served it exacerbated it. Mhm. Yeah. Yeah. Okay. I want to pivot to another endocrine system on that same HPA axis or HP axis not the A part the uh the thyroid system. All right. So, so let's everybody's heard of TSH and everybody kind of understands more or less the thyroid.

We we did a great podcast on it recently. Yeah. Um I think it's kind of intuitive to people that Well, maybe it's not actually maybe it's not. So, let's just take it away with how does the how do T does T3 and T4 and TSH interact with with the uh with with the system with the psychiatric system overall? Just to give an overview of it. um TSH is what the pituitary thinks of the thyroid axis. And what um what I find is that a lot of people with quote unquote normal values of TSH, which is often what the average internist measures in the average psychiatrist.

um people with normal range TSH let's say in the top 50% of that range. So if the normal range is 8 to 5.0 zero. People, let's say in the range of 2.5 to five, are often considered normal and dismissed, but that's often indicative of a real foundational deficiency in thyroid hormone because that's only a signal to the thyroid to produce thyroid hormone. And thyroid hormone there are two types. T4 which um has two functions. It's a prod drug and it gets into the central nervous system to be converted centrally there to T3 and it's also a prod drug in the periphery.

So there are two different types of de iodizenases enzymes that convert them. So free T4 is a very very important value and if free T4 is suboptimal in a patient with depression it's a signal to me that that person should have an endocrine consult or I myself should directly prescribe them thyroid supplementation. So do you rely more on the TSH level or the free T4 level? Yeah, free G4 and free G3. Yeah, but primarily free G4. And if the TSH level is um in the middle or low end of the range, but the free T4 is low, how do you act?

versus if the TSH is in the higher end of the range, but the free T4 is also in the higher end of the range. How do you act in those two settings? I'm not concerned about the TSH. I'm concerned about the free T4. So that's the biioarker that's more of interest for me. Yes. And then tell me in your experience where when this is being missed, right? Right. So if this is being ignored, yeah, where is it most showing up? Is it being is it showing up more on the depressive side of the axis?

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

Um like literally zero. Yeah. um their free T4 was quite elevated although not so elevated that you would think anything was going on but they when on questioning they were they had lots you know they had palpitations of their heart their resting heart rate was quite high uh they were sweating quite a bit and so that was a patient that we very quickly got into an endocrinologist uh for the appropriate medical management of that that that hot thyroid nodule. Yeah, there can be a hypertensive crisis, right?

Yeah, that's a good point. He had slight hypertension, but he wasn't in kind of a crisis. He was uh it required medication, but it was easy to manage on one drug. Yeah. Yeah. So, I've actually never seen it in my practice. Um but um less traumatic hyperyroidism I I have seen and that can absolutely manifest in anxiety and it's very physiologic. So, it's less the cognitive anxiety, worry, rumination, um, social anxiety and whatnot. And it's sematic anxiety, anxiety in the body, racing heart, um, restlessness, agitation, insomnia.

That that sort of anxiety is what's manifesting. Focusing on the hypo because that's the far far more common one that you see and we would all see, of course. Um, is your approach to treating this with monotherapy, T4 monotherapy? Do you like to use T4 and T3 together? Do you like to use desiccated formulations that combine them in fixed ratios or how do you Yeah. I like to use a combination of T4 and T3 where I can have more control over the exact um dosage. In the cases where you're prescribing it, presumably it's because of the psychiatric underlying belief or case that you're treating.

Yeah. Are those the symptoms you are titrating the drug to or do you look at something else such as the biomarker? No, the symptoms symptom. Yeah. I I I check the labs. Y I absolutely check the labs. But um I'm focusing mainly on symptoms. And by the way, there are exceptions where I sometimes only prescribe T3 for treatment resistant depression. Yeah. Yeah. Say more about that. Um, it seems to, for whatever reason, there's been research done on it for many years. It's a long-standing treatment for treatment resistant depression because it boosts metabolism and energy.

And when you say T3 for the listener, um, can you differentiate between the FDA approved T3 cytol, which is very short acting, versus the compounded formulations that are more timereleased. Yeah. Um, I I don't I avoid the compounded ones and I usually recommend twice a day like first thing in the morning and and then 6 to eight hours later, not too late because it could cause insomnia. And what doses? I mean, it's we're talking five micrograms. These are presumably relatively mild. Yeah, I start low. Yeah, I I I can even start at 2.5 twice a day.

But sometimes it goes high. It can go to 25 twice a day. 25 micrograms of immediate release T3. For someone who's very depressed. That's amazing. And responds to it. Yes. And has normal blood pressure and pulse. Yeah. So give give me an example of a p Can you do you can you recall a case of a patient in that required that much T3? Yeah. So what what had you tried before? I tried um a series of monotherapies with anti-depressants in combination therapies with anti-depressants and mood stabilizers and let's say lithium which is a so-called augmentation strategy but this was not bipolar this was depression no yeah unipolar depression unipolar depression and you've and I assume you're trying monoamine oxidase inhibitors.

No, you were all SSRI or SNRI. Okay. Yeah. Or buproprian. Okay. And which is Wellbutrin for the listener. So each of those therapies in monotherapy had not been successful. And then even when you layered on presumably a not a not a bipolar dose of lithium but or or an atypical antiscychotic because those are also indicated for treatment resistant depression. drugs like um Rick Salty um there are a number of them that are used now ailify y Brex Rexel is Brexipole Arapipra um zipa alanzipene um those drugs are often quite effective as augmentation strategies adding on top of an anti-depressant And despite all of those combinations, he remained depressed suboptimal.

Okay. So he got somewhat better but not Yeah. I think mentally I'm conflating several patients. Understood. Um, and when you used the T3, did you discontinue the other drugs or did you I always try to be as um minimalistic as possible, but when someone is depressed and has a partial response, I'm not going to take them off. Yeah. Later on when they're feeling good is the time where you have the luxury of peeling the layers of the onion. So, in that particular example that you've got your mind on, when the T3 um brought symptom relief, do you recall if you were also able to get any of the other agents off?

I know in the long run I tend to try to taper someone off if their regimen looks ungainainely and presumably there's an order. And I mean do you try to remove drugs in the order of side effects? So for example the order of efficacy. In the order of efficacy. Okay. So we we are slave to efficacy first side effect second. It's up to the patient. Okay. It's shared decisionm because some of those drugs like ailify have unwanted side effects like appetite increase or things like that.

Correct. Well much potentially worse than that. They can have delayed neurotoxic side effects. So what I mean by that is they can cause tardive diskynesia, tardive donia. Tardive diskynesia is a particularly disturbing side effect for someone to have. Um potentially irreversible. Now there are actual drugs to treat it with. Wow. Um, but it's uncontrollable movement of the mouth, tongue, and throat muscles that can be re really disturbing and even dangerous. It can interfere with eating. Um, yeah. So, the stakes are high if you're going down that route.

Yes, they are. And I always let the patient know and it that's a rare side effect and it has to do with dose and um length of exposure really over years. Now in a patient that ultimately ends up needing that much T3. Did their thyroid labs look that dramatic or not necessarily? Not necessarily. So that is not necessarily a patient that showed up with a TSH of seven or 10. Oh yeah. those I refer to endocrinology. I wouldn't go near that. This is remarkable to me.

Um why do you think in the case of those few patients that have required or or who many [clears throat] patients who are depressed and have low normal free T4 andor free T3 seem to respond quite well to thyroid hormone supplementation. And you believe that the reason is primarily through upregulation of metabolism and increased metabolic rate more than it is it could be central. Yeah. I mean thyroid upregulates kakolamine receptor response to so it could be norepinephrine that's they're they're getting more and dopamine. It could also be serotonin.

Thyroid increases um serotonin receptors density. Serotonin receptor density. It also increases mitochondrial biogenesis on a genetic level. So the pro the probability Yeah. The probability is it's doing more than one thing. How deep these hormones go. Yeah. Right. In terms of the overlap and the um co-mingling with neurotransmission and neural circuits. So of all the hormone. So when when I talk to patients about hormones, I usually say I think of them as four axes. Yeah. Okay. So I think of the the the the thyroid axis, the androgen axis, um the uh adrenal cortical axis and the fuel partitioning axis.

So your insulin, glucagon, etc. Um I think the one that is most challenging is the third one in that list I gave which is the the cortisol pathway because yeah um most people are experiencing too much and not too little and we don't have a pill that is an antidote. You can't treat it directly, right? So you have all every one of those other systems we can treat directly. We have so many amazing ways to treat. Yeah. Because you know it's they're usually problems of too little and we know how to fix it.

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

It's hyperarousal. Yeah. That should be reserved for a chronic state but is instead for an acute state. Sorry. That is instead in a in a chronic state. Yeah. And as we've just danced around, we don't we don't have a pill to block it. We don't we can't say go and take this pill and it'll make it go away. And [clears throat] even if we did, that may not really solve the problem. So, how do you with your endocrinology hat on, not your psychiatry hat on, think about that?

Or do you just say, I can only solve this with my psychiatry psychiatry hat on? I don't think that way. Okay. In other words, um I don't see any dichotomy between psychiatry and endocrinology. Um and so I I don't have different hats just just to be, you know, transparent about it. Um but I think I solve it. I don't solve it. I collaborate with a patient if that patient is willing to attack it at its source. So if whatever the source of the hyperarousal that's maladaptive, whether it's a caregiving burden, whether that person at work is taking on way too much, which I see a lot of, um whether it's a medical illness that they're not paying sufficient attention to that's causing hyperarousal um to address it at the source, the the cortisol is a signal.

As far as I'm concerned, um it's not really the primary problem. It's a secondary manifestation of a primary stress um problem that isn't being managed adaptively. And are you discussing it that way with a patient in the same way? Because it's if you're giving a patient estrogen, you're explaining to them why, right? This is this is what estrogen is doing. this is why we're replacing it. If you're giving a patient levothoroxin or cytol, this is this is why and this is what it's going to do.

So when the patient when you suspect that hey a big part of what's going on here is hyperarousal. Um how much I don't tell the patient that you don't? No. Okay. I don't have an endocrine centric vocabulary. So I just talk people talk like you know that boss you and that boss you know have you asked for a transfer or you know I know you're a very dedicated daughter but you know your father with Alzheimer's he's very wealthy you could hire nurses around the clock you could still have them, you know, live at your house, but you don't have to do all the work.

Um, you know, a more common sense approach. So, let's think about a couple of ways to illustrate this for folks and tie it all together, right? Which is um thinking about the the psychic pharmarmacology of the modern tools that you have. Yeah. plus some of these endocrine adaptive tools. Yeah. And is there a case or two that come to your mind where I mean we've already discussed one, right, which is and it was potentially a a few patients merged into one, but this this case of recalcitrant depression that responded to what I in my world would have been a very high dose of T3 and yet that was the unlock.

Do you have any other cases like that that come to your mind? say a woman who comes to me permenopausal age who says doctor I need hormones and I say what's going on and she says well I've always been the strongest person handling my emotions as far back as I can remember but menopause is overwhelming Okay. So then I asked her, "You've always been the strongest, had the strongest emotions. What does that mean?" "Well, I'm just a high energy person." I said, "Well, tell me about your 20s and 30s." "Oh, okay." And she smiles and says, "Well, they were chaotic.

I I started several companies. Um, I traveled. I spent a lot of money. I I had a lot of ideas. Sometimes thoughts would race through my mind faster than I could write them down. And I would ask more questions. And um, in this particular example, menopause was really happening. I investigated the hormones and the ginadotropins and it lines up as well as the symptom symptomatology but the um menopause was a clue to longstanding neglected bipolar disorder. So I started her um lamotra gene and that was a road to restitution of her life's narrative.

She didn't know what was happening to her her entire adult life. And with that organizing hypothesis, she understood all the difficulties she had sustained. And now looking forward, she had reason to believe things would be a lot different. Now, in the case of that woman, did she talk about any of the depressive? Um, yes. Okay. Yes. She had gone to a previous psychiatrist for a um I would call it a bipolar depression. Um an episode of depression that happened in her 30s after she had a extended hypomomanic period of incredible productivity.

She crashed and could barely get out of bed and went to the psychiatrist. He prescribed an anti-depressant. This gets back to what we were talking to earlier. What happened? Well, first it was miraculous. She says, "Then a couple weeks later, I started having those racing thoughts again, and they were the worst I'd ever had, and I couldn't sleep at all. So, I stopped it and never went back to that doctor." She stopped the medication. And what happened? Back to baseline. The the same hypomomania. Oh, yeah.

the roller coaster. Yeah. By the way, what do we know how much of what's happening in her brain is like do we know biologically receptor-wise what's happening in her brain that is causing the hypomomania? No. Isn't that amazing? Yeah. I mean, I can't imagine for you how amazing that is. Like for me, it's amazing and I don't treat these patients and yet you're looking at this person and you're watching their experience. Yeah. Well, it's clearly some limbic dysregulation, but it's I mean, this is why I think psychiatry is such an incredible field and such a challenging field is like, can you imagine a diabetist not understanding that there's a beta cell that makes insulin?

No. Like, and yet they have to somehow treat this person. on a molecular level, it's probably understood better than I'm describing in terms of ion channel function and whatnot, but it's very obstruuse and I don't think it's helpful for our audience to go there. So, I want to ask you, well, do you have another case you want to talk about? Because I have another question that goes back to kind of depression. Oh, tell me your question. Okay. So, you talked about recalcitrant depression. One drug we haven't talked about that's getting a lot of interest these days is ketamine.

Yes. So can you tell me your experience with seeing patients go through um ketamine therapy for um difficult to treat depression or just just yeah give me your your thoughts on the subject. Do you want me to tell you how it works? That would be great. Sure. So ketamine is an so-called NMDA receptor antagonist. So and we should just make sure people listening that is not the same as MDMA. This is totally totally unrelated. But I know people hear it and they think oh is that the same is that has any relationship to MDMA but it does not.

No none whatsoever. So um it antagonizes it blocks those receptors which are actually normally inhibiting GABA inter inter neurons that attach to glutamate. So what it does is it results in this massive release of glutamate and the excitatory response as well as the um um mTor pathway um and protein synthesis and synaptic remodeling. So sudden dramatic epic neuroplasticity. So it happens remarkably fast and it stops remarkably fast. So what's incredible about it is you can have a patient who's on the edge of being committable requiring hospitalization because they can't contain their suicidal feelings and you can send them for a ketamine infusion and the suicidal risk dissipates you know dramatically dramatically better.

the depression doesn't necessarily. So, um, basically in my experience, I've used it sort of as a bridge to finding the solution for that patient rather than it being the solution. Occasionally, it is the solution and the patient goes for ketamine treatments and goes into remission from their depression, but more often from than not in my experience, they don't. And you have to find the right drug or the right other approach to definitively treat their depression on a longer time basis. Do patients become um resistant to the effect over time?

Is there a tachilaxis that develops? Yeah. Um I'm not that expert in ketamine honestly. So I'm not sure. I haven't seen that. And for the patient practically it's very time consuming, expensive and inconvenient. The patients that you would send for this treatment, how is it administered? Is it administered introvenously? Yeah. With with monitoring? Yep. And what in the in the most severe cases, what is the frequency with which they would need those treatments if you are relying on that treatment solely to ameliate symptoms? That depends on the infusion center and and the practitioner.

I mean, some some people might be willing to give it three or more times a week. Oh, I was asking it more through the lens of how long the relief can last. Oh. Um, heterogeneous for for some people. Clearly, it can be only days if that's what you're saying. Yeah. Yeah. Okay. Yeah. And on the long end of that spectrum, people go into remission for all kinds of reasons either that are unknowable in any given individual. Um it could be spontaneous remission, it could be a placebo, it could be a true drug effect.

Um you know, it's hard to know. It's this is an emerging field. And how is it is it is the dose given in such a way that it's dissociative to the patient? Yes. Yes. I see. I mean, it it is a dissociative anesthetic. So, yeah, I just didn't know if it was given. So, I mean, I didn't realize the patient was completely dissociating because obviously it could be given at a lower dose, right? I wouldn't say completely dissociating. I would say typically from what I hear because I don't administer it, they're partially dissociated.

Some sometimes profoundly fully doesn't really Yeah. apply. I don't think but I think there's a spectrum and I'm not sure if there's a correlation like there is for psychedelic medicine where the degree of the um experiential effects of the psychedelic correlate to the therapeutic effects supposedly. That's the latest thinking from my understanding. So, do you have any concern about what appears to be a lot of recreational use of ketamine outside of these clinical settings? Absolutely. I mean, as we've established, it's a dissociative anesthetic. Um, so people who take it and dissociate from it um have reactions from that.

Plus, it can have its wellestablished mood changing effects that could go good or bad. It It absolutely needs to be controlled and supervised. If taken randomly, it's playing Russian roulette as far as I'm concerned. Have you seen any patients who have had negative experiences and have sought you out as a result of it? You know, something No, but I I have friends who have referred patients like that for addiction treatment. you know, you you sort of opened the door to to psychedelics. Did you see that study probably in the last few months about a patient with Alzheimer's disease who was given five grams, which is a full, you know, therapeutic dose of psilocybin that had some memory recovery.

Well, it was more than that. It was that Japanese woman who, and this is the ultimate NF1 study, by the way. Yeah. Yeah. Yeah. But so interesting. Yes. So, she got the five grams of psilocybin, but she supposedly had a diagnosis of severe Alzheimer's for a decade. Yeah. Which strikes me as unusual to say the least. And she had no urinary function. She was completely incontinent. She spoke at most monoselabically. She couldn't talk um beyond that. She couldn't have interactions. And then she took this dose of psilocybin and behaved dramatically differently and became somewhat normal um after it.

And how long did it last? I don't recall. Well, it it was a very confusing case report. because it all it says is something to the effect of it lasted until the second administration of three grams of psilocybin and it it doesn't say anything more than that and there is no there are no um studies there there are no metrics there is no neuroiming there is no anything with the studies so it's the ultimate end of I I I have an alternative hypothesis as to what the ideology was of the problem.

Some some people with post-traumatic stress disorder, particularly if they have mild cognitive impairment or mild Alzheimer's, can regress. And let me just preface to say someone having severe Alzheimer's and surviving 10 years don't go together in my experience. What what do you think about that? I don't think I have enough experience to say, but um yeah, again, it's a bit of a subjective title, right? Yeah. Yeah. Yeah. But yes, usually if if it's so severe that a that a Well, again, part of it comes down to basically airway protection, you know, I don't it's it's unclear how how capable she was.

So um this N of one study is something I can't draw any conclusion from but I find it theoretically interesting that so much adaptive capacity could be restored. So if um if PTSD was the ideology and she would re regress and this interfered and turned around the regression that's wonderful. what whatever it is if it helped this patient is a wonderful initial response I'd be very cautious about generalizing that to neurodeenerative disease now the Robin Carheart Harris reebus model relaxed belief under psychedelics is about neuroplasticity for adjusting maladaptive priors um people who have um beliefs that are um problematic for them in the underpinnings of a lot of depressive and anxiety disorders.

And administering classic psychedelics provides a therapeutic window within which a lot of neuroplasticity occurs. And with the right response either within the individual or between the individual and family or formal therapists. um change can occur in that critical window. And I find that of interest because of course estradiol creates a lot of neuroplasticity because it acts through BDNF and and NMD and glutamate. And so the hormones that change the conditions with within which neurotransmitters operate are very plastic under the right circumstances. optimal estradiol levels, for example.

And giving administering a psychedelic medication can also alter neuroplasticity is intended really um to alter neuroplasticity in the studies of psychedelics for the most part. Not all, but a lot of them are thinking of that set and setting model which is based on a concept of neuroplasticity. Now what what's your experience been of psychedelics? I have tried um in as clinical a setting as as as I think possible several of these um psychedelic agents. Um so I have I have tried um ketamine under therapeutic conditions once.

It was um it was I didn't find it to be a positive experience and I will never repeat it. Do you want to elaborate about the negative aspects of it? Um I you know I described it to a friend after as Guantanamo Bay for my soul and my psyche. I mean absolutely devastating. So just a endless spiral of death. Um did anything positive come out of that subsequently? Not a single positive thing came out of that. So you had a profound that's the only positive thing I would say is it gives me enormous um caution when I when I talk to my patients who themselves are are very curious about these things.

I I just caution them and and and say look you you know you you simply don't know how you're going to respond to these things. the therapeutic windows on these things are quite narrow. It's and and they're just not well understood. It's not like, hey, if we're going to give you, you know, we're going to give you Prozac. We sort of know that most people respond at this dose, some people need it to be at this dose. These are the side effects. If this happens, we're going to You're on to my Russian roulette concept.

Yeah. Yeah. So, so I think with these with these agents, I mean, with the exception of MDMA, I think all of these um these so-called psychedelics I think are and again there, you know, I've used psilocybin in a therapeutic setting that was incredibly positive. I've also had let's Yeah, but I've had experiences on psilocybin that were brutal. I mean, I've had one experience on psilocybin where I, you know, it's hard to know exactly how much time was was was passing, but but certainly for hours it it um I had a reoccurring um experience of being in a guillotine where the blade was dropping.

And so what I was experiencing was the sound of the blade as it's getting closer to the back of my neck, but it would always stop just before it hit my neck. So that would provide a modicum of relief, but then the blade would go back up and it would happen again. Wow. So that was absolutely awful. Again, nothing positive came of that experience. Um uh but I've had I've had very positive experiences on u uh guided MDMA and and with uh with with with another psilocybin experience.

What what what made the positive experience positive? Well, again, I think with MDMA, no, no, with the with the psilocybin. [clears throat] Um, it was I mean, it's hard to describe. I think it's it's this is over 10 years. This is about 10 years ago. It was an outofbody experience, meaning I was only witnessing myself from outside of myself, but at different places in my life. But they were very vivid. These were not vague images. This was you are back in this room at this moment in your life when you were 12 years old.

Yeah. And this is exactly what's happening. But what was very powerful about this was I was not experiencing it through my lived experience but through the other person in the room, in this case a parent. And um for me that gave incredible empathy to what was going on with the other person during an experience in my life. Yes. So that and the durability of that is a decade later that that will be lifelong durability. So I think um because that it's a fascinating description beautifully expressed about something fundamental about people maybe in a different category who revisit a traumatic experience from a more developed perspective in their lives and they're able to reassimilate it from a certainly a more advanced view and even have compassion for someone who who may have.

So this was an interesting experience. This was not a traumatic experience in my life at all. And so therefore it's very unclear to me in this particular instance why I went to that place. But instead what it gave me was um and it might have been that I was at the exact same age as my parent at the at in other words in my life I was the same age as my parent in this vision. Yeah. But now all of a sudden I was able to appreciate their life and how much harder it was than my life.

And that's but but in a way that I could never articulate now. I can't describe it now. I understand. It's it was the feeling of wow their life was so much harder than my life and everything I have is because of them. Yeah. And their sacrifice. Right. And it was and and all of the things that have frustrated me um are are are frustrations of someone who's never fully appreciated. It's about gratitude. Yes. And it was so it was I think one of the most beautiful experiences I've ever had in my life.

And what's interesting is it was the first experience. And therefore when you have such a positive first experience, what do you want to do? You want to go back to that well every few years. Yeah. Because if it was that transformative in this one regard, imagine what it could do for other relationships in my life. And unfortunately, it has never come close to reproducing that. It has been anywhere from neutral to negative. And so I made a decision about two years ago that I was probably never going to do that again.

I I was sort of and I I won't describe the litany of things I've tried, but but I will never I I just don't I think I think I think that's very wise. I've I've extracted something incredibly valuable. I don't want to tarnish it with anything negative. Well, it's beautiful that you got what you did out of it and also that you knew when to stop. Well, I I wish I could say I did. I I went back to the well a couple of times and and paid a very heavy price for it.

Wow. But I but that's it. But that's also you know there's the intellectual part of me the scientist right is completely interested in why there's nothing I can point to in set and setting and dose and deliver. Like there's nothing I can point to that was different. There's a certain randomness. No, there's Yes, exactly. And that's what makes it so so terrifying. In fact, the last time I did this was the most prepared I've ever been. The amount of work I did with the therapist ahead of time.

Yeah. the amount of journaling. I've never had a greater intention. Yeah. Going into this, right? I mean, you expected a masterpiece to come out of it. Yes. This was this was Michelangelo going into the the chapel. I mean, it was this was going to be the final elucidation of the three things, the three questions that still, you know, Yeah. I deal with. Yes. and instead I got put into a a a tumbler and ripped into pieces and spit out the back and I I just I mean it was it was very very difficult.

It took me a it took me months to recover. I've always been innately scared of those medications and have avoided them. Yeah. I think it's um I think there's a part of me that still remains optimistic that as more and more research is being done um the the the benefits of these things will outweigh the harms. I I think there's one point I should make just just for listeners who are wondering who say, "Wow, Peter, that's crazy that you would have those experiences." There's an issue with me that has been an issue when it comes to any medication or drug or anything that would alter consciousness or frankly any drug.

I am highly resistant to every medication for which there's variability in dose. So whether we're talking about caffeine, whether we're talking about alcohol, any medication you can put into a human body, I just need two to threex what every other person needs to experience an effect. Yeah. So, I could drink four drinks and I wouldn't feel a buzz. Um, I can drink four cups of coffee and I don't feel anything. So, the doses of these agents that I require to feel anything are much higher than other people.

And so maybe the reason my experiences have been so different is we're we're at a point on the PK of that drug that is just well beyond normal behavior. Um every time I have used psilocybin, it has been north of 10 grams. Wow. Because the standard five grams produces nothing. Wow. So, in other words, I say all of that to say you need more estrogen for the Yeah. Well, I mean, it it might just be that that that my horror stories have to do more with my with my dose where I am on the dose response curve.

Yeah. Um, it's interesting. I had a discussion yesterday with a patient about estradile. Um he was you know he had been under the care of a doctor before he came into our practice that was trying to give him arimidex uh which for the listener is a drug that prevents the aromatization of testosterone into estradiol and he had been taught so to speak that estrogen was bad and you want high testosterone [clears throat] and low estrogen. So needless to say we had a great discussion about why that was a very bad idea.

Yeah. Um, what hope do you hold out for the utilization, the proper utilization of psychedelics in psychiatric medicine over the next 10 to 20 years? Part of it relates to your positive experience. It's extraordinary that a single administration of a drug can produce a durable effect that you're projecting will last a lifetime. I'm 100% convinced it will last the rest of my life. And I believe I'm 100% convinced by you of the power of that experience and how transformative it is. So I find it remarkably exciting and promising, but I also appreciate the dangers and unpredictability.

So I'm hoping that they'll find a strategy. They meaning the the researchers in that field will find a 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 m [clears throat] maybe combination um phicotherapy because it is a pharmacotherapy it's the use of a psychotropic medication maybe concurrent use of other medications that don't block the serotonin 2A receptor that it has to bind to. That's where the classic psychedelic binds to. So if you block that receptor with another drug, instead of you needing twice as much, you may need 20 times as much.

So that's not reasonable. Um but finding an appropriate pharmacologic strategy that augments and augments the efficacy and mitigates the risk. Of all of the indications that are being talked about for these drugs, the two that to me seem the most exciting. Yeah. are obviously MDMA and PTSD um and psilocybin in end of life depression or frankly just all end of life related therapy. Um, what do you think do how much more evidence do you think the the the the medical community I mean the FDA aside, there's a whole issue with the FDA there, but but from a from a medical scientific standpoint, where do you sit on those two indications which are quite specific?

Yeah. end of life treatment, the riskreward shifts a little bit. If someone is struggling with existential anxiety on an absolute order, I think if there's something that could help them with that, they deserve the option of exercising that because there aren't many, but we don't want to make it worse. We don't want to, but it's pretty bad to begin with. Yeah. So, the riskreward may shift. It depends on your medical ethical model. If the baseline would shift the riskreward calculus about that, I'm not sure something worth thinking about.

But then the same would apply to significant PTSD. I suspect that it's not MDMA that's going to be the most effective for that. Do you think it will be psilocybin perhaps or certainly other drugs? Um I think MDMMA is a so-called impathogen. It increases empathy. um certain types of PTSD there you know PTSD like so many things is a very heterogeneous category. I think when epi empathy is called for related to reconciliation of relationships or traumatic experiences. Um it it might have a very strong role.

Um, so so much remains to be determined, but I am I do find it exciting that medications can have such adorable and powerful effects and I find it intimidating and disturbing that it can also go in the other direction. But I'm very optimistic that something positive will be found to reconcile that discrepancy. I think I would agree with all of that. Um but I do I do I do always feel the need to caution people. I think it's one of those things where um people hear a lot of the good stories.

I think they don't hear enough of the bad stories. And I I think there's I agree with you. I I think there's they are drugs and uh every drug has a side effect. Absolutely. Including the ones I prescribe. Yeah. Well, Lionus, this has been a really fascinating discussion. Um I've learned a lot and so I'm hoping by extension everybody listening has learned a lot as well. Um so thank you very much for your visit and for more importantly sharing your wisdom. Thank you so much. It's been an enormous pleasure for me.

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