Depression, Ketones, and the Brain: What the Newest Science Reveals
In this second part of the interview, host Nick Norwitz speaks with Dr. Brett Scher, a double‑board‑certified cardiologist‑lipidologist and medical director of Metabolic Mind and the Buzuki Group. The conversation weaves together personal narrative, the formation of the Coalition for Metabolic Health, recent research, and mechanistic theory. Dr. Scher explains how his cardiology practice led him to metabolic psychiatry, describing the pivotal role of a wellness center, his exposure to ketogenic therapy, and his partnership with the Buzuki family, whose personal experience with bipolar disorder sparked the creation of a philanthropic‑backed research movement. The Coalition, seeded with a $50 million initial investment, aims to unite clinicians and scientists across cardiology, endocrinology, gastroenterology, fertility, and psychiatry to confront the worsening metabolic health crisis. The interview then delves into a small, philanthropy‑funded pilot study published in Translational Psychiatry that placed 16 college students with major depressive disorder on a ketogenic diet for 12 weeks. All completers showed dramatic improvement (≈70 % reduction on PHQ‑9 and a comparable secondary metric), with 67 % adherence despite social challenges. Limitations—small size, lack of randomization, attrition reasons—are acknowledged, and Dr. Scher stresses the need for larger, controlled trials while noting the safety and practicality of ketogenic therapy as an adjunct. Mechanistic discussion follows. Dr. Scher outlines multiple, non‑exclusive pathways by which ketosis may alleviate depression: (1) shifting the GABA‑glutamate balance (drawn from epilepsy literature), (2) reducing neuroinflammation, (3) providing an alternative cerebral fuel when glucose metabolism is impaired, and (4) improving systemic metabolic health (weight loss, insulin sensitivity, hormonal milieu, microbiome changes). The conversation expands to recent findings on autophagy deficits in the lateral habenula of depressed mice and how both conventional antidepressants and metabolic interventions (ketosis, fasting) can restore autophagic function. A gut‑derived metabolite, homovanillic acid (HVA), is introduced as a microbiome‑brain neurotransmitter that is depleted in depression; animal work shows HVA supplementation rescues depressive behavior, prompting a debate about translational relevance versus lifestyle‑first approaches. The hosts also grapple with terminology, debating whether calling depression a “disease” is stigmatizing or legitimizing, and reflect on how to communicate complex metabolic‑psychiatric science without oversimplifying or alienating audiences. They close with optimism: the passionate leadership of the Buzuki family, the collaborative research community fostered by monthly meetings, and the vision of scaling metabolic psychiatry into mainstream practice. Resources are provided (metabolicmind.org, coalitionformetabolichealth.org, Metabolic Mind YouTube channel).
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much more powerful than just economic incentives.
The 100% improve and by about a 70% reduction or improvement.
Perfect. You gave me goosebumps.
Is needed in cardiology and endocrinology, fertility and reproduction, gastroenterology.
I am incredibly optimistic. I'm optimistic for what you just laid out implicitly.
What have we seen? That the metabolic health crisis, type 2 diabetes, obesity, overweight, prediabetes, metabolic dysfunction, it's just been getting worse and worse and worse and worse. So clearly we need a different approach.
Dr. Brett Scher, welcome back. For everybody that missed part 1 of my interview with Dr. Brett Scher, you should definitely go listen to that first. All of this is self-contained, so if you don't want to stick around, a brief bio on Dr. Scher. He's a double board certified cardiologist lipidologist with over 20 years of clinical experience, and he also serves as the medical director at both the Metabolic Mind Group and the Bizuki Group, where he's helping to lead some really groundbreaking work in the mental health and metabolic health space. So That's actually what I want to talk about in part 2 of this interview. So I want to start off with a personal question. So in addition to your expertise as a cardiologist and lipidologist, you now play this leading role in the broader metabolic health space and mental metabolic health space. So how did a cardiologist end up at the forefront of a mental health group?
Yeah, it sounds a little strange, right? And I acknowledge that, you know, it's sort of a bit of a circuitous route. So stick with me here for a minute. But, you know, in my cardiology practice, I, you know, quickly became sort disillusioned with the impact I was having on my patients, certainly from a preventive standpoint. So, I started a wellness center in addition to my regular cardiology practice. And, through that wellness center, I was lucky enough to get sort of turned on to— with this individual I was working with to what ketogenic diets are, ketogenic therapy, the impact on metabolic health, the impact on cardiometabolic health. And, from there, just sort of ran with this whole concept of metabolic health as a primary focus. And the role of ketogenic therapy in implementing that. From there, found my way to Diet Doctor where I was fairly visible doing YouTube videos and podcasts. Again, about with you as well, right? I had you on with the focus being on ketogenic therapy, ketogenic diets for treating medical conditions. From there, was lucky enough that Jan Buzuki found my podcast and YouTube page and asked me to moderate a discussion or a session she was having at her first metabolic psychiatry conference. And there were leading researchers and clinicians in this room in Santa Barbara, and I was, I was moderating this discussion. But more importantly for me is I was hearing all about this movement and, and about their family story. And about the personal journey and about their fam— the family's commitment to really revolutionizing psychiatry through metabolic psychiatry, through ketogenic interventions. And I mean, by the end of that 2-day conference, like, I would have run through a brick wall for them. It was just so inspiring and motivating, um, to go from the personal story and how emotional it was to the science, the research, the other clinical, the other clinical stories that we heard and one family's desire to change everything. So I was, I was just all in. And actually my first response when I heard they were looking for somebody to sort of run Metabolic Mind was, oh, I will totally. I want to do anything I can to help you. So I'm going to find somebody for you. I can totally find somebody for you because at first I didn't think it would be me. And then as I was learning more about what they were doing, I said, wait a second, you need somebody who can communicate about ketogenic diets as a medical intervention, about their efficacy and safety, and can help work with a broad field of psychiatrists and mental health professionals to help create content both for the individual and the practice. And I'm like, that's me, I can do that actually. And I am in because the ability to change an entire field of practice and the impact this is going to have on the lives of young adults. I mean, the impact it's having on people's lives is incredible to see. And just the passion that Jan and her family have to do this tirelessly is something that just I had to be a part of, and I'm so grateful that I am. So that was a bit of a long-winded answer.
No, that was perfect. You gave me goosebumps. I don't know if they show up on camera, but truly I'm gonna divert off this skeleton that I had for our conversation because I really want to, I'm gonna emphasize how beautiful this is. 'Cause you know, what we talked about in part 1 of our interview was a lot about incentive structures. And I think you can paint a very pessimistic picture that the conventional medical system is built in such a way that, you know, it is driven economically. Patients aren't at the forefront and metabolic health takes a backseat because guess what? It doesn't make money. That is a very abysmal picture. Picture, but I am incredibly optimistic. I'm optimistic for what you just laid out implicitly, which was the metabolic health movement. I'll call it the metabolic health coalition with intent. We'll get into that in a minute. Ibu kata is so powerful because it is motivated not just by money, but by genuine human passion from genuine human suffering planted by the scenes of genuine human suffering. And that's sad. It's sad that so many people have to suffer. You mentioned the Bizouki family, so philanthropists that were inspired to get into the metabolic health space because they had a son who suffered terribly with bipolar disorder. I can use myself as an example. The only reason I'm really here now is because my passion was excited by suffering terribly with my own diseases. I wish it didn't have to be this way where people, the right people, have to suffer to motivate them to get into this space. However, the fact that that is the case, and quite honestly, because of the metabolic health crisis, the inevitable case that the metabolically sick population is growing also gives the metabolic health movement and the Metabolic Health Coalition incredible power. You mentioned running through a brick wall, and that was just because you were infected by the passion and enthusiasm of suffering patients and families and saw that this is just something that is important and needs to be pursued. So I think what locks the metabolic health movement together, the Metabolic Health Coalition, is much more powerful than just economic incentives. It is that people are genuinely unified to fix what is ailing us.
Yeah.
So that's why I loved your response. With that, let's go on a tangent and talk about this exciting new Metabolic Health Coalition. What is it?
Yeah. Coalition for Metabolic Health. So this is also brainchild of, of Bazuki Group. For the first, I guess, 2.5 years or so, we've really been focused on mental health, um, ketogenic and metabolic therapies to treat mental illness and brain-based disorders. But at a number of the conferences that we've gone to and people we've talked to, it's clear that what we're doing in psychiatry is needed in cardiology and endocrinology, in fertility and reproduction, gastroenterology, right? Like, this approach is needed in so many different areas for the broader field of metabolic health. So, I mean, Jan and the powers that be are so committed to improving the lives of everybody who's suffering. So why not take on the broader initiative? And this is also where, I mean, we just have to acknowledge the, the individuals in this field who are likewise motivated and talented. So individuals like yourself, and just go on the website, and David Ludwig and Andrew Kutnick and Mark Kukizela and Ben Bikman and Dom D'Agostino. And if I don't mention your name, it's just because there are so many. These individuals who are so talented, so knowledgeable, and so passionate, realizing we have to do something different. So the ability to bring all these people together and say, okay, how are we going to, quote unquote, fix or improve or address this metabolic health crisis that we are in? Because clearly what we've been doing for the past 40+ years has not been working right under the auspice of you know, a government putting out guidelines and medical institutions putting out guidelines to try and supposedly improve people's health, what have we seen? We've seen the exact opposite, that the metabolic health crisis— type 2 diabetes, obesity, overweight, prediabetes, metabolic dysfunction— it's just been getting worse and worse and worse and worse. So clearly we need a different approach, and that is, is, is sort of at the core of this Coalition for Metabolic Health, is that we need to intervene and inform and really make an impact to stem this tide of worsening metabolic health.
Right. Just to emphasize, this isn't like, like, you know, a lot of times in medical administration they'll be like, oh, we have a problem, let's put together a committee. The committee does nothing. This isn't that. I think they put— I think Jan said she chose $50 million of the initial investment because like, this will get attention. And also because it can fund real research that changes lives. So let's talk about some of that. There was a study that just came out a couple weeks ago as we're recording this, or maybe even just a week ago in Translational Psychiatry, which is part of Nature Press. So, you know, pretty good journal about a ketogenic diet for major depressive disorder. What were the findings of that study?
Yeah, I mean, pretty impressive results. But you know, first the background of this study, you know, it's a small pilot. And this is the, the good and the bad, right? Research has to start somewhere. This is philanthropy-backed research, so we can't do, uh, you know, 10,000-person study for 5 years with, you know, one philanthropy funding it because it's incredibly expensive. So philanthropy-funded pilot study, and what they found was of the 16 people who, who completed the course of their ketogenic diet, um, 100% saw significant and dramatic improvements in their depression symptoms, which is pretty remarkable right now. You can't really compare it to, you know, drug studies and randomized controlled trials and whatnot, but if you were going to, you would see that in most of those studies, you know, maybe 50% or less respond, and their response is about a you know, 30 to 50% benefit on the, on the different metrics that are done. Well, in this pilot study, 100% improved and by about a 70% reduction or improvement in the metrics that were being used. So really dramatic findings. Now, of course, small pilot study that's not randomized. You can't say this is proof and, you know, is so much better than drugs. But my goodness, how could this not get your attention to say, okay, one, it's a dietary intervention, so maybe something we could try anyway. And two, let's study this further to really see, should this be first-line therapy? Should this be in the guidelines? You know, where does this fit in the spectrum of, of treatments? This deserves a ton of funding, a ton of attention, and really needs to be looked at. But I keep coming back to also, you know, like I said, it's a dietary intervention. When done with experienced clinicians, is very safe and effective. You don't need it to be FDA approved. You don't need it to be in the guidelines. If I have a family member who is living with severe depression, you better believe I was going to— I'm going to try this in addition to the standard of care that they're receiving. So, you know, for, for families or individuals who are looking to see, is this something I should try? It's definitely something worth bringing up with your clinician. As the studies are ongoing, they don't preclude one another.
Yeah, I appreciate your humility in talking about the study along with your excitement. I want to double-click on a few things about the study that, you know, could be seen as limitations, but I also see as immense strengths. So first of all, the effect size, tremendous. Yeah, a 69% improvement on one metric, PHQ-9, which people might take when they go to their doctor. It's a very basic survey. And then there was a secondary metric with a 71% increase. So two independent metrics both showing showing not just statistically significant— I know we like the p less than 0.05— but large and clinically meaningful and consistent improvements across patients is really incredible. Now that's number one. And even if it's not a controlled trial, even if there's some placebo effect— because honestly, from the patient's perspective, first of all, I don't think it's all placebo— but even if it were, they're reporting feeling better. I mean, the video on, um, the Metabolic Mind channel, which we'll link below, which was tremendous— like, you, you have the students, these are kids basically talking about their experience about like light coming back into their life based on what they put on their plate. That is such an incredibly individual empowerment tool cuz you don't need to go get a prescription. This is something that, you know, you probably should do with medical support disclaimer, I guess we need to say that, but like you can change your diet whether or not you go full keto. So it's a lot of individual empowerment. And then also, you mentioned 16 people completed the trial. There were 24 originally in the trial. Two things I wanna say about that. First of all, my impression was, um, even the 8 dropouts saw improvement. So the difference between per protocol, so completers and intention to treat, but I'm pretty sure even in the intention to treat, all 24, there was all improvement and including all 24, there was still an average 65% improvement.
So like even the people that didn't make it to the end still improved, but And I think for me, the most important point to emphasize about those who didn't make it to the end is why did they drop out? Right. And there in the paper and talking to the researchers, there was one person who dropped out that had anything to do with the dietary intervention.
Right.
And these are college kids. So one person moved away, one person went on an extended vacation, others just couldn't get to the lab to get their blood drawn. Right. So there is— it just shows like college kids, you know, they're probably hard to study for these reasons. But it wasn't because, oh, this ketogenic diet was terrible, it wasn't working, so I dropped out, right? That, that was not the reason for the majority of the dropouts, which I think is important to note.
Well, I also think that they're— it's like a cup half full, or I guess, you know, two-thirds full versus one-third empty kind of phenomenon, where you could say, yeah, there's like a one-third attrition over 12 weeks. Do people remember what it was like to be in college? The fact that 67% of students could stick it through for 3 months on a ketogenic diet and not just say, hey, I didn't eat carbs. They were measured to be in nutritional ketosis by blood finger stick.
So, right.
I think that actually speaks to the power of the intervention because I remember what it was like to be in college. I was starting to struggle with health problems in college. The culture, the, like the socializing, ma would make it extremely difficult to be on a ketogenic diet more so than other life stages, I think.
Yeah, we have a lot of content at Metabolic Mind about this, talking with Drew Decker and, and Dr. Jeff Volk and Dr. Ryan Patel about, about that concept. Like, how amazing is it that these college students were able to adhere to this diet and stick with it and doing so change their lives, right? It's amazing.
So the only way I think I can reasonably explain that 67% of college students could stick with it for 3 months with the social baggage that comes with the life inconvenience, you know, you stick on what is perceived to be an extreme diet if the benefits are like visible, pretty immediate, and outweighing the costs. So what are the costs here? The costs are social and, you know, just in the discomfort of really radically shifting your life. And the only way I think kids are gonna stick with it for 3 months is if they're actually feeling genuine benefit in their everyday life. So like, you know, for me, people are like, oh, you don't, don't you miss X, Y, and Z? I'm like, you know, it's a little bit difficult to go out. You know, dating became more difficult before I was with my, you know, current partner. Yeah, I love sweet potatoes, but guess what? When it's a choice between a sweet potato and having bloody diarrhea 12 times a day, the algorithm is very clear. And it's the same with mental health. So yeah, I wanna bring up the fact that, you know, 1/3 dropped out because 2/3 stuck with it. And I think that is a tremendous flex on the data and just, you know, props to all the students who were, you know, involved in the study and gave it a genuine shot. Those who dropped out and those who didn't. But I did want to emphasize that because I think it, it was worth emphasizing. Yeah. With that.
Yeah.
Um, I do want to talk a little bit more about mechanisms, but before I do, there was a question I, I jumped over that sits at the intersection between your, you know, experience in cardiology and now in the mental health sphere. So some people push back when I say depression is a disease or bipolar disorder is a disease. Um, as if it's disrespectful to people struggling with those disorders versus like, you know, you're a cardiologist, somebody has cardiovascular disease. You say you have cardiovascular disease. I've received thoughtful criticisms for using the word disease as relates to mental health disorders. Do you think depression is a disease like cardiovascular disease? And what do you think about using the word disease when it comes to mental health?
Yeah. So, I mean, I actually think it's really interesting to isolate out depression. My guess is more people would take issue with calling depression a disease than they would with calling schizophrenia a disease or calling bipolar disorder a disease. That would be my guess that more people would take issue with depression. I think the reason is because depression is much more, I guess you could say heterogeneous.
People get labeled as having cardiovascular vascular disease and obesity, they're all, you know, heterogeneous diseases pathologically, right?
Well, so, so what I mean by depression though, compared to like schizophrenia and bipolar disorder, like, you know, people are labeled as having depression and treated with SSRIs when they are sad because they got a divorce or lost their job. That is very different than someone who has major depressive disorder. And it's not that it's not real. It's not that it's not a real problem for that individual and they aren't suffering, but I think you could see them as two different things. And, and like Dr. Mark Horowitz, um, from Outro Health talks about this, that maybe that person does not necessarily need, you know, lifelong treatment. Uh, maybe with therapy, with changing their circumstance, the depression can go away. Psychiatrists see that, but that does not mean that depression is not a disease and that there aren't people who get depression that has nothing to do with certain factors in their life, right? Though, so I guess I can see why somebody would say that about depression because it seems more heterogeneous, whereas you don't have that same discussion about schizophrenia necessarily or about bipolar disorder necessarily. And if you have a heart attack, I mean, it's not like the heart attack just kind of goes away by changing your life. You still had that heart attack. You still are at risk of having another heart attack. So, but that being said, I mean, it's interesting how we, we talk about things of the mind different than things of the body. And we shouldn't. I think they are one in the same, the mind and the body. They're, they're one in the same. If you have a stroke, that's vascular disease in the brain. If you have a heart attack, that's vascular disease of the heart. They are diseases. They are disorders. It's not judgmental to call it so. So yeah, that's— I'm not sure if I actually answered your question or just muddied the waters there. No, I—
first of all, I think there are waters that need to be muddied rather than painted as black and white. And I raised it because, not like I was trying to set you up for anything, but because I genuinely struggle with it. Obviously on the individual level, if somebody says, hey, I prefer you not refer to my condition as X, Y, and Z, happy to respect it. But I think it's a catch-22 for reasons you were kind of like laying out, which is you don't want to stigmatize it, but you want to not trivialize it either. And so how do you not trivialize a mental health condition and say, hey, I see you. I see what you're struggling with. Even if I don't understand all the intricacies of brain metabolism, because it's harder to look into the brain than to say the heart, what you're going through is real and biological, just like someone with obesity or diabetes or cardiovascular disease. It's a medical problem. That deserves to be treated as such. Because if you don't do that, then the implication is it's an ephemeral mind thing and you can just snap out of it. So that's why I see it as a little bit of a catch-22. I think it offers respect to the patient to say, hey, this is a condition you're struggling with. It's real, it's material, and you deserve to have it be seen like a, you know, more conventional pathophysiology, like heart disease or diabetes. That's my current stance. Again, happy to respect the individual. I think it's an open discussion that just should be had. But with that, I do want to get more concrete and talk about mechanisms. Mentioned the keto diet and depression study, but that was a clinical trial. Me being a giant dork, I love to talk about like, how is this actually working in the brain and give a little bit more resolution, you know, to the pathophysiological picture. So there's a couple of ways we can run this. But first, way one is I'm gonna ask you, you know, what mechanisms do you think are at play in how a ketogenic diet could heal the brain from depression or other mental health conditions? And then we might play a game of Dr. Scher Reacts, where I toss new data at you and see what happens.
Sounds like an interesting game. Okay, well, so first when we talk about mechanism, I think it's important that we get out of this mindset of like, the drug mindset. We're going to create a drug with this one mechanism of action. And so, you know, the perfect example, depression comes from a serotonin deficit. So we're going to create a drug that increases serotonin, right? Like that, that is the drug-based approach, which is just wrong, right? It doesn't mean serotonin has nothing to do with it, but to say all depression is a serotonin deficit, we're going to treat it by increasing depression, right? So So we have to get out of that mindset. So, so when we talk about mechanisms in general, one of the things where we can really learn from the mechanisms of ketogenic therapy for brain-based disorders comes from the epilepsy world, which has been used for over a century, which has been studied for decades, which has over a dozen randomized controlled trials and, you know, consensus guidelines and so forth. And so there is knowledge there that being in ketosis changes the GABA and glutamate levels. So GABA is more of sort of like the, you can say, the calming effect, and glutamate is more the excitatory effect, right? So that's one mechanism that it clearly has on the brain. You can say it reduces neuroinflammation. Inflammation can, is definitely associated with, with the onset of symptoms of mental illness. You know, we have studies showing hypometabolism of glucose. The cells can't use glucose quite as well. So providing ketones bypasses that need for glucose and insulin and gives the brain an alternative fuel source, which it can then create energy more cleanly. All of these sort of roll up into one. Then there's the whole metabolic health concept. So we can use a study from Cindy Culkin where she looked at individuals with treatment-resistant bipolar depression and insulin resistance and randomized them to metformin or placebo. Now, metformin is an insulin sensitizer, works in the liver. It's not a psychoactive medication. And of those who took the metformin and converted to insulin sensitivity, they had dramatic improvements in their bipolar depression. So it's clear there's this connection between your, your overall systemic metabolic health and your psychiatric symptoms. So there's that. When someone goes on a ketogenic diet or ketogenic therapy, they're going to improve their metabolic health. So you can start to see the mechanism sort of piling up. It's not the razor's edge one mechanism, and I wouldn't expect it to be because you're changing so many things in your body when you're putting your body into ketosis from, you know, the GABA glutamate levels, from the neuroinflammation, from the fuel source, from the metabolic health, from the weight loss, from the other things that maybe you're doing in your lifestyle now because you're feeling better and having more energy and different energy sources. So there are a number of different mechanisms, and fortunately we're still learning, right? There's lots of studies going on with brain imaging, with different mechanistic sides to the study. But I think we already know quite a bit about potential mechanisms and, you know, the clinical outcomes are, are pretty impressive from what we've seen.
So just to summarize the mechanisms I, I heard you highlight, then I'm gonna make a point and then elaborate. There is changing neurotransmitter balance. We can extrapolate from some of the literature on epilepsy. So you're talking about GABA glutamate. So that's one changing inflammation in the brain. Quelling neuroinflammation, that's at least 2. Addressing underlying core energy dysfunction. So glucose metabolism, glucose metabolism is dysfunctional. Give another energy source. That's 3. And then 4, broadly speaking, is like peripheral whole body health. So losing body fat, that changes your hormonal milieu, losing visceral fat, changing your microbiome. So those are at least 4 different mechanisms. As Brett was pointing out, You know, if, if people kind of like shotgunning here, there's no quiz. You don't need to know the mechanism. You don't need to memorize them. You don't need to order rank them. The point here, at least as I see it, you take that study, which is one of many that we were talking about, the clinical study with college students and depression. You see a clinical effect. What you really wanna then do is say, is there biological plausibility here? And the answer is an overwhelming yes. Yes. And so we're developing that picture now to lean in to some of the things you were mentioning and just even, you know, add more detail. It's almost as if you were setting me up for some of the things that were on my mind, given the new literature that was popping out. So, um, let's talk about metabolic health and antidepressants because you mentioned, this is gonna be my transition, SSRIs, selective serotonin reuptake inhibitors. All right. If we boost serotonin in the brain, maybe it'll help with depression. But interesting thing that I'm sure you know, but I don't necessarily think the audience would know, is that, you know, these medications take— they immediately affect serotonin, but they don't immediately affect depression. So if it was as simple as just boost serotonin, why do these drugs take so long to work? Why don't they work as soon as serotonin gets boosted? And the reason is still being sussed out, but it probably has to do with how boosting serotonin rewires brain, brain plasticity, and also how it affects basic metabolic pathways. So an interesting paper came out, I'll send it to you 'cause you'll find it fascinating. I'm sure you'll wanna cover it for Metabolic Mind if you haven't already on autophagy in the brain. I think it was in Nature, don't hold me to that, but it was a 2025 paper. And what they were looking at is this process of autophagy. Autophagy is like cellular recycling. And what they found is that in depression, autophagy was reduced in a particular brain region that was associated with depression called the lateral habenula. Now the reason this is important is You mentioned GABA and glutamate. So if you have a dysfunctional recycling system, what happens? Things build up. What things? In this case, glutamate receptors. So receptors for the brain's main excitatory neurotransmitter in the depression center of the brain.
What happens?
Despair and depression feelings get turned up because you have more excitation of the depression center of the brain. Then what they found is, guess what? Different antidepressants, be it ketamine or SSRIs, restore normal autophagic function in that brain region, which is fascinating because it brings in one, a very basic metabolic function into the depression picture. Two, explains how different depressants converge on that pathway. And also three, well, what also impacts autophagy, ketogenic diets, fasting. So it all kind of makes sense. Which, you know, I don't know if you, had you seen that study before or heard of that mechanism?
I haven't. It sounds fascinating. I'm trying to wrap my brain around it. There's a lot there, but that sounds super interesting.
Yeah. I'll send you the paper. I mean, admittedly it was done in mice, these sort of studies, like the brain's a black box. You can't always do these studies in humans because you can't genetically manipulate humans and you can't chop heads off at the end of studies to kind of stain brains. Some people are like, it's a mouse study. I'm like, Do you want to sacrifice your head for science? Probably not. Probably wouldn't pathognostic for, but still these are pretty conserved pathways. So, um, interesting mechanisms. And you mentioned there's another paper coming out talking about inflammation, like inflammatory cytokines in the brain literally act as neurotransmitters. One's called IL-17, like, like dopamine or serotonin. It will bind to receptors in the brain and amp up, in this case, feelings of anxiety. But a study I wanted to make sure to mention to you and then share with you Have you heard of homovanillic acid? I've heard of it.
Yes.
Okay. Let me give more detail. This is, um, uh, speaking of serotonin, a pet peeve of mine is when people say, oh, gut health is important for brain health because 90% of the serotonin is made in your gut, which is true. But serotonin, as you know, in the gut does not cross the blood-brain barrier, but other hormones and neurotransmitters do. So homovanillic acid is a neurotransmitter. That is made by the gut that can cross the blood-brain barrier, that is depleted in depression in humans, along with the gut bugs that make it. So some scientists had this brilliant idea of doing controlled experiments in animals, multiple animal models of depression. So you can have like very diverse models, some with corticosteroids, some with— I think it's called Chronic Unpredictable Mild Stressors. You can kind of guess what what that is, but a lot of the things that we're exposed to in, in, in normal day American life. The bottom line is HVA, this homovanillic acid is depleted in human depression. And then what they were able to do in animal models is either give back the gut bugs that make it or just orally give what is just an amino acid basically derivative. It is a cousin of dopamine. It crossed the blood-brain barrier, pretty safe. They gave it and across animal models consistently improved depressive symptoms. I don't know if we're going to have a, like a protein probiotic mix for depression in, in the future, but you know, I was listening to your, um, coverage on Metabolic Mind of this keto depression study and just the student talking about like how powerful what you put on your plate is. And the idea, as extreme as it sounds, it's also very basic. What you eat affects the thing that is at the interface with the external world and your body, the microbiome, which makes metabolites that can circulate in your blood, go to the brain and act as neurotransmitters. We know that this has associations in humans, and when you do experiments with animal models, just giving this cures depression or treats depression. What is your reaction to like science like this in the metabolic mental health world?
Yeah, I mean, I'm scientifically fascinated by it and I think it's super interesting. I'm also very hesitant to get too excited about animals. I think we've, we've, we've seen a lot of animal models not translate to human intervention. So I am very hesitant to get excited about it. But I think scientifically it's interesting. Clinically, I just stay a little bit reserved. And I guess it also kind of brings up this concept, like, are we looking for the probiotic, the medicine, the thing that we can just give to replace? Or are we looking to say, well, what can we do to prevent this from happening in the first place or completely reverse it by the lifestyle we're living? So it's a couple— two, two different approaches there that I just want to be a little bit cautious of because I think a lot of the research is looking for that one thing, like the UDCA, what we talked about in the, in the previous interview about the statin reducing GLP-1s. But if you give UDCA, you can reverse it. Now, ironically, that was sort of, you know, not talked about and sort of swept under the rug. But that's the concept that, oh, all we have to do is give the UDCA as opposed to saying, well, if statins can reduce or can, can harm your insulin sensitivity and increase insulin resistance, we better double down on the lifestyle interventions that can prevent insulin resistance. Right. So it's a little bit of a different mindset and approach in how to interpret that.
I, I'm having like a little personal epiphany right now because, because there are different, you're right. There are very different ways to relate to the data. So when I read that study, my mind did not go towards, yes, let's bottle HVA and cure depression.
I guarantee you most people did though.
So, so you're right. You're right. That's the disconnect, I guess, that I need to be aware of as a communicator, because honestly, when I read that study. The way I felt about it was it's evolving this beautiful web of mechanisms that helps us understand the clinical trials or the clinical studies like the one we talked about earlier. So, you know, for me in my, my metabolic health journey, the thing that has made it not just sustainable, but an absolute pleasure is, is appreciating the awe, the fascination, and the beauty. For what's going on inside me. The idea that what I eat can change the microbiome to make this particular neurotransmitter that circulates in the blood and binds to receptors in my brain. And if that's just one thread on a greater web of which I'm gaining resolution as I read these studies, that's why I get excited. Not because I'm looking for a silver bullet, but I totally hear what you're saying in your more reserved response. And, and, and I was saying a little bit of an epiphany there because I don't know, I mean, I guess I'm conscious of that disconnect, but I don't know if I compensate for it because I relate very differently to these sort of data than I think your average person does. And that is something for me to be aware of as a communicator. So thank you, Brett, for, for instilling that wisdom in me. Um, by, by way of, uh, Spartan epiphany. I appreciate that.
Very good. I think your, your level of curiosity and appreciation is going to be higher than the average person too, I think. So you gotta factor that in.
My job though is to bring them to me. That is my, my career aspiration. Figure out, because I, maybe we disagree on this, I don't know, but like, I think human beings are innately curious. I was actually just at, uh, I was apple picking with my girlfriend over the weekend and she was like, what are you staring at? We were sitting in this little like, you know, secluded area with a bunch of little kids running around. She's like, why are you watching these kids? It's creepy. I don't mean to be creepy, but I was watching these kids just like jump around on things. This little girl like stuck her hand in a candle and I'm like, why are they jumping around and exploring the world like that? Like little kids do. What is their drive? And I think the drive is curiosity. They're exploring their bodies. They're exploring the environment around them because everything's new and they want to understand it. And I fundamentally believe that is what part of being human is, but we lose that with a decreasing amount of novelty as we get older. And then just the complexity of life. And when I rediscover that through reading the science, I feel more human. I could say childish, but I genuinely think it's human than ever. So like, you know, in writing for social media, it's complicated because everybody wants the do X to get Y. But I really want to fold in there that like, this is so cool. I can get goosebumps reading about it. I don't know. This is just me reflecting on how I relate to science in the world. And that— do you think everybody can capture that? Fascination with the natural world.
So I hope so. I wish everybody could. I think the world would be a very different place if everybody did. I think everybody is capable of it, um, but I don't— I certainly don't think everybody does, but I think everybody is capable of it. And I appreciate how you were trying to lead people to that point. And I actually remember an interview I did a number of years ago with, um, Dr. Lucia Aronica, and, uh, she, she spelled it out. She's like, we need to be curious like kids. She said it much more eloquently and I remember I sort of got chills the way she said it, but the same concept. I, I wish we all could be. Yeah.
Well, with leaders like you, I think people can, can approach it. I wanna wrap up by asking a couple questions. What gives you the most hope for the future of metabolic psychiatry, taking it from the fringes to mainstream practice?
Yeah, I mean, one of the things that gives me the most hope is just seeing the passion of Jan and Dave Buzucki and the way one family has really been able to impact the world of medicine. And if we can, you know, have, you know, 100 families like them in different areas of medicine and including metabolic psychiatry, we can change the world. And to see Dave and Jan's passion and to see their commitment is, has just been Absolutely, absolutely inspiring. Um, and the community, I mean, it's, it's, it's easy to think, you know, philanthropist just throwing money at the problem, but that's, that's only a fraction of, of what they and we have done at Buzuki Group and Metabolic Line. It's building this community and seeing the community come together. One of the things, just a, a slight, um, diversion here, but one of the things we've done Dr. Julie Mildor has really spearheaded is building this community of researchers where every month, and sometimes even more often, we get together and talk about research studies that someone's doing, and people chime in and give suggestions. Have you tried this? Oh, I can, I can do this to help. And it's really magical. And at the surface, it may not sound like much, but the feedback is like, I've never been part of a research group that is this collaborative. There's so much competition in research, like, oh, we don't want them to know what we're doing because we got to publish this first and get this done. And there is a lot of that in research. So this, this spirit of collaboration, how people truly want to design the best studies to answer the question as best they can, to help the patients as best they can, to change people's lives, it's really there and it's magical to see. So that type of concept is, um, I, I mean, it's just amazing to see. Um, so I'm extremely hopeful and, and enthusiastic about the future of metabolic psychiatry and for the broader future of metabolic medicine.
Amazing. That's a good place to leave off, but can you just tell us where can people find out more about what you're doing at the Coalition for Metabolic Health, that Bazooki Group, Metabolic Mind? Where should people check out?
Yeah, so metabolicmind.org, Metabolic Mind on YouTube and our podcast and, and now coalitionformetabolichealth.org. So yeah, very, we're putting a lot of content out there. We really wanna reach as many people as possible. Yeah. So check us out.
Well, thank you for this part 2 of the discussion. Thank you for being a shining star and lighthouse in the metabolic health space. And thank you for being a great teammate, friend, and colleague. Thanks for coming.
Right back at you, Nick. I really appreciate it. Thank you.
