Fix Your Brain by Fixing Your Body: Metabolic Psychiatry Explained by Dr. Shebani Sethi - Transcript

Dr. Shebani Sethi
One in three people have insulin resistance in The United States, and that doubles your risk of developing depression even if you have had no psychiatric history.

Dr. Mark Hyman
This is this sort of weird moment in psychiatry where I think we're converging these two massive paradigm shifts. One is around psychedelic medicine, metabolic psychiatry. Mhmm. And you can't do one without the other.

Dr. Shebani Sethi
Doctor Shivani Sethi.

Dr. Mark Hyman
Is the founding director of

Dr. Shebani Sethi
Stanford's metabolic psychiatry program. Where she unites nutrition, metabolism, and mental health care. She's rewriting mental health

Dr. Mark Hyman
By fixing the body first. What is metabolic psychiatry?

Dr. Shebani Sethi
Metabolic psychiatry is thinking about metabolism and mental health connection, but it's the study of all of the metabolic dysfunctions, both systemic as well as central. So you can have dysfunction in the brain, and you can have dysfunction outside the brain in the body. And those two elements are important in thinking about how that affects psychiatric disease and mental health.

Dr. Mark Hyman
The thing that I think people are wondering about is where do I start?

Dr. Shebani Sethi
Mhmm.

Dr. Mark Hyman
Like, I'm depressed. I'm anxious. Maybe I have bipolar disease. Maybe I've got a form of schizophrenia. Like, what do I do?

Welcome, Shimani, to the podcast. It's good to have you back. We had a chance to talk about your work a few years ago, and I just wanted to revisit it because it's it's such an important piece of work you're doing in the world to look at mental health from a new lens, which is how the body affects the brain. It's something that, you know, is kind of this weird anomaly in psychiatry because historically, psychiatrists never looked at the body. I mean, the joke in medicine is neurologists pay no attention to the mind and psychiatrists pay no attention to the brain.

And, also, I would say psychiatrists pay no attention to the body in terms of what's happening that could be influencing the brain. You're sort of highlighting the the opposite of the mind body effect, which is the body mind effect. And it's bidirectional, but but mostly, we focus on the mind body effect. Yes. Stress can cause illness and so forth, but physiological changes in the body that are emerging because of our lifestyle and our crappy diet and stress and toxins and all these things have an effect on the brain.

And we really have neglected this area, and and the body has only so many ways of saying ouch and brain even less. You know, when your when your knee hurts, if you sprain your knee, you know, it hurts. Right? But if if your brain is inflamed, what happens? It doesn't hurt and they don't get a headache.

It creates mental illness. And so I I wanna unpack with you today this whole field that you sort of are deeply involved in that you coined the term for, which is metabolic psychiatry. So maybe you can start off by saying, how did you come up with this? Where did it, like, originate from in your mind? And and what is metabolic psychiatry?

Dr. Shebani Sethi
Well, thank you, Mark, for having me back on your show. You actually wrote a book twenty years ago or fifteen Yeah. Years ago making some of these connections.

Dr. Mark Hyman
Yeah. The Ultramind Solution. Right?

Dr. Shebani Sethi
Here we are fifteen, twenty years later talking about it.

Dr. Mark Hyman
Yeah.

Dr. Shebani Sethi
These ideas of metabolism and mental health being connected, they're not new. They've been around for hundred years hundred years ago in psychiatry, we had seen that there were levels of lactate that were elevated in serious mental illness and that there were, levels of glutathione, which were low. They were low, and it is an antioxidant. And so these markers were markers of bioenergetic dysfunction. And so

Dr. Mark Hyman
Lactate is like when you exercise too much and your calves hurt because you're you've got lactic acid in your muscles, that's happening in your brain.

Dr. Shebani Sethi
And so there's also a preferential area of energy production towards glycolysis, that produces lactate, and that tends to be more common in certain diseases. So we see that in neurodegenerative conditions. We see that in serious mental illness, like bipolar disorder and schizophrenia and major depression. So when I say serious mental illness, I'm talking about these three illnesses primarily. Yeah.

Knowing that these were biomarkers that we saw a hundred years ago, and then we went in different directions over the last hundred years focused on neurotransmitters and, you know, other systems, which are only just part of the picture. There's a much bigger picture when we think about metabolism. So metabolism is really just thinking about food breakdown into energy, and everything that happens in between is detail. Metabolic psychiatry is thinking about that metabolism and mental health connection, but it's the study of all of the metabolic dysfunctions, both systemic as well as central. So you can have dysfunction in the brain, and you can have dysfunction outside the brain in the body that are connected.

Right? And those two elements are important in thinking about how that affects psychiatric disease and mental health. And so when we look at how that dysfunction affects psychiatric symptoms, whether it's prevention, whether it's progression of disease or treatment of disease, that's really what metabolic psychiatry is about. I think other instances, metabolic psychiatry has been defined as brain energy metabolism only, or it's been defined as just the ketogenic diet, for example. And I wanna clear that up because metabolic psychiatry really is a more holistic term that incorporates all systemic as well as central metabolic dysfunction and how that affects psychiatric disease.

Dr. Mark Hyman
Yeah. So so just for people listening in medicine, we talk about metabolism, and people say I have a slow metabolism and the lay culture, I have a fast metabolism. They mean a little bit different things. So metabolism is, yes, how you eat food and it converts into energy. But there's an enormous number of metabolic pathways.

If you were to put on a wall in basically microprint, it would be a giant wall. All the metabolic pathways, you know, these set of seeing we see in medical school. And every single one of those pathways are part of the biochemical reactions that happen across every system in your body. And there's 37,000,000,000 chemical reactions every second in your body. All those are part of the your metabolic system.

And all those things, I think, affect our our mental health and every everything else in terms of disease. So understanding that is really important, and it's kind of a neglected thing in medicine. We sort of give lip synchros to it in the first year of medical school. We pretty much ignore it after that. We don't learn much about things like insulin resistance, but even less about nutrition, which is driving a lot of the metabolic systems.

Right? Because every one of those biochemical pathways requires a nutrient to actually work. So in a sense, metabolic psychiatry, you're saying is is the bigger rubric that encompasses all of that, not just sugar and glucose and metabolism from that perspective.

Dr. Shebani Sethi
Right?

Dr. Mark Hyman
Yeah. Exactly. So I think I think that's important to understand. And those metabolic pathways affect everything. So it's very complicated.

We kinda like look at that chart and maybe learn a little bit about it, but it's it's kind of not this thing that we pay attention to. But it ends up being the kind of, I would say, holy grail of how to actually think about health in general, and particularly psychiatry. And and the fact that you've you sort of are pointing to the fact that the way we thought about mental illness might not be totally accurate. And and I think this is part of the problem in our society is that, you know, if someone has rheumatoid arthritis, their joints are damaged, we don't say, oh, there's something wrong with you. Like, go, too bad.

I'm sorry you're suffering from this. Like, how can I help? With mental health, there's a lot of stigma around it, and there's a lot of judgment around it, and there's a lot of attribution and meaning to it. And I think through history, there's been this this phenomena of different views of mental illness throughout history, and I think we're in this new era of of understanding mental illness through the lens of metabolic psychiatry, and also, I don't know what you call it, trauma informed psychiatry or, you know, psychedelic medicine, which is addressing a lot of these other aspects.

Dr. Shebani Sethi
Yeah. I think one of our the dean of our medical school at Stanford Medicine had said, I think during a medical school graduation, that the greatest discoveries are discovered in between in this intersection between fields. And sometimes I think we forget that the body is related and, you know, organs are not just isolated and Right. You're working in a whole system.

Dr. Mark Hyman
Yeah.

Dr. Shebani Sethi
So, you know, if your city is, you know, running and it's not if if there's a issue in the power grid and you're not having enough power and the light's flickering somewhere, there's there's something that's wrong. And it even though it's working, it's not working optimally. And so metabolic psychiatry takes different fields of endocrinology, immunology, and so forth. And we really wanted to have at Stanford, we wanted to put a name to it so that more, clinicians and researchers and, you know, people out there do more work in this area. Yeah.

It really gives us a communication tool and map to be able to label something and and to be able to work in a more collaborative way.

Dr. Mark Hyman
And and the truth is, you know, for the serious mental illnesses that you're talking about, I mean, people suffer from anxiety, depression, major depression, more serious psychiatric illnesses from that spectrum. But then there's things like schizophrenia and bipolar disease, which are pretty intractable and Mhmm. Chronic. And the medications come with a lot of downside effects. Obesity, it kinda makes it even worse.

We're seeing, you know, studies that show in the work some of the work you've done that you see profound changes in these untreatable mental illnesses when using this approach of metabolic psychiatry and nutrition and food. Can you kinda talk how did you because you you you kinda came from the field of obesity medicine and also psychiatric medicine. So Mhmm. Was that what kinda got you thinking about this? Or

Dr. Shebani Sethi
Yeah. So for me, I think I was one of those really lucky at a early point in my career when I was in medical school, I had exposure to nutrition, which usually is not typical. I think normally it's maybe two days of lectures of nutrition in medical school. Although, I'm optimistic it's changing. I had an opportunity to really delve more into obesity medicine, starting in medical school, and that got me very interested in nutrition as well because I started seeing differences, in in patients when it came to psychiatric symptoms.

And, one patient in particular who had schizophrenia and treatment resistance schizophrenia, I spent a lot of time talking to these patients in an obesity clinic. From there, I learned more about obesity treatments, and so I really just follow my heart. In a lot of ways, I I didn't have plans to be a physician scientist or an entrepreneur. I just had plans to treat patients, and I I did that, and I really enjoy it. But I felt that a lot of times these things were not being treated, whether it was, metabolic syndrome or insulin resistance or, met metabolic issues.

And I thought it would be, you know, helpful to to do that. And so I started really with a strong interest, and that just led me with my curiosity to go further into obesity medicine. I knew I wanted to do psychiatry, and I went into psychiatry with an interest in metabolism.

Dr. Mark Hyman
Mhmm.

Dr. Shebani Sethi
So I veered towards obesity medicine because that was what I I had a great mentor, in medical school, and I went in that direction. He was an obesity medicine specialist. And from there, that's how I learned about ketogenic therapies, for seizures. And then I worked with some of the folks, or neurologists who do that for epilepsy, and then understood how I could adapt it for psychiatric conditions. And then I started studying that.

I sent it with my patients. I started studying it. And here I am many years later doing research trials. Then I and I started the program at Stanford, which is focused on metabolism based interventions for, those with bipolar or schizophrenia or depression and also eating disorders. I had Yeah.

Done some work in eating disorders and trials and with obesity drugs, and I have realized over time that there are other options and tools, which I do believe is important to integrate into psychiatry. I I felt that it was missing, that we oftentimes kinda segregate ourselves a little too much from other fields, and there's just there's so much connection and relationship. And I'll give you one example.

Dr. Mark Hyman
Yeah.

Dr. Shebani Sethi
So in primary care, I saw a lot of patients that had diabetes. Right? Diabetes or hypertension. But the folks that had the more severe depression tended to have insulin resistance, or they had some other metabolic condition. And so in primary care, the folks with diabetes who weren't doing well had depression.

So that's that's the the thing that I saw, and then I just got more curious about this and that than that connection.

Dr. Mark Hyman
Yeah. There's a big crossover. Like, what? Forty percent of people with with diabetes have mental illness. Right?

Dr. Shebani Sethi
It's pretty high. Yeah. So in bipolar illness, about thirty seven, almost forty percent have metabolic syndrome.

Dr. Mark Hyman
Prediabetes, essentially. Yeah.

Dr. Shebani Sethi
Full blown metabolic syndrome. Yeah. You know, if you have insulin resistance, there one in three people have insulin resistance in The United States, and that doubles your risk of developing depression even if you have had no psychiatric history. So there's a lot of relationships.

Dr. Mark Hyman
And it depends on how you define prediabetes too. Because I think if you look at some of the work out of Tufts, they looked at people with what they sort of determined was metabolic dysfunction, which is either you're you have a high blood sugar, high blood pressure, abnormal cholesterol, you're overweight or obese, or you've had a heart attack or stroke. And if you combine all those, which are all related to the fundamental biology of insulin resistance, which I want to unpack with you Mhmm. That's ninety three point two percent of Americans. So it's it's more than one in three that have some degree of this.

That's concerning to me because our diet is so bad. It's so high in sugar and starch. It's such a destructive force for not only our body, but also our brain. And people don't understand that. People don't understand that, yeah, okay.

Guess if I eat too many cookies or have too much soda, I'll gain weight, and I'll get overweight. But they don't connect the dots with mental health. And I think and then it becomes a vicious cycle. The more depressed you are, the less like you are to take care of yourself, and you spiral. And that's what happens a lot in these patients.

So can you talk about, like, the the the the dive into this whole phenomenon of insulin resistance in the brain and how it it affects you and and how it's somehow different than in peripheral insulin resistance. Could you talk about, like, cerebral hypometabolism, which means low metabolism in the brain? Right? And how it affects the brain and how insulin resistance plays a role in this. Can sort of unpack that?

Dr. Shebani Sethi
So cerebral glucose hypometabolism, in the brain globally is a central pathological characteristic of neurodegenerative conditions and, also present in, schizophrenia and bipolar in particular. Mhmm. And that's really when the certain areas of the brain cannot use glucose for energy. Even though glucose is present, it can't process the glucose, well, and you develop insulin resistance as well. And when you have insulin resistance centrally, there's a problem with insulin signaling and glucose signaling in the brain.

And we see this even before the diagnosis of psychosis. Before medications are given and before the diagnosis, it's present. So we think there's a relationship between, psychiatric illness and insulin and glucose handling in the brain. When you have insulin resistance in the brain, that doesn't necessarily mean that you'll have insulin resistance in the body. You know, measures of that, differ.

And a lot of the medications, that that we tend to use in psychiatry, unfortunately, some of them do have effects on insulin resistance peripherally, which is different than, insulin resistance centrally. It can affect the hypothalamus, the nuclei in the hypothalamus. It it can increase food intake. So it makes you it increases your appetite.

Dr. Mark Hyman
Hungrier.

Dr. Shebani Sethi
Yeah. It makes you hungrier. And with the, peripherally, it can increase insulin so that you are releasing more insulin and become insulin resistant by nature of the medication. But there's also, elements of the medication that occur in the brain as well where it improves insulin signaling depending on the drug. So it's actually kind of complicated.

And I'll give you an example. Lithium, it also improves insulin signaling in the brain. But to get back to, you know, this insulin resistance concept in the brain and why it's important, it's really important because it's important for neuronal plasticity. Neuron neuronal growth, remodeling, shaping. It's extreme insulin signaling is critical for that.

It's one of the reasons why it's important. When you have insulin resistance peripherally, so outside the brain, it leads to degeneration and atrophy of some of the hippocampal neurons, as well. And so it's structurally altering the brain when you have insulin resistance peripherally. So that doesn't necessarily mean that the insulin resistance centrally is doing that. It's the peripheral insulin resistance that's leading to that.

So there is this bidirectional relationship that you mentioned earlier, and that bidirectional relationship is that, you know, on one side, you have if you have type two diabetes or obesity or insulin resistance, it's leading to symptoms, psychiatric symptoms. It leads to a psychiatric diagnosis. Eventually, it's affecting the brain. But then there's also intrinsic metabolic dysfunction and insulin resistance as part of that in psychiatric disease that then leads to HPA access dysregulation or it leads to sleep disturbances, and it leads to the obvious peripheral signs of metabolic dysfunction as well.

Dr. Mark Hyman
So so basically, what you're saying in English is that Sorry. Is that Yeah. You know, you've got the there is some resistance in the body that affects the brain structurally. It can shrink memory centers and other key areas of the brain that make it not work well, but you also have the psychiatric symptoms making you have worsened ability to regulate blood sugar insulin peripherally too because it affects your stress response. It affects your your whole metabolic system.

Dr. Shebani Sethi
Yes. In addition to medication side effects and so forth. But even the intrinsic metabolic dysfunction that exists in psychiatric conditions can also make someone more vulnerable in developing Yeah. Those other conditions.

Dr. Mark Hyman
And we and when you look at type two diabetics, their their mitochondria function at half the rate at as regular people who don't have type two diabetes. So mitochondria are essentially the little energy factories inside your cells, and there's anywhere from hundreds to thousands and tens of thousands in the brain. It's the most dense

Dr. Shebani Sethi
Mhmm.

Dr. Mark Hyman
Per brain cell is the most mitochondria of any cell in your body. So energy is really important in the brain. What we find is if you're a type two diabetic or if you have insulin resistance, your mitochondria don't work as well. Mhmm. And that creates a whole downstream set of consequences.

It can create more oxidative stress. It potentially can create more inflammation, and it's also inflammation can cause mitochondrial dysfunction. So it's a a kind of virtuous or maybe a vicious cycle.

Dr. Shebani Sethi
It's a vicious cycle.

Dr. Mark Hyman
Vicious cycle of dysfunction. Yeah. But on the other hand, that you can create a virtuous cycle by the interventions that you're finding with your your team and and and group at Stanford looking at metabolic interventions of diet nutrition, like keto diets for helping reset the brain energy system.

Dr. Shebani Sethi
Generally, there's four mechanisms of metabolic disease. There's plasticity you mentioned, the inflammation. There's oxidative stress, and there's mitochondrial dysfunction. And so anything that's gonna target these areas, whether it's a diet or whether it's, you know, medications that that target these pathways, there is a potential for improving the both the metabolic disease and the psychiatric disease because there is a shared relationship. There's a shared pathogenic relationship between mental health and metabolism.

Dr. Mark Hyman
Yeah.

Dr. Shebani Sethi
So that's that's really what we're studying, and that's what we're we're trying to, you know, go further into with a lot of mechanistic, you know, studies as well as looking at clinical outcomes and metabolic markers and so forth. I can go into that in detail. But I mean,

Dr. Mark Hyman
I think the inflammation piece is really important because when you look at people with type two diabetes or insulin resistance, they often have a high c reactive protein, a marker of inflammation. Yep. And they often have systemic inflammation. And when we start to look at all these neurodegenerative and neuropsychiatric illnesses, a common feature is inflammation. And and I've even seen some stupid studies looking at, like, tin alfalfa blockers for depression, which is like, you know, a drug we use for rheumatoid arthritis or severe autoimmune diseases.

It's $50 a year, and there's a lot of side effects. And they're you know, they think, well, it's inflammation in the brain. Let's give you an anti inflammatory. Like but it doesn't work like that. I think we have to think about what's causing the inflammation, get to the root cause of it, and it's this metabolic dysfunction that tends to be both the cause and the consequence of it.

Dr. Shebani Sethi
Yeah. And I think we can think about all of these, you know, whether they're drugs or even diets or there are different tools Mhmm. In the toolbox that we can use to target a metabolic pathway or an improvement in symptoms. For example, you could take metformin. A lot of us know.

Right? Metformin improves glucose. Yeah. It improves insulin sensitivity, but it also crosses the blood brain barrier, and it has a neuroprotective effect. It helps in the TCA cycle.

You know, within the mitochondria, we have machinery to produce energy, to produce ATP, and there are deficits in that energy pathway, whether they're enzymes or cofactors, they're not present. Metformin helps, support that to some degree.

Dr. Mark Hyman
Mhmm.

Dr. Shebani Sethi
And it also does decrease inflammation. So in some studies, it's been shown to reduce TNF alpha or reduce interleukin six, reduce other cytokines. And we know cytokines also are pro inflammatory. Right? And they end up also affecting serotonin synthesis.

It affects tryptophan metabolism. Yeah. Hey. That's neurotransmitter. Right?

And that's that's one part, but that's one part of the equation.

Dr. Mark Hyman
Yeah.

Dr. Shebani Sethi
And so there's a study a colleague, of mine did looking at metformin and, treatment resistant bipolar depression, and that showed an improvement. And those who are treated with metformin and also had the psychiatric medication on board, it allowed the psychiatric medication on board to work better. So that's that's just one example of how a metabolic intervention or tool can improve, psychiatric symptoms that goes beyond just, you know, let's improve insulin resistance, but there's so many other pieces, that that are also being affected by it.

Dr. Mark Hyman
And we amazing what you're talking about is this so up until now, most of psychiatry has been sort of downstream. You're oh, neurotransmitters may be a problem, but the question is, why are they so messed up in the first place?

Dr. Shebani Sethi
Mhmm.

Dr. Mark Hyman
Right? And and what's causing that? And it seems like what your work is finding is that a lot of our lifestyle and diet related problems that are driving blood sugar dysregulation and mitochondrial dysfunction, inflammation, our ultra processed diet, and sedentary lifestyle, all these things that sort of accelerate the problem Yeah. Actually Exactly. Makes, like, these neurotransmitter problems worse downstream.

Mhmm. And you can treat the neurotransmitters, or you can treat the cause. Right? Yeah. You can treat the symptom, you can treat the cause.

And I think the metabolic psychiatry approach, you know, like you said, has many tools. Like, metformin is a drug that helps improve it. But there are many other things, right, that are including diet, lifestyle, exercise, we know is very effective for mental health. And how does that work? It may partly work by improving insulin sensitivity.

Right?

Dr. Shebani Sethi
Yeah. That's one. And Yeah. You know, increasing b d BDNF, which you and I talked about last time, I think, on your show, like, now five years ago, the time has flown. Yeah.

But you you you described it as miracle grow, and I really love the way you described it. Yeah. That's exactly that's exactly what it is. That was one you know, with exercise, it's it's shown to, you know, improve those levels and improve cognition and so forth. So there's a lot of tools.

Dr. Mark Hyman
And the mitochondrial therapies, I mean, I you know, there's a woman named Suzanne Go who's, looked at a lot of, mitochondrial dysfunction in autistic brains. And whether you have ADD or autism or you have Alzheimer's or Parkinson's or depression or bipolar schizophrenia, it's all this spectrum of brain dysfunction. Mhmm. And and the there's a lot of common pathways involved in all these. Yeah.

And and her workers found that, yeah, there's energy deficits in these kids in the brain just like and it may show up in one subset of people with autism and other subset is schizophrenia, but essentially, it's the same mechanism. You know, she talks about using mitochondrial therapies, essentially cofactors that are involved in these metabolic steps, these biochemical steps require helpers. And so they use nutrients like amino acids or co g ten or other compounds that actually help improve brain function. So I wonder, are you are you exploring any of these sort of nutraceutical approaches that are using the body's own things that uses to actually make energy, but giving them a a sort of a higher doses or through supplementation as a as a tool for helping metabolic psychiatry patients?

Dr. Shebani Sethi
Yeah. It's it's an interesting question, and I love her work, by the way. And I think looking at mitochondrial dysfunction, it's a a lot of shared mechanisms with these different conditions. So it it does make sense when we're studying, serious mental illness and other conditions to be looking at vitamins, cofactors, things. So we test for that in our clinic.

We test for, all of these things, and we optimize. So we we have a approach that we use to make sure that people are not deficient in these in these things. Because if someone's deficient, does that make sense? Right. To treat them only with medication and ignore the fact that they're deficient or malnourished in some way.

If they have insulin resistance, obesity or metabolic syndrome, sure. Let's treat that. But let's make sure they're also not malnourished. Most of them are malnourished. Yeah.

And you mentioned ninety something percent of the population is having some kind of metabolic abnormality.

Dr. Mark Hyman
Overfed and undernourished.

Dr. Shebani Sethi
Right. Yeah.

Dr. Mark Hyman
So calories, not enough nutrients. Yeah.

Dr. Shebani Sethi
It's almost like a crime to not to not, be thinking about it. And I that's why I think it's really important, to have that approach. And to answer your question, while I'm not specifically looking at one supplement and its effect on psychiatric outcomes, I'm really looking at, the whole kind of the whole picture and making sure they're optimized. Give an example of research that's been done, in our field by colleagues who looked at omega three supplementation, at least one gram, including EPA per day

Dr. Mark Hyman
Yeah.

Dr. Shebani Sethi
For I think it was a total of eight to twelve weeks period Yeah. Which significantly it had a good it was modest evidence that showed benefit for psychosis, early phase schizophrenia, early phase psychosis. And it's also been a treatment as an adjunctive treatment for depression. Things like this are helpful Yeah. For us to know about.

Unfortunately, didn't have the same effect for chronic schizophrenia. Yep. But that's why prevention is so important. And mentioned earlier about fasting insulin, right, and development of depression. Like, why aren't we checking these things more routinely or more frequently to prevent conditions or prevent exacerbation of,

Dr. Mark Hyman
you

Dr. Shebani Sethi
know, symptoms that are so severe like psychosis?

Dr. Mark Hyman
Yeah. I mean, I think that you're you're bringing up is important, and and, you know, medicine's very reductionist. Likes to go let's look at omega threes. Let's look at vitamin D. Mhmm.

Let's look at magnesium. Let's look at whatever Yeah. B vitamin. And and the body is so complex that it requires all the ingredients. It's like if you wanna grow a healthy plant, you can't just have soil.

You need water and light, you know, and vice versa. Like, the human body is very much the same way, and I think we we often will not be sophisticated in how we think about providing all the components needed for optimum function of mitochondria, of your immune system, of, insulin resistance. And and I think that one way to navigate that is sort of emerging from our understanding of met metabolomics and proteomics and and gene expression products that are helping us understand the body in a more nuanced way. And I I think one of the things I think a lot about is what are the biomarkers of mental illness? And what are the things we should be looking at that that can play a role?

Rather than just treating one thing, you have to find everything that's off and fix it. In other words, if your omega three is low and you take it, great. But if your vitamin D and magnesium are also low, might not work as well. Right? Yep.

Yep. And so you kinda have to think holistically about all the various factors. So can you talk a little bit about your work in the frame of of the biomarkers of mental illness and what you're thinking about in terms of evaluating that? You know, you talk about lipids and triglycerides and HDL and blood sugar, anyone's seen all that. But Yeah.

It goes deeper than that.

Dr. Shebani Sethi
It does. And I I'm glad you're pointing that out about the, you know, optimization can't just be, a reductionist approach of one thing. We really have to look at at everything, and and that's what we are doing with our treatment approaches. It is important to, you know, obviously monitor those things as well. But biomarkers are biomarkers.

They're in psychiatry, I don't believe that there's just gonna be one biomarker. It's gonna it's be a group of, markers. And thinking about certain metabolic disease states, certain conditions, how much the progression is based on those biomarkers is is really where I think, we're heading. And, also, part of the effort in our, trial, we're starting a randomized controlled trial generously funded by, some philanthropists, including Peace Corps philanthropies, at Stanford. And we're looking at mechanistic approaches, for a metabolic intervention like a ketogenic diet, in schizophrenia, bipolar, and depression.

And we're looking at a lot of these biomarkers. I'll give you one example, and that is looking at triglyceride HDL ratio, for example. That's been something that has been shown, with a lot of good data

Dr. Mark Hyman
Mhmm.

Dr. Shebani Sethi
That depression severity and chronicity is, associated with that marker.

Dr. Mark Hyman
And that's directly related to insulin resistance. So the higher you get higher triglycerides and lower HDL, and the ratio becomes higher as you get more insulin resistant. So it should be like one to one.

Dr. Shebani Sethi
That's right.

Dr. Mark Hyman
And then can go two to one, four to one, ten to one. You know, if if your blood if your triglycerides are one fifteen, your HDL is 30, that's a five to one ratio. That's not good.

Dr. Shebani Sethi
What was interesting about that study is that insulin sensitivity wasn't associated with the chronicity of depression, but it was for the severity. But the triglyceride HDL ratio was associated with both. So it there are some interesting nuances, in the literature about about kind of looking at the biomarkers, a little bit differently. And, I think there's there's a lot of different biomarkers that will be helpful, in in even for example, with insulin resistance, since we're talking about that. When we look at insulin resistance, we see that even with bipolar disorder, you have more rapid cycling, you have more treatment resistance, and you have more suicidality.

So that's another thing that we could use as a biomarker as well.

Dr. Mark Hyman
Yeah. I think it's it's so many different things. I mean, I when I think about it, it's you wanna check your nutrient levels that affect mental health, like vitamin d and homocysteine and methylmalonic acid and

Dr. Shebani Sethi
Mhmm.

Dr. Mark Hyman
Omega three fats and omega three index and hormonal effects like thyroid and sex hormones and Mhmm. Your iron levels and

Dr. Shebani Sethi
zinc levels

Dr. Mark Hyman
and insulin insulin measurements, and some resistance scores are now available through Quest that you do at function health, which measures

Dr. Shebani Sethi
Right.

Dr. Mark Hyman
Right. C peptide and insulin mass spectrometry, which is a really accurate way of measuring some resistance and triglyceride HDL ratio and particle size and particle number, inflammation levels, CRP. So all these things are blood tests that that actually can help clue you into many different problems. But Yeah. But actually, if you see there's abnormalities, and we see a lot of it, like with functional health, we're seeing, like, seventy percent have a nutritional deficiency at the minimum level that's actually recommended by the dietary

Dr. Shebani Sethi
Not surprised.

Dr. Mark Hyman
No. It's just like not like what's an optimal

Dr. Shebani Sethi
level Unfortunately.

Dr. Mark Hyman
Vitamin D or what an optimal level of homocysteine is, but, like, homocysteine levels are in the lab up to 14 or 15 and should be probably, you know, six to eight that measures your Yeah. Folate or b 12 or b six status. And so we're seeing a lot of that. We're seeing, you know, ninety five percent with metabolic dysfunction through the lipid particle size, and we're seeing forty six percent with high CRPs, and we're seeing a lot of really significant inflammation. So we started to go, wow.

The population is at the at large is sick. We're seeing increase in mental illness, and no one's really talked about how do we how do we think differently about treating things systemically. And I think your your your what you said is really important because it's a paradigm shift from thinking of the body as a bunch of different organs and parts to how the body's a network and everything is connected, that and we have to treat the network, not the symptom.

Dr. Shebani Sethi
Exactly.

Dr. Mark Hyman
Yeah. And so that's a lot of what your work is doing. And I wonder also the schizophrenia part. You know, seventeen percent of people with schizophrenia have elevated gluten antibodies, which can drive a lot of brain inflammation and create a lot of neuropsychiatric symptoms.

Dr. Shebani Sethi
Absolutely.

Dr. Mark Hyman
Yeah. And then again, you're taking that out when you give people a keto diet. That's even part of it. You know?

Dr. Shebani Sethi
It's a good thing that we should test before and after too, which we're doing in our next study. So Yeah. We will be doing that. And and also looking at

Dr. Mark Hyman
Looking at gluten antibodies?

Dr. Shebani Sethi
Yeah. We're planning to.

Dr. Mark Hyman
Amazing.

Dr. Shebani Sethi
Yeah. Just looking at mitochondrial deficits too. So we'll be we'll be looking at that.

Dr. Mark Hyman
So how are you doing that? Because it's it's something in medicine we, you know, we don't really pay attention to. We learn about mitochondria in the first year of medical school. We learn about the Krebs cycle, you call the TCA cycle, which is the energy cycle, how you turn food and oxygen into energy in the body. And then we kind of forget about it.

And it's not part of clinical medicine. We don't talk about how do we evaluate mitochondria, how do we test them, how do we treat dysfunctional mitochondria. Yet it's one of the central features of most illnesses that are chronic, from mental health to neuropsychiatric disorders to metabolic disease like diabetes to heart failure, many, many problems or mitochondrial issues.

Dr. Shebani Sethi
Yeah. I don't have an answer as to why we don't do it more, but I think it's, you know, something that is probably difficult and hard to to treat in some ways. But the more research I think that we have in this area, the better it's gonna be for more targeted interventions. So I'm hopeful, you know, for that. One thing that I thought would be helpful in when you're describing the mitochondrial dysfunction in various conditions, what we are seeing in psychiatry also is that, you know, the brain is volumized.

It makes up 2% of our body, but it consumes 20% of our energy. And it's so delicate, extremely delicate that if there are deficits in insulin and glucose handling and that, you know, Krebs cycle machinery, to produce energy, then there's more metabolic vulnerability in psychiatric conditions. There's more metabolic vulnerability in specific areas of the brain. You and I talking right now, we're maybe using 80%, you know, of our capacity. We have if we're, you know, talking a little bit more deeper in science, you know, it'll be a 5% increase.

Our daily, you know, activity is a bit less. And for someone that maybe has genetic predispositions or, have environmental stress, it's gonna be a little harder to have that, you know, perfect machinery producing energy, and there's more metabolic vulnerability there. And so those differences between one region of the brain and another is is pretty critical for functioning, cognition, mood, and mental health symptoms.

Dr. Mark Hyman
And and how are you thinking about measuring mitochondrial function as you're talking about in your in your upcoming studies?

Dr. Shebani Sethi
I believe in a lot of collaboration. I love collaborating with other scientists. So University of Toronto, Mayo Clinic, a lot of other departments at Stanford. I have a faculty member, chair of genetics who at Stanford will be looking at all omic profiling, so all expression of proteomics, metabolomic data, wearable HRV data. Another faculty member is gonna be looking at ketone metabolites because downstream of ketone metabolism, there may be, say, an amino acid called phenylalanine attached to beta hydroxybutyrate, which is what ketones will break down into.

Yeah. And if you have that, the end effect of appetite reduction or weight loss is present. If not, it doesn't work as well. The mitochondrial testing is a collaboration with Mayo Clinic and University of Toronto, and that's looking at all the different metabolites in the mitochondria. Lactate's one of them, but there are a lot of other there's succinyl CoA, different dehydrogenases.

So we'll be looking at all the all the levels of that.

Dr. Mark Hyman
Before that. Normally can get at a regular lab test? No. Is there a research based test looking at mitochondria? Yeah.

I mean, clinically, it's been a a tough thing for us to look at because you could do a v o two max test, which is basically an exercise treadmill test that measures Yeah. Sort of indirectly your mitochondria. You can measure organic acids, which are urinary metabolites. Mhmm. And I think, you know, we all have sort of subtle changes in our metabolic pathways that affect different things, and Yeah.

We can see some of those changes. But there's now, you know, cheek swabs that look at the respiratory chain, which is, you know, basically the assembly line that turns food auction into energy. And there's some interesting, you know, kind of ways to start to think about how do we sort of clinically measure this in people? Because it's such a big it's such a big black box, and it's so important.

Dr. Shebani Sethi
Yeah. And then

Dr. Mark Hyman
you can actually even be specific and say, oh, this pathway that requires co q ten is a little slow. Mhmm. So what if I give extra co q ten? It's gonna speed it up.

Dr. Shebani Sethi
And it becomes more personalized that way. Right? Like, a bit and more specific. And I forgot to mention we're also looking at epigenetic data. So looking at DNA methylation and gene expression, it's a 120 patients, randomized controlled trial, and we'll be collecting a lot of data, continuous ketone monitoring.

Dr. Mark Hyman
Mhmm.

Dr. Shebani Sethi
Abbott donated the devices.

Dr. Mark Hyman
Glucose monitoring.

Dr. Shebani Sethi
Grateful for that. Yeah. Glucose monitoring and getting more we're still fundraising for the trial, but we have gotten enough to get started, and we're looking at all these measures. And it's exciting. We're Yeah.

Excited about it.

Dr. Mark Hyman
You know, what what you're offering to people is not here, take this pill for your mental illness, but here here's a lifestyle change that can have profound effects. How do you do that? Because these are patients who are often mentally ill, which makes it harder for them to make good choices. Right? Mhmm.

And so you're asking them to do a ketogenic diet or you're asking them to do severe lifestyle changes. How how are you getting people to do that?

Dr. Shebani Sethi
Yeah. That's a good question. And, you know, I do wanna recognize that it's it's not always easy, especially when you have a condition like schizophrenia, but there's a lot of support that is involved in providing care that's important in those cases and caregivers that get involved. So we do support groups. We really help them with, you know, adjusting to making changes in the home to be able to not necessarily thinking about it as a diet, but really think about it as a lifestyle change and a metabolic therapy for their illness, which is improving their quality of life, which is our primary outcome.

It's the thing we care about most as clinicians. Right? So, you know, we we want them to have a better quality of life. They want a better quality of life, and that's what also motivates them to stay on on the on the diet or the approach as well. Yeah.

So I think a combination of that

Dr. Mark Hyman
A lot of good side effects. Yeah.

Dr. Shebani Sethi
Yeah. A lot of good side effects. Yeah.

Dr. Mark Hyman
I mean, in your clinical trial, you're doing a ketogenic diet for bipolar and schizophrenia that recently published with twenty three patients. You had a 100% reversal of the metabolic syndrome or prediabetes. You had 12% reduction in body weight. You had a 36% reduction in belly fat, 27% reduction in insulin resistance, which, by way, the HOMA IR is probably not as good as the this new insulin resistance score that Quest is doing through

Dr. Shebani Sethi
Oh, yeah.

Dr. Mark Hyman
Yeah. Aspect.

Dr. Shebani Sethi
We're doing that now.

Dr. Mark Hyman
But, you know, dramatic reductions in psychiatric symptoms. And so improved sleep, life satisfaction, all these great side effects. You know?

Dr. Shebani Sethi
Yeah. In four months.

Dr. Mark Hyman
Yeah. Yeah. And when you you take a drug for schizophrenia, all the side effects are bad. Right? You know, all the side effects are good.

And and does that encourage people to stick with it more because they're seeing positive effects?

Dr. Shebani Sethi
It it does encourage people, to stick with it more. And I think, you know, over time also organically, the more, mutual patients with other clinicians in cardiology, endocrinology, or or primary care see their patients improving with reduction in visceral fat and improvement of, you know, other metabolic markers aside from the psychiatric markers, and people start to appreciate it and are grateful that their patients are doing better. And the patients themselves also themselves feel like they have more control over their life. It gives them hope. And a lot of the patients that were in that pilot study that I did was published last year, but are still my patients today.

A lot of them are still my patients today, and I and a lot of them are still on a ketogenic diet. So it does speak to, I guess, the feasibility Yeah. Of being on it over time. And I I said earlier that my goal was I like seeing patients. I enjoy seeing them get better.

A lot of these conditions are hard to treat. Having a tool like this and seeing that it's helpful is very encouraging. I thought that doing research is important for our field in order for it to, you know, go past just beyond me and other people do it. Yeah. Want it to just die with me.

Yeah. I really want this to be out there. So when I'm not around, my son can grow up in a world where there are more things that, you know, his disposal and, you know Yeah. That that my patients have at disposal and, you know, people that we can reach beyond just the academic centers, beyond research. I think that's why it inspired me to go outside of that too and and start something, and found a company that's really just focused on providing that care.

Yeah. Because otherwise, research just stays in research and in academia. It doesn't not going out doesn't feel doesn't feel right to me, I guess.

Dr. Mark Hyman
I mean, it takes decades for scientific discoveries to end up in clinical practice. So I think the fact that you started metabolic psychiatry lab, which is an online platform for engaging people who want to try this out is is important. And it it allows it to scale up and people to get access to it and to and what you're doing is so revolutionary. I mean, think about the fact that, you know, nutrition has not been a topic in medicine that is really thought to be a serious subject. And it's sort of this sort of stepchild, fourth cousin, once from who?

Dr. Shebani Sethi
Not science enough.

Dr. Mark Hyman
Yeah. No. But what what you're talking about is a nutritional therapy that has effects of orders of magnitude more than our traditional therapies. So it's not like it's an equivalent therapy. It's it's so much better.

And I wonder if in in terms of your your work at Stanford, are you are you finding resistance, or are you finding encouragement or openness to this idea? Because it's it's sort of a

Dr. Shebani Sethi
Yeah. A lot of people ask me that question, and I appreciate that. I I have found a lot of support. With anything, there's there's always waves. Right?

But but I have found a good amount of support, especially with all the activities I'm involved in. And I'm in Palo Alto, Silicon Valley. Right? It's pretty common for professors to spin out companies Yep. Outside academia as well.

I love doing the research. I I believe it's important to have evidence based science, so I'll still continue to do that. But also, you know, having having the support to be able to move between these worlds is is something that I'm grateful for.

Dr. Mark Hyman
And so so your psychiatry colleagues are not going what are you doing using food in in medicine? This you should be using drugs?

Dr. Shebani Sethi
I think some people are are like, how do you stay on that? How do you stay on a ketogenic diet? Right? But, again, I think it's the way you approach it. I think understanding I think education and understanding around it's a it's a therapy, not a diet, really.

In in my mind, it's really a therapy just like a drug would be. It requires monitoring. It requires physician or someone trained in that area. And there are other metabolic tools. I wrote this in Nature paper along with 12 other authors focused on, you know, what is metabolic psychiatry?

Why is this important? But also, what are the what is the current evidence for these different metabolic based treatment interventions, and why should we care? And where are we going in the future? I'm more hopeful because there's a global group of scientists, and researchers that do care about this and are working on this. And I think it was just yesterday that the Senate Appropriations Committee came out with a recommendation for the NIMH to put more money and funding into, guess what, nutritional science or nutritional ketosis work in serious mental illness specifically.

I'm psyched about that. I can't wait to apply, and I hope that I can do more research with metabolic psychiatry labs or at Stanford. But I I care about the science, and I care about patients getting access to these treatments. And so, you know, I love that Function Health has been able to really improve the access to get these labs. Yeah.

And what we're doing at Metabolic Psychiatry Labs is putting together the biomarkers, the personalization, using AI machine learning algorithms to improve the disease states of someone with schizophrenia versus someone with bipolar, and really provide that wraparound care for them and work with their psychiatrist or their therapist or their PCPs so that they're not alone, in this whole world. And I think or in the health care system, which I don't know how much we wanna go into that. But I I wanted to share with you that the reason why I was, I think, compelled or felt obligated to go in this is myself, after I had a child, I had a really significant, tailbone injury Ugh. And I couldn't sit for nine months.

Dr. Mark Hyman
Okay.

Dr. Shebani Sethi
And so and, yeah, it was it was horrible. But a lot of people couldn't see that I was injured or suffering in some way because, you know, I wasn't walking around with a a cast or, you know, I, you know, I didn't have it it was invisible. Right? There was a colleague of mine that sent me a book on, tailbone pain. Oh.

And there was a chapter on the psychology of tailbone pain. And when I read it, it just felt so validating. It was like an advocacy of of how do you walk through the health care system Yep. And how do you tell your OB guy, and or, like, what the issue is because it gets often missed. It was so helpful for me, that book.

So I decided that I wanted to do something similar, like a patient advocacy manual or book, and I'm still writing it. Who knows when I'm be done? But I wanted to do that for those with serious mental illness. Starting metabolic psychiatry labs is part of that reason.

Dr. Mark Hyman
And and you mean you're starting with the sort of most extreme case. Right? Schizophrenia, severe bipolar disease. But, you know, the spectrum mental illness goes from just a little anxiety and depression to OCD to more serious things. So Spectrum.

Across that whole spectrum, this approach can work. Right?

Dr. Shebani Sethi
It's not just serious mental illness. It can be depression, anxiety that may be less severe, but still debilitating for someone and they're suffering from it. And and having a metabolic approach, especially if ninety, you know, something percent have metabolic abnormalities, why couldn't they not, you know, benefit from from something that's tangible and targeted and specific and evidence based?

Dr. Mark Hyman
I mean, it's really interesting because I I first started to understand these ideas when I was treating people with a lot of chronic illnesses that were were not really psychiatric in nature, like an autoimmune disease or insulin resistance or microbiome issues or gut issues. And all these psychiatric problems would go away or get better. Mhmm. And I was kind of like sort of shocked. And it's really why I wrote this book, The Ultra Mind Solution, How to Fix Your Broken Brain by Fixing Your Body First.

Because I was like, wait a minute, nobody's talking about this. And I don't know if this is a thing or not, but it's certainly repeatable in my practice. And if you pay attention and observe what's happening with your patients and listen to them, it's like, cow. You know, you you treat someone's microbiome and their OCD gets better, or you you treat someone with some nutritional deficiencies and they get better, or you fix their blood sugar dysregulation, and their anxiety goes away, and their panic attacks get better. And, like

Dr. Shebani Sethi
And see, I think the reason why you ended up maybe putting that together is because you're probably you know, you were treating patients. You were coming up with something for them. You saw them get better, and it it it went from there. And that I think really where the heart is of, you know, when you're really seeing patients and treating them, you you see that. Probably motivated you to do what you're doing today.

Dr. Mark Hyman
Totally. I mean, I I mean, I I jokingly call myself the accidental psychiatrist because I I just didn't treat people's mental health issues, but then I I started to. And I and then I wrote a book, and then, boy, I got a flood of patients Yeah. Who had mental health issues and autism and ADD and Alzheimer's.

Dr. Shebani Sethi
You're trying to find solutions.

Dr. Mark Hyman
Yeah. And they and it was amazing to see how much they got better when we just applied this sort of systems approach to dealing with all the variables that go wrong, and not just being a reductionist sort of single Mhmm. Mhmm. Vector or single

Dr. Shebani Sethi
I think you'll be excited to know that we're also looking at microbiome. We're testing the microbiome Yeah. Also before and after with the trial. So genetic, you know, data too. So it's really like a a big library of data that we'll collect and happy to collaborate.

Dr. Mark Hyman
Yeah. I very fascinating. I mean, I I mean, I think, you know, our our dataset is function health is interesting because we won't share it or sell it or use it for any purpose other than, you know, just helping learn. You know, anything we learn will be from an anonymized dataset that's Yeah. You can't tell who's who.

But, we're learning so much about the population, and it would be it'd be it's gonna be an interesting strategy to how do we start to study what's happening. And we actually had a talk with Lloyd Miner, who's the dean of Stanford, about collaborating on some research projects.

Dr. Shebani Sethi
Oh, good.

Dr. Mark Hyman
Because, you know, it's hard to do a study. I mean, you wanna do a study with a 120 people. It's millions it's millions of dollars. Yeah. It's a lot of effort, and you know, the costs are really high to do the diagnostics.

But here, we have almost 300,000 members and

Dr. Shebani Sethi
Yeah.

Dr. Mark Hyman
Hundreds and biomarkers on each one, which is tens of millions of biomarkers.

Dr. Shebani Sethi
Good way to collaborate. Yeah. I mean

Dr. Mark Hyman
Literally, we have available to sort of figure out what's happening with the population when they change things or do this, and I think it's gonna be interesting

Dr. Shebani Sethi
Absolutely. Data set. We should talk more about that, and I'd love to. Actually, Lloydminer is a huge supporter, you know, of the work, and actually wrote me a very nice email after the pilot study came out and was really grateful for what I was doing. So it it's it's very encouraging.

That actually answers your other question about how supportive is Stanford.

Dr. Mark Hyman
I think people who have an open mind I found this at Cleveland Clinic that, you know, people who were in these sort of elite institutions typically had more open minds because they were curious. They were asking questions. They were willing to challenge orthodoxy. And, of course, there was always the pushback, but this is this is this sort of weird moment in psychiatry where I think we're kind of converging these two massive paradigm shifts. One is around psychedelic medicine, trauma, and and then metabolic psychiatry at the same time.

And it feels like they're complementary. I love to see them sort

Dr. Shebani Sethi
of Yeah.

Dr. Mark Hyman
Combine all of the pieces because, you know, you can't just do one thing. Like, you know, if if you have some serious trauma, yes, you have to fix your metabolic function, your nutritional status, get your thyroid working, get the toxins out of your system, then your brain can work better.

Dr. Shebani Sethi
Right.

Dr. Mark Hyman
Right? I always say it's a lot easier to be enlightened if you're not mercury poisoned or your thyroid's working, you're not b twelve deficient. Right? Absolutely. But but if you also have to look at the other end of the equation, which is, you know, what are the what are the psychological impacts that imprint on the brain and on our genes and epigenetics that actually drive our psychiatric symptoms.

So it's it's sort of bidirectional. Mhmm. And you can't kinda do one without the other. You know, one of the things that you talk about is eating disorders. And and I I was sort of curious about that because the the orthodoxy and eating disorders is don't restrict anything for these.

Dr. Shebani Sethi
Mhmm.

Dr. Mark Hyman
Yeah. Often young girls, sometimes boys. And yet you're talking about putting these kids on a ketogenic diet, which is extremely restrictive. Right? So what what have you found with these these

Dr. Shebani Sethi
Yeah. I've I

Dr. Mark Hyman
have some colleagues. This is one of the most life threatening illnesses is anorexia.

Dr. Shebani Sethi
I have a colleague who's doing a trial looking at ketogenic diet and anorexia specifically. You know, as a whole, when we look at eating disorders, whether it's anorexia or bulimia or binge eating, there are disruptions in several different pathways. There's serotonin, dopamine, and opioid pathways as well. A lot of the literature on anorexia and restriction has been largely and with bulimia too is that you would exacerbate the symptoms when you're restricting a diet, but a lot of that literature is based on low fat, low calorie diets. Not necessarily thinking about, well, if you add fat back in and you have moderate protein and, you know, you have kind of you nourish yourself in kind of the right way.

So to me, it's not it's not a diet. It's actually the way we should we should be eating more like this. Is that changing neurocognition? Is that changing the obsessions or compulsions, for example, that you sometimes do see in anorexia and rigidity? And that data isn't quite out yet, but there are there is some preliminary data that is showing improvements, especially with binge eating and bulimia.

We published some case series on this and recently published an article a couple weeks back on improvement in food addiction symptoms, which is a separate clinical entity from binge eating disorder and Yeah. Obesity, but it, tends to be in a subgroup in both conditions. And and in that subgroup tends to be worse, outcomes when you have the food addiction as well. So there are reductions in binge eating and purging and, you know, so forth. So we, you we have we have been looking at that That's incredible.

In that data.

Dr. Mark Hyman
But it's not easy to do a ketogenic diet. That's the hard part. It's like you got to get rid of grains and beans and sugar.

Dr. Shebani Sethi
And And it's a personal choice. If that's some if someone wants to go down that path, you know, we will support it as long as it's clinically appropriate for them. I did a trial in the past with a colleague of mine, Deborah Safer, at Stanford, which we looked at a obesity drug, FDA approved obesity drug called Qsymia, and we looked at that in binge eating disorder and bulimia and achieved abstinence rates of sixty three percent while on the drug, versus the control group, was about six percent. So there was a pretty significant difference between those that were taking the medication because it affects reward pathway. It affects glutamate and GABA transmission.

It was shown to be helpful for them.

Dr. Mark Hyman
That's amazing. Where are the big gaps in our knowledge that we have to fill in this field? And how do how do we how do we do the types of studies that are needed? Because, you know, I remember Thomas Ensell, who I met once, who was the former head of the National Institute of Mental Health. I said, what do you think of the DSM-five, which is the Mhmm.

The diagnostic and statistical manual that you use to describe psychiatric illness? And essentially, it's describing symptoms and categorizing people according to their symptoms, not causes. Yeah. He goes, well, I think it has a 100% accuracy, but 0% validity.

Dr. Shebani Sethi
Mhmm.

Dr. Mark Hyman
Meaning, it's great at putting people in categories of symptoms like you have schizophrenia, you have ADD, you have bipolar disease, you have depression, you have anxiety, you have OCD, but it doesn't tell you anything about why. And and also, it doesn't help you differentiate in those groups the different causes Mhmm. Because you could have 10 people with depression with 10 different causes. You need to treat each one differently instead of this one size fits all medicine, which is kind of what we do.

Dr. Shebani Sethi
Yeah. I remember him saying that before too. And, you know, he's right. It's it's one way that we have as a field to, categorize, the symptoms. Where we would like to go is, you know, you talked about biomarkers earlier and thinking about what are the right biomarkers Yeah.

And, you know, what's the the right way to have a tool that you can predict, certain symptoms arising and thinking about the metabolic pathways that are involved, specifically looking at more mechanistic understanding, of that energy vulnerability and differences Yeah. In diagnosis and disease state can be can be helpful. But, again, there's a lot of shared pathology, shared characteristics, and thinking about more of that root cause of what are the dysfunctions and why it's occurring. And is it happening in all conditions? A lot of times with psychiatry, there's a lot of different causes, and it's heterogeneous.

Right? And so it can can be quite complex. But I think the more targeted we can be and the more the more specific we can be with our treatments, who's gonna do better on what treatment, I think that's that's where we wanna go in collecting our data. So, you know, with the data that you guys are collecting with labs and the outcomes and the treatment, you know, that that we're collecting, I think that would be a really good way of figuring it out.

Dr. Mark Hyman
A 100%. I mean and we're seeing this convergence of, like, the understanding of sort of the measurement of our sort of different metabolic pathways that are off. Yeah. But also sort of the the personalization. So we sort of combine medic metabolic psychiatry with personalized psychiatry.

It becomes much more effective.

Dr. Shebani Sethi
More precision. Yeah.

Dr. Mark Hyman
Right. And I think that's what I've always done with functional medicine is, you know, everybody's got a different treatment even if they have the same disease because it depends on what their particular dysfunctions are, and you can actually assess those and measure those. Exactly. Look at the microbiome. We look at mitochondria.

We can look at, you know, the gut and and food sensitivities. We can look at nutritional status in different people. We could talk and load in different people. We could look at all these different things that play a role. I think we need we need to sort of better accelerate this because so many people are suffering.

Yeah. And and, you know, around the margins, there's these cracks in our conceptual framework in medicine. There's a crack in the ideas that we all were trained in medical school, which is that diseases are these entities that show up that we have to treat with drugs that we don't really know why they happen necessarily, and we don't understand the causes, and we just gonna have to do our best downstream. We we have to get to upstream medicine, root cause medicine, systems medicine, network medicine, whatever you want to call it. Yeah.

And and I think, you know, the the work that you're doing at Stanford around metabolic psychiatry kind of breaks that through, but it's it's it's it's true across all of medicine. You know, this is these cracks are happening everywhere, whether it's autoimmune disease or neurodegenerative diseases. The the thing that I think people are wondering about, I'm sure if you're listening, is where do I start? How do I like, I'm depressed. I'm anxious.

Maybe I have bipolar disease. Maybe I've got a form of schizophrenia. Like, what do I do? What do what do you what would you advise people to?

Dr. Shebani Sethi
First, understanding that there are tools out there right now that can be delivered, and over time, obviously, will be refined and improved.

Dr. Mark Hyman
Mhmm.

Dr. Shebani Sethi
But that there is a place to go to get care. We have a, you know, we have a line for people to contact us. We will recommend where we think it makes sense for them to get care. We offer care both at Stanford and at Medical Psychiatry Labs. And so there's a lot of, you know, research trials.

I'm involved in several now. So, that's also an avenue that that patients can take. Hopefully, we can get to a place where I have a manual recommendation where they can kinda navigate. But for now, I've been able to set up, you know, a line where people can contact and get information. And if they want to enroll, in care, they can.

Not bound by a geography, not bound by one academic center. Right? And it's scalable on digital. Yeah. Every state.

Dr. Mark Hyman
And that's the metabolic psychiatry labs. Yeah. And is that operational now? Are people Yeah. Able to

Dr. Shebani Sethi
It's operational. It is venture backed, and it is gonna grow.

Dr. Mark Hyman
That's pretty exciting. I mean, because I think talk therapy is helpful, but it's it's not gonna fix people if they don't have these underlying things.

Dr. Shebani Sethi
No. Correct. It's just one tool.

Dr. Mark Hyman
So I think we have to use all the tools in our toolkit, whether it's trauma informed therapy, whether it's psychedelic medicine, whether it's metabolic psychiatry, nutritional psychiatry, microbiome psychiatry, I don't what you wanna call it. Integration. The job guy who says, you know, your psychiatrist doesn't check your poop test when you go to the doctor and you have depression, but they probably should. Yeah. I actually speaking of the microbiome, I don't know how much you're looking at that, but it was such a huge unlock for me to understand when we looked at people's bowel overgrowth of bacteria or Right.

Metabolites.

Dr. Shebani Sethi
You could

Dr. Mark Hyman
check-in organic acids, and you would treat them. And sometimes I would treat psychiatric problems with antibiotics. Mhmm. Out bacterial overgrowth or fungal overgrowth, and people would come back to life. You know?

I remember this

Dr. Shebani Sethi
That's right.

Dr. Mark Hyman
Yeah. Little girl I had who was beautiful nine year old girl who was just a terror. And she was kicked out of her class, like, routinely in school on the bus ride home. They have to stop the bus 15 times to deal with her disruptive behavior and violence, aggression. I did a urine test, which looked at metabolites of bacteria and yeast in the gut, and she just was off the chart.

Like, with fungal metabolites and bacterial metabolites and something like I'm just gonna go back to first principles and reset her gut and Yeah. Give her an antibiotic and an antifungal and give her some probiotics.

Dr. Shebani Sethi
Good. She had you.

Dr. Mark Hyman
It was like the lights just came on in this girl overnight. She went from like this terror to being this sweet little girl.

Dr. Shebani Sethi
Yeah.

Dr. Mark Hyman
And I was like, oh, wow. This is more here than I understand in terms of what's affecting the brain and how the brain responds to different things that are happening in the body that we haven't really begun to uncover. And so I'm excited to see, you know, twenty years later, there's now this is actually emerging as as a field of inquiry, you know, as something that people are paying attention to in major academic centers like Stanford. It's it's pretty exciting.

Dr. Shebani Sethi
It's about time. Right?

Dr. Mark Hyman
It's about time. Yeah. About time.

Dr. Shebani Sethi
Actually, the PANSS autoimmune with OCD and depression that

Dr. Mark Hyman
PANSS.

Dr. Shebani Sethi
PANSS. Yeah. It's call it PANS clinic at Stanford. But I've seen a lot of cases there where antibiotics are really helpful for the psychiatric symptoms. Yeah.

There was another biomarker like a l acetyl carnitine Yeah. That my colleague actually at Stanford had looked at as a marker of depression. And with anti it's low on depression. And so with, antidepressants, it resolved the marker Really? With treatment response.

Yeah.

Dr. Mark Hyman
You mean, like SSRIs improve carnitine levels? Mhmm. Interesting.

Dr. Shebani Sethi
Yeah. The acetyl L carnitine level. Yeah.

Dr. Mark Hyman
So it's interesting that, you know, we we might be giving drugs thinking they work one way, but they might work another way. Right? Yeah. Statins may not really work by lowering LDL, but they work by lowering inflammation.

Dr. Shebani Sethi
Exactly. So that's why that's why metabolic psychiatry is really thinking about the whole picture, and that there's multiple tools both with medication and nutrition and how it all gets put together.

Dr. Mark Hyman
Yeah. And I I'm excited doing the omics work and the metabolomics and mitochondrial testing because before, we really had a hard time. Like, it was like it was like looking at the sky without a telescope and or looking at, you know, bacteria without a microscope. It's hard to see. And now with the advent of of deep diagnostics that are available, not just regular biomarker testing, but

Dr. Shebani Sethi
Yeah.

Dr. Mark Hyman
Looking at what we call the omics, which is your metabolomics, all the metabolites you have in your blood, the proteins you have in your blood, proteomics, epigenetic expression, we can start to map out what's happening and see these patterns Yeah. And then use AI and machine learning to help us make sense of them, and then kind of see how we can create more targeted solutions for people based on these these large datasets,

Dr. Shebani Sethi
which Exactly.

Dr. Mark Hyman
Are are becoming radically deflationary. I mean, I think your whole genome sequence you can do for $300 an hour used to be a billion dollars. That's Yeah. We were

Dr. Shebani Sethi
poised at a very good time right now to be able to use technology to really understand, you know, the science and the mechanisms. Yeah. And it's not just the sky. There's a whole universe now. Right?

Between the, you know, breaking down of food and production of energy and waste products, what we call metabolism. Yeah. Right? So there's a whole universe out there and excited to continue to explore it.

Dr. Mark Hyman
Exciting work. I'm gonna keep following what you do. I'm gonna maybe see if we can work together to figure out the mental health biomarkers. That would be something. Right?

Yeah. See a psychiatrist to make a safe care to get a panel of biomarkers for mental health. Let's make sure you don't miss anything. Yeah. You know, it's

Dr. Shebani Sethi
I'd love to.

Dr. Mark Hyman
It'd be amazing.

Dr. Shebani Sethi
I mean, it really takes multiple brains energy Yeah. Since we are all in limited supply, to to create something really wonderful.

Dr. Mark Hyman
Well, thank you. How can people learn more about your work?

Dr. Shebani Sethi
Metabolicpsychiatry.com or metabolicpsychiatrylabs.com, is the two websites. It's a free resource. Metabolicpsychiatry.com is a free resource through Stanford, that we created and happy to help anyone looking, for, you know, anything specific. And metabolicpsychiatrylabs.com is, of course, the virtual, remote care for metabolic psychiatry care that's nationwide. And

Dr. Mark Hyman
And then there's a for those nerds listening, there's a great article that you've written called Metabolic Dysregulation and Metabolism Based Approaches in Mental Health, a narrative review of metabolic psychiatry, sort of trying to lay out a whole field, what it is, what we know, where we are now, what are the options for therapy from nutrition to metabolic therapies to drugs that can modify these pathways. And I I think everybody should have a a good look at that paper. We'll put it in the show notes so we can track it. Thank you for your work. Gonna keep following you doing.

I'll have you back maybe a few more years. Yeah. Love having next. I really appreciate what you do in the world.

Dr. Shebani Sethi
Yeah. Likewise. Thank you for having me, Mark.

Dr. Mark Hyman
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