2022/12/20

There is no metabolic difference between sucrose and pure HFCS. However, some HFCS-sweetened drinks contain unhydrolyzed starch, which can significantly increase the caloric load and trigger inflammatory reactions if absorbed into the bloodstream. Play From10:15

Chronic stress elevates cortisol, which stimulates lipolysis and blocks glucose uptake and metabolism. This leads to insulin resistance and diabetes, as well as increased fat storage, especially in the abdominal area. Play From36:06

Ketogenic diets can initially help with weight loss, but over time, they can elevate cortisol and increase lipolysis, leading to a catabolic state. This can cause muscle loss and insulin resistance, making it difficult to maintain or return to a normal diet without weight gain. Play From39:58

The Randle Cycle is a metabolic process where the availability of free fatty acids inhibits glucose uptake and utilization. This can lead to a buildup of pyruvate and lactate, and ultimately, the conversion of glucose to fat rather than its complete oxidation to ATP. Play From01:02:48

Starchy foods can increase the production of endotoxins in the gut, leading to inflammation and serotonin production. Better carbohydrate sources include simple sugars like honey and ripe fruits, which are more easily absorbed and do not trigger the same inflammatory response. Play From01:47:36

Serotonin is primarily a metabolic regulator that inhibits oxidative phosphorylation, especially in the brain. High serotonin levels can lead to depression, psychosis, and fibrosis, which is a precursor to cancer. Serotonin antagonists have shown promise in treating these conditions. Play From01:35:48

Organ meats like liver and heart are rich in essential nutrients like vitamins A, B, and minerals like copper and zinc. They provide protective factors against stress and inflammation, and can help balance the amino acid profile of the diet, which is important for metabolic health. Play From01:50:55

Muscle meat is high in tryptophan, methionine, and cysteine, which are anti-thyroid and can be harmful in excess. Collagen, found in tendons and skin, contains glycine and proline, which can balance these effects and reduce inflammation. Ground beef and organ meats can provide a more balanced nutrient profile. Play From01:59:33

Markers like CRP, ESR (erythrocyte sedimentation rate), and whole blood serotonin are reliable indicators of chronic inflammation. For cortisol, testing both AM and PM cortisol levels in the blood or using 24-hour urinary cortisol can provide a comprehensive picture. Play From54:20

The Ray Peat diet emphasizes the importance of carbohydrates, particularly from fruit and honey, to support thyroid function and reduce stress hormones. It also focuses on limiting polyunsaturated fats and including organ meats to provide essential nutrients and protect against metabolic issues. Play From01:00:21

00:00

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01:54

heartandsoil.co. On this week's podcast, I have the honor of talking to Georgie Dinkov. He is a really smart human, guys. Like so many, he is from the tech world, not originally trained in biochemistry, but this man has done the research. He's got

02:11

gotten interested in this sort of Ray Peet type of philosophy. So I was interested to talk to someone in that world. And many of the ideas that he shares are very compelling and interesting. They're a little bit different than some of the things I've thought about traditionally, but I love getting out of my comfort zone, thinking about things in an outside of the box way. And Georgie was a ton of fun to talk to. So if you listen to this podcast and you find some of the concepts challenging,

02:34

Take a deep breath, review the research, and come along with me as we expand our minds and continue to journey toward optimal health without dogma, without things limiting us.

02:44

us. You all know that I've had lots of growth in my life in terms of what I believe is optimal for humans. I started out pure carnivore, then realized that carbohydrates were beneficial for humans. And now I'm just continuing to learn and explore things. We talk about all kinds of interesting things in this podcast. What's the deal with Mexican Coke? Obviously, I'm not a fan of Coca-Cola because of the other additives and stuff, but is sucrose, table sugar, or raw sugar the same as high fructose corn syrup? We talk about that one. We talk about sunlight, EMFs,

03:13

We talk about hormones. We talk about all kinds of interesting stuff in this podcast with Georgie. We go deep into polyunsaturated fatty acids and your mind will be blown. Again, if it's challenging for you, put on your mind expanding cap, your open mind cap, and I think you will get a ton out of this podcast with Georgie. I really enjoyed our conversation.

03:33

and hope to have him back soon. We can continue with more questions from Georgie if you guys would like that. So if you're watching this on YouTube, put more questions for Georgie at the bottom in the comments, and I'll ask him the next time I get him on. There's so many things to talk about here. Serotonin, polyunsaturated fatty acids, estrogen, endotoxin, starch is damaging the gut. It's an incredible conversation. Enjoy this one with Georgie Dinkov. I appreciate him coming on.

03:57

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09:11

Georgi Dinkov, thanks for coming on the podcast. It's good to have you here. Thank you. Thanks for inviting me. I think Dr. Conover provided the introductions or no, Joe Mercola, right? Yeah, Joe Mercola introduced us. So I appreciate that. I've been listening to a lot of your talks with Danny Roddy on generative energy and really enjoying the things you talk about. I really think you guys are doing a good job of asking some interesting questions. I love questions.

09:38

Questions, and I love trying to step outside of what we all know to be true in very emphatic air quotes. So I appreciate the borderline iconoclasm at times. And I think we'll get into a lot of technical, interesting questions in this podcast. But I thought we'd started off with something kind of high level.

09:58

What's the deal with Mexican Coke? Are you a fan of this? Is it different than regular Coke? I don't drink either of them, but I'm super curious. And the implicit question here is, is there a difference between sucrose, like table sugar, and high fructose corn syrup?

10:15

If you get them both in pure form, there is metabolically no difference. Unfortunately, several studies where I can send you links later did some analysis on the ones that were sweetened with HFSCS, the high-procure corn syrup, and they found out a ton of unprocessed starch.

10:30

So basically the caloric value that was listed on the label, it only took into account the actual high fructose corn syrup, but didn't take into account the two to three times more calories as starch, which converts into glucose, obviously. So that was one explanation of why drinks sweetened with high fructose corn syrup may tend to be more fattening. If it says 150 calories in a bottle, it was actually 600 calories.

10:56

Yeah, basically a lot of unhydrolyzed starch from corn. It somehow ended up into these soft drinks. And that may be one explanation. But as far as the actual composition, I mean, high fructose corn syrup is, what, 55, 45 in favor of fructose?

11:12

sucrose is 50-50. I don't think there is any metabolic difference. And I've done some studies myself using an outsourced lab, and we don't see any changes, any significant changes between the two groups of animals in terms of

11:26

you know, blood sugar, hyperlipidemia, insulin response, cortisol response, things like that. They seem to be metabolically largely equivalent, assuming you're getting the actual pure high fructose corn syrup without any sort of like starch particles dissolved in there. There's like a second aspect of it. I'm not sure to what degree it's true, but if you do have an undissolved starch, depending on the size of the starch particles, they can actually absorb through the

11:51

lumen through the intestine and get into the bloodstream. Now, if that happens, then it's obviously going to trigger an allergic slash inflammatory reaction and you can get some like additional symptoms because of that. Now, if that is true and happens on a regular basis, I think that is something much more worrisome than the actual caloric value of the

12:09

of the high fructose course of sweetened beverages because human studies demonstrate that you don't really start synthesizing lipids from carbs until you basically hit the 500 gram mark daily intake of carbs. Most people don't do that. They don't come anywhere near that, right? The novel lipogenesis, you need about a pound of sugar a day to actually start synthesizing palmitic acid from sugar.

12:32

But if it does trigger, if you have these tiny, very tiny nanoparticles of starch and they're getting into your bloodstream, I think that's actually what may be responsible for a lot of these inflammatory reactions that drive insulin resistance and ultimately diabetes type 2. To me, that's a much more plausible explanation versus high fructose core soup is somehow evil. I mean, if it's pure, it should be indistinguishable from sucrose metabolic. It's such an interesting thing because

12:59

I'm sure you may know some of my history. I think we have similar histories in trying ketogenic, low-carb diets and crashing and burning. And so for a long time,

13:12

When I wrote my book about the carnivore diet, I mean, Danny Roddy, your friend emailed me and said, when you come around to carbs, let me know. So shout out to Danny Roddy that I came around to carbs. But in the beginning, I was reading this literature about fructose. And there's a lot of literature about fructose that looks bad, primarily in animal studies with mice or rats.

13:35

And Robert Lustig has done some studies in teenagers who are using fructose sugar-sweetened beverages, and it looks like they improve their metabolic function when they cut these things out. And Rick Johnson has done studies where people… There's two groups of people. It's all hypocaloric, but the processed fructose group…

13:55

when they cut that out, they do well. Interestingly, and I've spoken about these studies in the past, the other arm of those studies is they don't eat any processed fructose, but they eat fruit and they seem to do just fine. They have the same metabolic benefits. And so I've been trying to wrap my head around this. And when I heard you guys talking about this, and I think that the Ray Peet community, which you're a part of, and we can talk about Ray Peet. I know he just died. So we can talk about all the cool things that he talked about in his life.

14:20

They've done a good job of kind of saying, hey, maybe sugar isn't the problem. And I couldn't understand, is it the processing of the sugar? Because there's some good studies in humans with honey. And there's a lot of good studies in humans with fruit that say, this doesn't really make you metabolically unwell. What's going on here? But I'm thinking in my head, well, fructose is fructose. It's this molecule. And then glucose is glucose. And if you put them together, you get sucrose.

14:45

why is high fructose corn syrup somehow spawn of the devil the way it looks in literature? So this is an interesting explanation that it could be just these derivatives of corn that aren't purified from it.

14:59

Yeah, and actually the studies were pretty clear about it. And in fact, as a corroboration, you can find several studies showing that if you feed animals cornstarch, they did get this inflammatory reaction basically after every single meal. So if you are getting an inflammatory reaction from a meal, regardless of what it contains, I think we can all agree that over time you will become insulin resistant.

15:18

simply because of the rebound reaction of cortisol, because you will need to dampen inflammation down. And now cortisol is already known as the primary driver of the high blood glucose that is seen in type 2 diabetics. About 80% of that comes because doctors worry about, oh, if you're type 2 diabetic, you should cut out all sugars. Turns out that cutting down the dietary sugar does not diminish that much the blood glucose level because about 80% of them are coming from the liver through the process of gluconeogenesis. And what drives that?

15:47

primarily cortisol. So if you are in a chronically inflamed state, you will probably have higher baseline cortisol. And we, the metabolic community, believe that over time, this will lead to insulin resistance and diabetes. Some indirect evidence comes from the patients with Cushing syndrome or Cushing disease, or Cushing disease, I don't know if you pronounce Cushing or Cushing, right? They are all invariably Cushing, right? Cushing.

16:08

They're all invariably insulin resistant. And recent studies found that the cortisol blocker, which is in the medical community, is known as the abortion pill, because it's also a progesterone blocker, the IU486 or myfepristone,

16:21

actually led to sustain, first of all, cure the insulin resistance of the Cushing disease people who weren't eligible for surgery because the tumor was too big or they were concerned they're going to do brain damage. They're trying to remove it. Basically, they weren't candidate for surgery, so pharmacological treatment is the only way. They gave them the cortisol blocker. These people, which are normally also centrally obese because of the cortisol, it creates this very unique phenotype.

16:45

Very skinny limbs and like central obesity, right? And also buffalo hump and, you know, just a classic hypercortisolemia. So they gave him the cortisol blocker. Not only it reversed the insulin resistance and their high blood glucose, which kind of confirms the cortisol is involved, right? Reversed that and also led to sustained, I emphasize, sustained weight loss.

17:06

So this kind of gives you, like, gets you thinking, like, wow, maybe type 2 diabetes is an endocrine disease, right? Just like, I mean, everybody says, medicine has already admitted that type 1 diabetes is an endocrine disease, but they're saying it's a failure of the pancreas, right? We're going to give you insulin, and that's it.

17:23

Turns out type 2 diabetes, there's a very strong evidence that it is also endocrine disease, largely driven by basically the hyperlipidemia, right? But now the question is, okay, which one comes first? The obesity drives the diabetes or the diabetes drives the obesity? Well, they actually feed into each other. They feed off each other. But it looks like initially it starts with either some kind of a high stress, chronic high stress, which elevates the cortisol, right?

17:47

or eating a diet that will get you to a point of basically obesity or at least a significantly overweight state, right? Where if you're significantly overweight and or obese, you will have higher than normal lipolysis. Now, lipolysis is known to block the uptake of glucose. It's known to block, I mean, the free fatty acids, but they're coming from the lipolysis.

18:08

It blocks the effects of insulin at the receptor level, blocks glucose uptake, and also due to the Randall cycle, the cell at any point can only metabolize either glucose or fats. Now, if you're flooding your organs with fat, right, whether from the diet or from your internal stores, if you're already obese, then no matter what glucose you have, whether it's coming from gluconeogenesis or from the diet, you will not be able to metabolize it, hence hypoglycemia.

18:32

And in addition, all of that glucose floating around, whatever gets absorbed into the cells, uptaken into the cells through the glute receptors, GLUT, I think there's like four of them or something, because the cell cannot, it's in beta oxidation. In other words, it's metabolizing all this fat that it's being provided with, cannot metabolize the glucose. So the glucose will go through glycolysis and it will end at the stage of pyruvate.

18:54

And pyruvate starts to accumulate. Because it cannot proceed further due to this Randall cycle block, this accumulation of pyruvate, something has to happen with it. And because the production of pyruvate consumes NAD and produces NADH, the cell will say, I need my NAD in order to live. If my NAD levels, the oxidized version of the cofactor NADH,

19:17

nicotinamide, adenine, if my levels of NAD drop too much, I'm going to die. So I need my NADH oxidized back into NAD. What can I use? Well, my Ruvaid is the emergency oxidant. But guess what?

19:28

After you use Peruvian, you get lactate. And you see this invariably in every single case of type 2 diabetes. They're higher than optimal levels of lactic acid. They're, of course, higher than optimal levels of free fatty acids, right? And to the point where basically the free fatty acids rise to the level of completely blocking the effects of insulin, then you get diabetic ketocenosis.

19:50

And these people get rushed to the hospital. They're already in type B, I think it's like type B lactic acidosis as well, which has a very high mortality rate, which I'm sure you've seen in the hospital as well. So these people basically have to get rushed to the hospital, get injected immediately with a very high dose of insulin and pray to God because it's still not guaranteed that they'll survive.

20:09

So really lipolysis and the excess amount of fat in the bloodstream can wreak havoc on just the entire metabolic process. And further studies recently showed that the actual damage to the peripheral organs that is very commonly seen in people with type 2 diabetes, such as kidney damage, liver damage, all of these is apparently driven by these elevated levels of free fatty acids, predominantly the polyunsaturated kind.

20:33

And conversely, so people say, oh, George, a nice theory. So what do we do about it? Well, there is a drug on the market which is apparently already approved, not very well known, but it's called ACPmox, derivative of vitamin B3. Basically, it's a niacin molecule with I think like an additional hydroxyl group. I have an

20:50

looked at the specific, but it's a derivative of vitamin B3. What does it do? It blocks excess lipolysis. And guess what? When you give it to people with type 2 diabetes or insulin resistance, their triglyceride levels fall, which is normal, right? Because they block excessive lipolysis. Their blood sugar normalizes, right? And then who knows what happens over time? I haven't seen any long-term studies with it, but there's a good indication that the metabolic disturbances of type 2 diabetes and obesity are largely driven by this excess fat

21:18

that we store. And of course, if it's mostly the polyunsaturated fats, which we store, that's how body seems to be dealing with it. Then when they get released into the bloodstream and get processed by all of these other tissues, in addition to their

21:31

Just a pure anti-glucose metabolic effect just because of them being fats. They're also pro-inflammatory. They feed through the cyclooxygenase pathways, the lipoxygenase pathways. They themselves, the polyunsaturated fats, synergize with estrogen and cortisol and activate a number of different… They increase the production of tumor necrosis factor alpha. They increase the production of serotonin, which I know many of the medical community think it's a very good thing. But it's not.

21:57

It actually really isn't because some of the best drugs that we have for reversing incurable things like pulmonary fibrosis, heart failure. Now Pfizer is running clinical trials behind the scenes with a drug which is a serotonin antagonist to reverse these things that are so far considered incurable, universally deadly. Anyways, long story short, fats can kill, especially if they're of the polyunsaturated kind.

22:21

So we just foreshadowed a lot of cool things that I want to get into in this podcast. We talked about serotonin. We talked about estrogen. You mentioned polyunsaturated fats or PUFAs from seed oils primarily. We're going to get into all of that in more detail. I want to just…

22:36

rehash what you were talking about for the listeners so they understand. What I'm hearing you say, Georgie, and correct me if I'm wrong, is that there's really, I mean, I'm sure there's multiple pathways to insulin resistance and diabetes, but there's essentially two main pathways. Some sort of chronic inflammation leading to high levels of cortisol. All you're eating is cornstarch, which is so interesting that cornstarch, an ingredient in a lot of things that I ate growing up, that's a thickening agent.

22:59

If this is what's causing the inflammation associated with high fructose corn syrup, then think about how many foods corn starch is in. So chronic inflammation, and we can talk about where these inflammatory things might come from. That'll probably tie into endotoxin and other ideas that your community has talked about. That can lead to chronically high cortisol. And you were talking about this drug, mifepristone, RU486, which is colloquially known as the abortion pill, but it just…

23:24

mechanistically, mechanistically, it blocks cortisol and then it causes the abortion of the fetus, but it can also block cortisol in these pharmacological realms as well. So that, that might be useful for diabetes. That's interesting mechanisms. And then the second pathway that it seemed like you were talking about with diabetes is kind of this broken excessive lipolysis. And I've spoken about this on my podcast as well in the past, because when I've dug into this research, it's been really fascinating to look at the adipocytes, specifically the fat cells

23:52

And what happens to them when they're exposed to the breakdown products of polyunsaturated fatty acids like linoleic acid, this 4-HNE. I did a podcast with Tucker Goodrich and Jeff Nobs, and I've spoken about this repeatedly. But there seems to be some pretty good evidence that when there's excess breakdown products of linoleic acid, the fat cells can't do hyperplasia, meaning they can't divide. They can only hypertrophy. So you see this broken adipocyte, this broken fat cell that is like this guy on Monty Python that just keeps eating and then he bursts.

24:18

It's just these fat cells grow and grow and grow, and they can't divide. They just burst, and they spew out lipokines. They spew out inflammatory mediators, and then they also spew out these free fatty acids into the blood. And so if I understand what you're saying correctly, it's all these excess fatty acids in the blood that do trigger peripheral insulin resistance. They're signaling to the muscles, hey, be insulin resistant, to the brain, to the liver. If you have high levels of free fatty acids,

24:44

That's signaling insulin resistance to the body. And in situations of pathological insulin resistance, it can maybe come from cortisol, chronic inflammation, but also these broken fat cells, which maybe we get there through seed oils. It's such a fascinating thing to think about this because this pathology is

24:59

of insulin resistance is at the center of so many chronic illnesses we see in the Western world. We have to understand that. Did I get all that right? I mean, do you think that makes sense? Specifically that metabolite you mentioned, 4-H, I think it's 4-hydroxynone now. Yeah, 4-HNE. Yeah.

25:14

Yeah, among other aldehydes that are peroxidated byproducts of PUFA, that one specifically is now being recognized as a biomarker for Alzheimer's disease, for Parkinson's disease, for multiple sclerosis. So we're seeing either the byproducts of PUFA, right? It's peroxidated byproducts, which we know are pathological. We don't like them, right? Most of the aldehydes are toxic. Malon de aldehyde, which is one of the biggest ones, one of the most common ones, probably represents about 80% of the aldehydes produced, you know, degradatively from PUFA.

25:42

It's a known carcinogen. I think it was just recently recognized as a known carcinogen and mutagen, right? So we know that the peroxidative breakdown of PUVA is not good, but also their enzymatic byproducts, such as the COX and LOX and whatnot, right? They're also turned out to be highly pathological. Some of the most successful drugs we have

26:00

are cox inhibitors, right? They block part of this, which should be natural and good pathway, but it turns out that if you feed way too much spoof, well, this enzyme is basically going to produce, it's substratodependent, right? And in its normal state is what I think medical committee calls non-saturated state, right? So it means if you give it more, it will process more. So it will get you into this chronic inflammatory state. And then also the lipoxygenase pathway

26:26

several of the drugs that are locks inhibitors or inhibit the, uh, activity of the end products known as local triads, right? They're now actually being tested for Alzheimer's disease. Uh, and recently the study in the animal model completely reversed all of the cognitive dysfunction in an animal model of Alzheimer's. So just everything that about UFO specifically, whether broken down or it's in the intact state seems to be leading to a pathology, uh,

26:51

And that pathology is associated with chronic inflammation, right? High cortisol, high estrogen, I would add, because they feed off into each other. Cortisol stimulates the aromatase enzyme, by the way. And so do many of the synthetic glucocorticoids used in the medical practice. Guess how many people on dexamethasone?

27:07

Or like Betamethasone or any of the other, or Medro, right? I mean, a ton of people for inflammation or like rheumatoid arthritis or whatnot, these pills are being doled out left and right. And by the way, to the pharmaceutical company's credit, it does have a black box warning. It says, listen,

27:23

If you take too much cortisol, I mean, too much of a glucocorticoid for too long, you're at risk of insulin resistance, diabetes, heart attacks, strokes, neurodegenerative disease, osteoporosis, right? All of these things. So I'm thinking, okay, this is now known and recognized, but why is there a disconnect at

27:42

between knowing that these drugs, which operate in the exact same way as the endogenous cortisol, knowing that these drugs can cause all of these things, why can't we admit that endogenous cortisol, maybe we'll never get to the point of the potency of these synthetic drugs, but still, elevated endogenous cortisol, we know it can cause trouble. We have Cushing disease, right? It's caused by high endogenous cortisol. These people have the exact same symptoms as the warnings for the side effects of these synthetic glucocorticoids.

28:11

So to me, it's really like it's pretty obvious where this is going is that most of the coronary diseases we have are actually metabolic in origin. And it starts with something as benign as eating all of these foods that have these hidden ingredients that are not listed on the label. It says, I don't know.

28:26

20 grams of high fructose corn syrup, but it doesn't tell you that it's another 80 grams of corn starch. And most people don't taste it. There's no way to like recognize, you know, corn starch, especially if it's, you know, putting together with some of these other ingredients, which mask, not that it has any taste, but I can kind of taste the starchy food. But if it's like in an ice cream, which is very, very commonly is if it's in something like a,

28:47

like a cake or if it's something like a soup. I just recently found out that the local Whole Foods, which is supposed to be, it has like a food bar. My God, they put this cornstarch in everything, everything. Cheap, right? It's a filler. So if they want to give you a cake, chances are that 80% of that cake is not butter. It's not like heavy cream. It's not chocolate, but it's actually cornstarch. And then just a little bit of dressing on top. So…

29:12

To me, the evidence is clear that we have serious evidence that many, if not most of the chronic degenerative diseases we see in society are actually due to simply suboptimal dietary supply chain. And conversely, when many people move out of this environment for a little bit, like here in Costa Rica, you probably eat a lot of ripe fruit. Of course, there's many factors, like you probably lower stress. I'm hoping it's lower stress.

29:35

Yeah. Right. So if it's lower stress, better food, right? A lot of sunshine, probably less polluted. You're out in nature. I mean, it's a lot of jungle support here in Costa Rica. So all of these things combined, I mean,

29:46

I mean, people that go on vacation that I know that work right here in D.C. or generally in Western societies, I don't know people in America. I mean, Europe is actually worse in some of these health situations. When they go on vacation and come back, they look visibly younger. Right. And they act better. They're in a better mood. Right. So everything about them screams, I'm better.

30:06

When I move away for a little bit, and then they come back. And you can tell by the time when they come, it's like, ah, now I need a vacation from a vacation. I can't get back to this meat grinder. I don't want to go to a meat grinder, but you have to. And it's kind of like that activates another thing, which is like the learn, help, assist, which is like, well, I don't want to do this thing, but I have to do this thing. And it's known that in situations like that, again, cortisol, HPA axis gets activated, serotonin rises, right?

30:32

And really the goal of serotonin is to make you get through difficult times that are unavoidable, right?

30:37

It blunts the pain response. It blunts the ability to be easily sort of like, you know, impressed by events around you that are not particularly pleasant, that kind of thing. But over time, of course, you know, if you do that, then basically a very high serotonin, we know medically, undisputed, it causes fibrosis. Antagonists that one of their serotonin receptors, specifically 5-HT2B, are the most potent antifibrotic agents that we have. Now,

31:04

Now, if we have something that causes fibrosis when chronically elevated endogenously without administering a drug, not like cortisol that has synthetic corticosteroids. So if this thing causes fibrosis endogenously, then we don't want it to be chronically elevated. But it gets chronically elevated if there's inflammation. Again, serotonin activates the enzyme tryptophan hydroxylase. So it's going to synthesize serotonin as well. It's really just the cycle of sort of like –

31:28

I call it the sickness field, right? The disease field, because it's, it's meant as an adaptation. When, when you present it with a challenge, right? The way our organism, I think has evolved is basically we, we sort of like shut down functions that are energetic and very expensive, but currently are not needed to meet that challenge. Right. And then the idea is that after this challenge passes, the idea is that should be temporary, right? Then you revert back to normal. Well,

31:52

Well, in our daily lives, it turns out that we're basically subjected to chronic low-grade stress pretty much all the time. And there's this established model in animal research called CUMS, chronic unpredictable mild stress, universally accepted to cause depression, bipolar disorder, schizophrenia. These are all animal models, but they're pretty reliable in terms of mimicking the mental states of humans.

32:15

So if chronic unpredictable mild stress can cause all these mental diseases, right? Also insulin resistance and diabetes and whatnot, then why wouldn't the same thing be true in humans as well? I've spoken to several people who actually kind of do like a, they're kind of like a liaison between animal and human research. And most of the time they say,

32:31

We as a society are not ready to accept that our lifestyle is killing us. Yeah, we're just not ready. Whether it's economically or politically, we to ourselves are not ready to admit that basically what we do on a daily basis in the vast majority of cases is basically driving us into chronic disease. And that's how it is.

32:52

Isn't there a disease? I forget the name of the disease in Japan. It's like the overworking syndrome. They actually have a diagnosis for working yourself to death. They have a named diagnosis, the equivalent of this animal model, chronic mild stress. They probably have chronic moderate stress. But one of my friends did a documentary on this. Maybe I'll find a link to it and put it in the description. And it was about these Japanese workers and they work themselves to the bone. So I

33:20

By the way, the country with one of the highest rates of suicide. That's not by accident. That's not by accident, right? I just want to make sure I heard you properly. Did you mean to say that cortisol increases tryptophan hydroxylase and that increases serotonin in the brain? Okay, yeah. I think you might have said serotonin increases tryptophan hydroxylase, but just so people know. No, no, serotonin has a feedback mechanism, a negative one, but cortisol

33:40

activates both aromatase and tryptophan hydroxylase. And unfortunately, these two, estrogen, which is the byproduct of aromatase, and serotonin, they go right back and activate 11-beta-hydroxysteroid dehydrogenase type 1, which synthesizes cortisol. So this really pernicious mechanism that basically these chronic stress cycles feed off of each other

34:01

And we really have to break out of the stress or administer something that sort of like blocks one or both of these pathways or how many pathways are there. Because at the end of the day, if you don't stop it, then it's not going to stop by itself. It's a positive feedback cycle.

34:15

So one of the things that I think humans can do, and I found this out firsthand when I added back honey and fruit to my carnivore diet, is eat some carbohydrates. Let's talk a little bit about your perspective on ketogenic diets. I've done a couple of videos on YouTube about why I stopped ketogenic diets and the dangers of ketogenic diets. But

34:35

Let's talk about ketogenic diets. They're widely felt to be beneficial to humans, but I think there's another side of this that people don't always hear. And it ties into all of this chronic stress and perhaps this negative feedback loop. Well, they're very good for three to six months, which is what I experienced. And after that, basically, I hit a wall. And if you continue pushing yourself, which I was stubborn enough to do, then you basically really crash. And it's not a pleasant situation.

35:00

because let's say while you're doing the low carb, your insulin may decline, your blood glucose may decline, but in the process, because of the elevated cortisol and the elevated lipolysis, and you're also eating a low carb diet, which means even more fat, you're really upregulating the production of cortisol and you're making yourself insulin resistant, but you don't feel it at the time. But if you stop this diet and then you go back to a normal diet, let's say about equal proportion of the macronutrients, 33% of each, you will probably gain quite a bit of weight initially,

35:28

And people are like, oh, well, there you go. It's a proof that eating carbs makes you fat. I'm like, no, it's the proof that eating carbs after being on a low carb diet makes you fat. And there's a very good reason for that. There's a great study. It's an animal study, but it's really hard to argue with because it demonstrated either chronic fasting

35:47

or exhaustive exercise, and worse if you do both, leads to a very highly elevated baseline production of cortisol, which, by the way, was so severe that when the animals reverted back to their normal state, they weren't fasting and they weren't exercising. They basically had the equivalent of a subclinical Cushing syndrome. Guess what happened to them?

36:06

As soon as they went back to the normal diet, not fasting, right, or like not exercising, they ballooned, which is expected if their cortisol is high. And they had to give them the REO486 to get them back to normal. So really the message for me to this study is that do not kill yourself, you know, do not overexert yourself because the price you pay, I mean, I know we've all heard the saying no pain, no gain, right? I agree with that to a degree, but there's a corollary. More pain doesn't necessarily mean more gain.

36:35

So there's maybe an optimal amount of pain when it comes to dieting and exercise. But if you feel like you're hitting a wall, I would strongly advise against pushing forward against that wall because the wall is going to win. There's just no way. Eventually, metabolically, you're going to hit a wall. I mean, the wall is collapsing on top of you, and then you have no choice but to go back to your normal diet, right? But now you're metabolically kind of decontaminated.

36:59

And I'll give another example. The human show, The Greatest Loser. I don't know why they call it that. The Greatest Loser, yeah. My goodness, what an apt name. So these people went to tremendous, really rigorous dieting and exercise regimens to lose the weight for the show, right?

37:16

And as soon as they stop, not only did all of them without exception regained all of the weight that they basically had before, but actually they regained it while maintaining their now reduced caloric intake. And the question is, oh my God, what happened? Where their basal metabolic rate essentially got tanked by about 40%.

37:34

So now they're getting fatter by eating less. Can you imagine these people were eating and now they're like, oh my God, I look just as horrible as before, but now you've removed my one joy in life, which was eating. And it's really a very unpleasant situation. But to me, obesity is an endocrine problem. It should be evaluated by an endocrinologist. Thyroid, cortisol, estrogen, androgens.

37:57

In most men, as soon as you start accumulating fat around the abdominal area, chances are your testosterone levels are probably below the 500 mark.

38:05

Chances are. In fact, there are studies confirming that below 500, you cannot beget children naturally. You need some kind of a help, either an IVF or intrauterine insemination, I think they call it, a number of different things. And precipitously, basically the levels of testosterone have been declining over the last two to three decades. So that alone can explain a lot of this obesity that we're seeing. But anyways, digressing a little bit, the bottom line is when you're low-carbine,

38:31

and also potentially exercising, which a lot of people do. Both of these things, when it cuts carbs, potentially raising cortisol. Why does low-carbbing raise cortisol? Well, the brain prefers to burn predominantly sugar. And if the supply of sugar from the diet stops, then the brain has two options, basically. Get the sugar from somewhere else. It can synthesize it from either amino acids or…

38:55

Now, the synthesizing of glucose through fats is a very energetically expensive process, and that's reserved for really last measure. So most of the time, you're going to synthesize glucose from amino acids, right? So some of the amino acids will come from a diet, but let's say they're about 100 grams of amino acids daily. When you deaminate them, you'll get about, let's say, 60 to 70 grams of glucose. That's not enough for the brain. So the brain wants more. It wants more.

39:19

And what happens? You elevate cortisol, and the cortisol starts shredding your lean muscle tissue, your skin, your bones, everything that contains amino acids that can be converted into basically glucose through the process of gluconeogenesis in the liver. Some people say, well, why your bones? Aren't bones calcium? No, they're actually 40% collagen, which is amino acids, which can be used for synthesizing glucose. So

39:43

This is one dangerous aspect. And I imagine if you're also exercising on top of that, no doctor would deny that exercising elevates cortisol. That's what it's supposed to do, right? You're pushing yourself to go at a higher rate than you normally do. So cortisol is supposed to rise.

39:58

And if you combine both, you get in a really dangerous situation. It just depends on how resilient you are and how long you can go on like that. But almost every person that I know that has gone on this low-carb diet, I survived on it for about 11 months. Every other person that I know, basically, I don't know anybody who's done more than 12 months without some kind of a pharmacological intervention because they started getting basically edema or heart problems and whatnot.

40:25

Or they just stopped. They just said, this is not for me. I lost some weight, thank you, but I'm going back to my normal diet.

40:30

And unfortunately, most of the weight that is lost while you're on the low-carb diet is actually water. Cutting carbs works very similarly to diuretics. And a lot of people will see very immediate results. They'll say, oh, my God, look, it's been one week into the keto diet, right? Or like the low-carb diet. And I'm like, I don't know, 10 pounds lighter. Most of it was water that you were retaining before that for a variety of reasons. So it's, you know, and some of the…

40:56

latest studies, University of San Francisco, there's a big study, big center database that focuses on intermittent fasting and also like low-carb and exercise as well. The lead scientist there, based on the latest study he said, he's been like an intermittent fastener for the last 10 years. He said, not only did I stop it myself, but I stopped recommending it to my patients either. They lost lean muscle mass at

41:17

alarming rates, right? Well, they also lost some fat, but not nearly as much as they lost muscle. It's just how the body structure because the glucose is preferential as a fuel and

41:28

adrenaline and cortisol will rise when you're in a caloric deficit, right? But cortisol will actually shred more than adrenaline would. So over time, you will lose muscle mass, which is really terrible because your base of metabolic rate is determined mostly by the ratio of lean muscle mass to fat mass. In other words, how much lean muscle mass you have. And if you lose most of that, just like the biggest loser did, people did, then you go back to what they call skinny fat,

41:52

I think the doctors call it sarcopenic obesity. Yeah. Terrible, terrible situation to be in because now you have, you accumulate tremendous amount of fat, no muscle to burn it. The muscles burn predominantly fat at rest, but they prefer glucose when they're exercised, right? And now you're basically like hypometabolic and you sit there shivering like a little mouse and then you eat like these tiny portions and you're still getting fat.

42:14

Yeah, I don't want to be there. It's horrible. So in the month of January, we've got this challenge coming up at Heart and Soil called Animal Based 30. And

42:24

In this part of an animal-based diet, which is kind of my conceptualization of a good diet for humans, I've included a lot of carbohydrates. Because I think for people who are metabolically healthy, who are exercising, carbohydrates are amazing. And one of the questions that I think this podcast has already helped me clarify was, what should I recommend to people who are obese and diabetic? And we touched on this earlier, so I'm circling back.

42:48

to this idea, but the idea that in people who are obese or diabetic, elevated blood glucose is not necessarily from the sugar you're eating. It's from inappropriate gluconeogenesis at the level of the liver because the liver is insulin resistant, probably because of increased cortisol or increased free fatty acids because you have broken fat cells. So tell me what you think of this. But I think that if we're doing any sort of intentional diet,

43:11

and we have people joining this challenge, this Animal Base 30 challenge, and they're diabetic or obese, they probably would not be well served to limit their carbohydrates to excessive levels. They probably don't need to eat 300 grams of carbohydrates a day like I do because they're not surfing for three hours. But I would think like anywhere from 120 to 170 grams of carbohydrates might be good for somebody with diabetes. We kind of talked about this idea that I've heard this magic number around

43:40

A hundred. Like, I think that even people with diabetes probably want to get at least a hundred grams of carbohydrate today, or your body's going to shred the muscle and increase the cortisol to make that. What do you think in terms of levels of carbohydrates for somebody with diabetes or frank obesity who's doing this eating challenge? Like, I don't think they should really limit too strictly. No.

43:59

No, I've never seen anybody improve on a strict carb, like a very severe carb limiting diet. Eventually, they call it like the honeymoon period. The doctor tells them, listen, I'm going to put you on a low carb diet, but guess what? In five years, you will be diabetic. Right now, you're pre-diabetic, but in five years, I'll see you here in my office and I'll give him metformin, right? Or whatever, or one of the newer ones that are, you know…

44:19

what are they called? The GLP antagonist. Yeah. Some of the newer drugs, right? And yeah. And usually that's how it turns out. So I will actually, before considering, I mean, worrying about that, I would actually put them through a battery of like endocrine tests. I will test cortisol. I will test prolactin very often elevated in people like that. I will test like the androgens in males, progesterone in females, and also adrenal androgens in females, such as the hydroepiandrosterone.

44:46

DHA. Yeah, DHA. It's associated in multiple studies that demonstrated very strong inverse correlation between obesity and DHA in both men and women. But in men, the predominant basically androgen is or should be testosterone when the gonads are working. You don't want to be having too much DHA. Not only converts easily into estrogen, but also like very high DHA is not a good sign. Signs of adrenal hyperactivity could be like an adrenal tumor or whatnot.

45:11

You don't want to play too much with that. But anyways, if it's low, that's bad. And I would actually consider supplementing. So do the endocrine test, right? Oh, speaking of the prolactin, the drug, anti-prolactin drug bromocriptine is actually approved by the FDA. Not many people know that. It's approved as a treatment for type 2 diabetes. Wow. Yeah. What would…

45:32

a bromocriptine have to do with diabetes? Well, in addition to being a dopamine agonist, it is actually a serotonin antagonist, which tells you that serotonin plays a big role in diabetes. But what does serotonin have to do with diabetes? Serotonin is the most potent controller of the cortisol release in the body. It turns out that the cortisol that we start producing through exercise or through any kind of exertion or through any kind of stress is actually a downstream effect of the synthesis of serotonin

46:01

which then activates, stimulates the pituitary to release ACTH, and that ACTH triggers the adrenals to start raising cortisol. Conversely, anti-serotonin drugs have successfully been used to cure Cushing disease, which is like the worst kind, right? And also Cushing syndrome. So which means bromocriptine, by lowering serotonin, or at least opposing it, doesn't lower it, but blocks it at several of the receptors. This means it has an anti-cortisol effect. Boom, yet another…

46:27

sort of like indirect or direct evidence that cortisol is involved in diabetes type 2. So diabetes type 2 endocrine problem. Check all of the hormones. Check prolactin, which, by the way, is also a good surrogate for serotonin. But if the insurance covers it, I will probably check whole blood serotonin. That's key. Not serum because it's almost always normally serum, but it's whole blood serotonin.

46:46

And then if nothing is out of the ordinary, or at least severely out of the ordinary, then I think about equal ratios of the macronutrients is probably a good diet on a daily basis for most people. Now, if you're very, very active, then you have to increase the carbs because otherwise, just like we discussed, we're basically like you're starting your body with the glucose and it will find some way to get it, right?

47:08

But if you're, let's say, like a normal, I don't want to say sedentary lifestyle, but the normal city lifestyle where the movement is from the house to the car to the office, maybe walk around, maybe walk around like a mile tops daily, then about equal macronutrients, 33%, 33%, 33% is probably wise, right? I would certainly not drop.

47:28

Yeah, by calories. Yeah, okay. And we could think about how that breaks down in macros. Obviously, fat is twice as much in terms of calories. So 33% of 2,000 calories is about, let's say, like 600 calories divided by 450 grams of carbs, right?

47:42

150 grams of carbs, 150 grams of protein. And then about half of that, 75, exactly 75. Yeah, interestingly. You know, when I do my chronometer, Georgie, you guys would appreciate this. I'm eating 33 to 3,400 calories a day. Amazing. Amazing metabolic rate. Yeah.

48:04

It's pretty good metabolic rate. And last week I did a blood work podcast for anybody that's interested and showed all my recent blood labs. I did get testosterone and yeah, I want to talk about iron too. But you mentioned prolactin. What do you think of as an optimal prolactin?

48:20

The range keeps getting revised upwards, which to me is, first of all, it's scary because every doctor will agree prolactin should not be high. Woman, man, doesn't matter, right? It's one of the most potent bone dissolving things that we have. I mean, that's actually its primary role is in the female body, prolactin starts to get elevated towards the end of the pregnancy and it stays elevated while the woman is breastfeeding. But the woman also produces progesterone, which has anti-prolactin effects. So the woman is protected. But if

48:47

But if high prolactin, if prolactin is elevated, it has no carcinogenic effects. Breast cancer, especially the estrogen-sensitive breast cancer, is known to be driven by prolactin. There was a study with bromocriptine, once again, showing full cure of 70% of the breast cancer cases. Full cure, full remission, nothing else. No surgery, no radiation, no other chemotherapy other than the bromocriptine. So prolactin, currently I think the upper limit is maybe 20 or 21%.

49:13

For males… The lab work I just did, they said the upper limit was 13 or something. Mine was 7. I think that's good. Basically, you want to be in the bottom 50th percentile because that's actually historically what puts you to where most of the healthy male prolactin was. I think for females, they give several ranges depending on which part of the cycle they are, whether they're pregnant, menopausal, and whatnot. But…

49:37

again, if they give you a cycle for a female or a male that says like, oh, you're in this stage of your life, so production should be higher. No. It's like saying cortisol. Oh, you are older. So cortisol should be like two times what is for a young person. No. Cortisol has pro-aging effects. In fact,

49:53

I think a human and animal study showed that you can reproduce all of the phenotype of all of the signs of aging external by administering a very high dose of cortisol for a prolonged period of time. So cortisol is most certainly pro-aging hormone. It's just there for like, it's acute management. If somebody's chasing you, right, something's endangering you, you need to produce a lot of energy. And it doesn't matter if you're going to, you know, shred a little muscle.

50:19

The idea is that it will stop. Anyway, so the prolactin, yes, if the upper limit is 13, I think something like 7 is great. In the U.S., the range that LabCorp and Quest report, the upper range for males was recently raised to, I think, 22. It used to be 18, maybe like three or four years ago. Before, it used to be 16. So now it's like 22. 22 is, I mean, not a good number. I would say you have to be below, in my opinion, below 15 to be in a decent health.

50:46

And several studies show that men who have prolactin over 15 but still in range complain of sexual dysfunction. And conversely, anti-prolactin, just like bromocryptine, are very commonly used to treat sexual dysfunction in males who do not have any other endocrine problem, like a low testosterone or anything like that. So many things. Cortisol. If you're testing cortisol, are you testing AM cortisol? Are you doing like a salivary 24-hour cortisol? Two measures. Yes.

51:12

Both. Yeah. I mean, it unfortunately means like two blood draws, but you can do like a cannula, right? So you start a cannula, you draw in the AM and then you do in the PM. Not many people would agree to that. If you can handle two pricks, then like one arm and then the other like in the PM. But it's nice to have them both tested in the same day. If you do salivary cortisol, I would always pair with either blood or urine. 24-hour urinary cortisol is also a very, very good measure.

51:37

but I wouldn't do just one or the other unless it's blood and unless it's both AM and PM. I think that's the only one that we basically, what kind of gives you an idea of what's happening. But because cortisol changes so rapidly, unless you're in a really pathological state like Cushing syndrome, it's not going to tell you much. Some people have the so-called white coat syndrome. They're afraid of doctors. They go to a doctor, they sit down to get blood drawn. The cortisol spikes above the normal range, right? I mean, that's,

52:02

you know, the doctor will freak out. He usually will say, well, come back in like two weeks or come back in a month and we're going to retest it. So, so, um,

52:10

I think if you're going to be doing cortisol, there's probably no way to avoid getting at least two or three tests in succession, maybe over a period of three months, and do both AM and PM for the blood. If you're doing saliva, probably even a single one is good, but I would pair it with urinary cortisol because the salivary glands are capable of producing quite a bit of cortisol themselves.

52:32

So it's not particularly clear what's the correlation between systemic cortisol and the salivary one. Some studies claim good correlation. I found others that claim actually no correlation, zero. So you don't want to rely on only a single method, like let's say salivary. Urinary is established, but urinary basically has the disadvantage that it mostly tells you how well your kidneys are working.

52:56

Because, you know, if your kidneys are working very well, your cortisol may not be very high, right? But if the kidneys are working very well and the liver is working very well by glucuronidating the cortisol, then you're going to be urinating more cortisol. Not in the pathological level, but still. So it really depends on the results. If you're getting somebody who is like four times higher than the normal limit,

53:15

that person has problems. There's just no way physiologically they're going to be like in a normal state. But if somebody is like mildly elevated or maybe up to the two times limit, two times higher than the normal, the upper limit of the normal, then it probably warrants a repeated test. Actually, for the liver test, the doctor started doing that now. They're saying like if you're, at least my primary care physician did, and I saw studies based on which I think he's basing his recommendation, saying, okay, if your liver enzymes are not higher than two times,

53:42

the upper limit, I'm not going to consider this pathology. I'll call you to come back in one month and then we're going to retest. So again, it really depends on the results. If they're not too pathological, it warrants a repeated test. If they're normal, then I think it's safe to assume that the person is okay because you have some serious pathology, your cortisol is not going to somehow magically drop, throw back to normal at the time when it's being tested. If anything, if anything is going to rise, right? Because people are, most people are like, oh, I'm getting tested, you know, I don't know what's going on. Yeah. But,

54:11

But I think that there's, people will also know, we're talking a lot about lab tests, which I want to give people as tools, but I think

54:20

I think people will also know, like, I don't feel good. Oh, yeah, yeah.

54:42

who are great people, but we think about things differently. And in that conversation, this physician I was talking to said, if I eat fruit and honey, I know that I will get fat. And I'm thinking, well, number one, you haven't tried it to know if you'll get fat. Number two, you haven't done labs in three years. So I have no idea what any of your hormones or your thyroid is doing on your long-term reported ketogenic diet. But it was interesting because in the comments, there were a few people saying, when I eat fruit and honey, I gain weight.

55:11

and my triglycerides go up. And so this is interesting that it's like, well, this may be that you have crossed a metabolic bridge and you've actually damaged yourself. My response to those comments was, get your lab work done, show me your hormones and thyroid. And I think that's why you're gaining weight on these things. This ketogenic advocate physician, who's a friend of mine, who I respect, kind of wanted to paint it

55:35

as a perspective, like Paul, you're an anomaly. You're living in Costa Rica and surfing every day. You're this hyper active person. You're this Marvel character who can do this, but not everybody can do that. And I'm thinking, I don't think that my physiology is unique. We all have different genetics, but I don't think I'm that unique genetically. I think there's something else going on physiologically. So that actually was really great to hear you say that. That's really interesting. I hope it helps a lot of people. The other thing is the

56:02

The red fruit and the honey, they have a lot of the cofactors that are required for metabolizing the sugar. The fruit, many of the fruits have a decent amount of B vitamins, which are required cofactors, especially vitamin B3, B1, and B2. Now, if you're drinking something with just pure fructose and pure high-

56:19

pure sucrose and pure high fructose corn syrup, it may get to the point where you're depleting a lot of these cofactors, right? So if the glucose cannot get metabolized, it will get converted to lactate or fat. There's just no other pathway. Or if you really overwhelm yourself, the kidneys are going to start peeing it out. And then the doctor will be like, oh my God, you're diabetic. You know, like come back in like, I don't know, two weeks and we're going to redo the test. So yeah. So, I mean, I agree with you that if people are eating

56:44

let's say they're not eating hypercaloric diet, they're not overdoing one or the other of the macronutrients, they are kind of eating like a well-balanced diet, but they're still getting problems from sugar, especially coming from natural sources such as honey, ripe fruit, right? Then there's probably something going on endocrinologically. There's just nothing else that can cause it. Right?

57:04

So far, I mean, I'm sure you know, the medical industry would love to find a gene for obesity, would absolutely love it, or for diabetes. Believe me, the quest has been going on for, what, 50 years now? Nothing like this has been found, not even a group of genes, not even a network of genes. And now recently they did a so-called GWAS, Gene 1 Association Study. They couldn't find any pattern that was different, right?

57:28

statistically significantly different in the obese people versus the lean people. So we have all the evidence that it's probably not genetic. It's something to do with the environment and most likely with what we eat and the way we eat it, right? If you're on the go all the time, which means your cortisol is probably higher than normal, and you're eating something, chances are that even if that thing is honey,

57:50

I mean, the body's probably not going to process it very well because if cortisol is high, adrenaline will be high, lipolysis will be high. You're getting some sugar inside. It cannot get processed. It'll get converted to lactate or fat, right? Most wild animals refuse to eat when they're under stress, even if they're ridiculously hungry. They know it's not a good situation. They think they should be down and humid. Exactly, exactly. Cortisol, by the way, primary effect of cortisol centrally,

58:15

aside from making you agitated, right, is actually appetite suppression. And if you get drugs that suppress cortisol, you get extremely hungry. Yeah, a number of people have told me that if they take like a cyproheptadine, which is a serotonin antagonist, or people get treated with the ARIO486, they're sitting there saying like, I'm feeling ravenous all the time. So really that's what it is because the blood sugar drops, right, when you're post-cortisol. And then people, the body says, oh my God, you need to eat. I'm going to send a signal to eat.

58:42

And then increases glucagon and all the other like in the stomach acid and then you're like, okay my stomach rumbles I need to eat. That's really the signal. So To me it's pretty simple. It's pretty kind of obvious where things are going with this I think there's there's some pushback against like the recognition that stress can cause a lot of these diseases because then a lot of people like you know What like I said initially I may not want to admit that I don't know working 18 hours a day kills me but it looks like it is or at least driving me towards diabetes and

59:10

Please tell me you're not working 18 hours a day, George. No, not me. Not me, but a doctor like you. I'm sure you know a lot of doctors and probably you yourself. When you have to pull long shifts, didn't you have periods where you work 18, 20 hours a day, right? Oh, yeah. In my residency, there were periods where they made us, where we were required to work 36 hours straight. It was sort of part of the earning process.

59:31

your stripes process. Yeah. You don't pay your dues. You have to pay your dues. It's crazy. You made me think about something else there. I want to make sure I've never had a whole blood serotonin. So I'm going to add that to my next blood work panel and maybe I'll send it your way. I don't know what levels to look for, but that's an interesting thing. I want to get into talking about serotonin now as well. And we can move back to a few other things, but I want to touch on the Randall cycle briefly before we get to serotonin because

59:56

Some advocates in the keto community, it's so funny, Georgie. I do carnivore and I love that people benefit from that, but I think it's kind of the same thing as keto. You benefit a short term and probably benefit because you're getting rid of starches and cleaning up the quality of your diet and maybe getting more organs, which I think are hugely important. I want to talk about organs in this podcast as well. But then the people, when you go out of that…

01:00:21

people in the community just want to attack you. It's not okay to change your mind or to learn. So there's people in the strict carnivore community who look at my diet and say, Randall cycle, Saladino is eating sugar with fat because I'm eating whole milk. And my diet is basically whole milk, honey, maple syrup, cheese, butter,

01:00:41

meat, organs like liver and heart or desiccated organs and fruit. That's basically my diet. And so the keto community looks at that and says, Randall cycle, we got him. He's eating fat in the meat, you know, or fat in butter occasionally or fat in the whole milk. And he's eating sugar. So he's basically storing all that fat

01:01:01

or metabolizing all that glucose to fat. And I guess they're sort of ignoring the fact that I have like 10% body fat. Like, I don't know where all this fat is going. Like, I don't know how I'm so broken from a Randall cycle perspective that I have like 10% body fat. But can you just speak to that a little bit? We've kind of touched on that a little bit by saying-

01:01:19

Like, polysace will change the way your body metabolizes glucose. But is this the reason that you think having some kind of balanced macros is a good idea? Or, you know, I just want to talk about this a little bit so people understand the perspective.

01:01:33

So a couple of this first accusation against you that like eating whole milk will somehow get you fat because of the random cycle. They're misguided because if you look at the label, whole fat milk, it has like five grams of fat per serving. But it has like 20 to 25 grams of lactose to actually eating mostly a high carb food and a decent amount of protein as well. It's the carbs are the highest micronutrients in milk.

01:01:55

Even in the whole milk. So let's talk about meat. Most of the meat, if you're eating like red meat, like the lean meats and whatnot, they're actually not that high on fat. And a lot of the fat in them is actually short chain fatty acids, which are not subject to the Randall cycle because they basically, they get transported into the cells through a known L-carnitine dependent mechanism.

01:02:17

They metabolize similarly to sugar, and they don't seem to be triggering the same sort of like a Randall cycle effect. Now, what drives the Randall cycle effect?

01:02:24

When you're oxidizing primarily fats, what I call the master conductor redox modulator, which is the NAD to the NADH ratio, specifically the intra-mitochondrial one, drops. And basically the NAD to the NADH ratio, which kind of signals how oxidized versus how reduced you are, right, metabolically, that ratio basically turns out to be the primary factor

01:02:48

a regulator of whether pyruvate dehydrogenase will accept pyruvate and convert it into acetyl-CoA and then continue with the Krebs cycle and the electron transport chain or not. In other words, high ratio of NAD to the NADH when you're very, very oxidized favors the activity of pyruvate dehydrogenase. So you will not be accumulating pyruvate. You will not be generating lactate. But if you're eating a lot of fat,

01:03:09

The NAD to the NADH ratio drops, and then the buildup starts to happen. And then basically pyruvate accumulates, lactic accumulates. And then the Krebs cycle is basically, I mean, Krebs cycle is working because it's accepting acetyl-CoA from the beta oxidation, right? Because that's how the fat acids get oxidized. But the glucose that you're eating, it cannot get metabolized for that reason.

01:03:30

And basically, that's really the gist of the… Oh, the other thing is when you're eating a lot of fats, you're also consuming a lot of the FAD, which is the flavinidinucleotide, which is a derivative of vitamin B2. And without a sufficient amount of FAD, in other words, the FAD to the FADH, F as in Frank, ratio also drops when you're eating a lot of fat. And the FAD to the FADH ratio is the primary determinant of

01:03:56

of how well electron transport chain complex 2 will work. And if a lower ratio there blocks the electron transport chain, if the lower NAD to the FADH blocks ETC2, and a lower NAD to the NADH blocks the pyruvate dehydrogenase, there's really two steps, two key steps where you're blocking the metabolism of glucose because glucose has to pass through these steps ultimately to meet oxygen and become ATP and water and carbon dioxide.

01:04:22

So that's really the gist of the Randall cycle. When you're providing too much of this one micronutrient, and by the way, the same thing is true of glucose. If you're providing a lot of glucose, in theory, you should be able to out-compete the free fatty acids, right? And then basically you should be oxidizing more glucose versus less fat. But, you know, that all depends on how much glucose can get into the cell.

01:04:43

And unfortunately, when you're eating these high fat diets and we have a higher lipolysis, the actual uptake of glucose into the cell is already like largely blocked through these glute receptors, which depend on insulin. So free fatty acids not only block the metabolism of glucose, they also block the uptake of glucose into the cell. So they prevent the sort of like positive effects that glucose would have had in terms of competing with the free fatty acids because it also blocks their uptake as well.

01:05:10

So that's really the random cycle. Basically, too much fat blocks your both uptake and utilization of glucose. And whatever glucose is uptaken, you largely tend to convert it to non-beneficial byproducts, such as lactic acid. And if it even gets into the Krebs cycle, low levels of NAD to the NADH favor these fatty acid synthase pathway cycles.

01:05:35

from citrate, which basically glucose when it gets into the script cycle. So it's really, that's really the gist of it. Fats make you fat directly. Fats make you not metabolize glucose, not uptake glucose. And if you even metabolize a little bit of it, they favor its conversion into fat versus its, you know, sort of like percolating through the electrotransport chain and becoming ATP, carbon dioxide and more.

01:05:57

If that was too technical for you guys, just listen to it back. That's an awesome summary. Thank you. It's taken me a long time to wrap my head around a lot of that, even though I went to medical school and the biochemistry we learned in the Krebs cycle, but that's really interesting. So

01:06:12

Here's the question to you from your perspective. So if I'm eating and people can insert their calorie number here, if I'm eating 32 to 3,300 calories a day, sometimes 3,400 calories a day, and my weight is pretty stable, I'm five, nine, 165 pounds, and I'm probably about 10% body fat. Um,

01:06:31

What do you think too much fat for me would be? I'm just trying to do the calculations in real time now and thinking about what macros I do. So if we take 3,400 calories, would you just divide that equally fat, protein, carbs? So a couple of things. First of all, it depends on the type of the fat. I'm hoping you're not eating a lot of poofo, right? I eat no seed oils. So the only fats in my diet are butter and milk fat and fat from the

01:06:58

red meat that I'm eating. Excellent. So in terms of micronutrients, so let's say it also depends on the chain, the carbon length, the chain of the carbons of the fat. Now, if these are medium chain triglycerides, in other words, medium chain fats, actually you can eat 100%

01:07:14

and you will not get fat. They actually get metabolized mostly like glucose. They don't trigger the rental cycle, right? Yeah. If you mix like, let's say MCT oil, like with a decent amount of like, I don't know, honey, you will probably be doing just fine. It's like, and you will not gain fat and you act probably very, very highly metabolic. In fact, I do it every once in a while. I mix it as well.

01:07:33

like basically like a tablespoon of coconut oil, which is not entirely MCT. It has like some lumberjake fats, but you can buy MCT, which is entirely liquid, right? So you mix some MCT with a little bit of honey, stir it, and then basically ingest it. And I've never had this like sort of like, I call it the post-

01:07:51

the post feeding responses. Like when I know that I've eaten something that doesn't sit well with me metabolically, when I know that I've triggered, you know, like too much lipolysis or like too much fat from the actual diet. I mean, I get like, I start sweating, you know, basically I start, I start getting shaky. So like the, the hyperinsulinemia and then the, the hypoglycemia response of when eating something that's not sitting well with you. So if it ultimately goes down to triggering a stress reaction, which is high cortisol, high adrenaline, it gets to shaking, right?

01:08:19

I don't shake right now, so this should be okay. But if you're eating, that's actually a pretty good test, maybe how well you're handling life in general. If after a stressful day you can raise your hand and it's not shaking,

01:08:33

Probably okay. Your reserves are fine. You have glycogen. You're not in an overly cortisolic state. You're not in a hyperadrenaline state, right? Sleeping well is another very good step. Anyways, going back to the fat, if you're eating basically decent fats, mostly saturated of animal origin, I think that having basically where it starts to get a problem, basically, usually in animal research, anything over 30% of fat is considered a high-fat diet. They've lately modified it to be over 35%.

01:09:01

So if you're doing the 33, 33, 33, means you're actually okay. You're basically, this is like a normal diet. I would ideally would like to see it lower for people who are struggling to lose weight because most of the fat when you're ingesting it, you know, these people will get very easily stored. Eating fat basically is a very good way to get yourself fat if that fat cannot be processed. And because a lot of obese people have problem with liver,

01:09:26

A liver can actually oxidize itself a lot of the saturated fats that you're ingesting. So they won't even get to storage. The liver will simply process them.

01:09:33

But if your liver has a problem, 70% of, I think, Americans now, the studies say they have NAFLD or even something worse, non-alcoholic fatty liver disease. So if that's the case, you don't want to overdo the fat because most of the fat will not get processed. It will get converted back into triglycerides, sent to the bloodstream, and then stored. So I would say that for a person who wants to lose weight, probably about 15% will be the cutoff mark.

01:09:58

I've tried going on a very low fat diet. That's really about 15% calories from fat. Okay. Yeah. I've tried 5%, but I couldn't do it. It's just, I was craving fat to the point where one night I just woke up and basically ate a pint of ice cream.

01:10:13

I just couldn't resist it. I was like, something is wrong. I mean, it may be very energetic. It raised my temperature quite a bit, right? I was probably hypermetabolic. I have a capnometer at home, which measures the exhaled carbon dioxide, which is a very good indication of how your metabolism is working, right? And then it was basically, I think the upper limit is like 40. I was at like 42. So I was producing a lot of carbon dioxide, but it was not a nice feeling. Yeah.

01:10:38

You couldn't sleep, right? You couldn't sleep. I was hungry yet agitated. So I said, the hell with it. I got up, ate the ice cream, and then went back to bed and slept.

01:10:47

So 5% for me is like too extreme. But yeah, there'll be very several studies that were the most in the 80s when the whole like low fat diet craze came about. And they show that on a 10% diet long term, you can expect to lose predominantly fat, though not at the very fast rate. You will keep most of your muscle mass, right? Assuming you're not doing anything crazy with the other macronutrients, such as completely cutting out carbs or like raising protein to the level where it fries your kidneys.

01:11:13

Exactly. Yeah. But basically, 10% fat, even though it's low, it was tolerable. People tolerated it. And over a period of two to three years, they lost a decent amount of fat mass and they kept most of their free muscle mass. But,

01:11:26

But again, based on what people can tolerate, most people that I know, they can't stay on a 10% diet for too long. It's just they feel like something is missing. I mean, the absorption of the fat-soluble vitamins, you do need actually quite a bit of fat to absorb those and to absorb most of those, right? So maybe about 20% is what you actually feel best on. To me, it's a good compromise. And it doesn't require too much of me like reading the label and becoming…

01:11:53

Orthorexic, I think is the term. Yeah, I was going crazy about it. Yeah, exactly. So 20% is easily doable without too much effort. 33% is basically what you should be eating without a care or worry in the world, sort of like your average Joe Small diet without exercising or doing anything special and without any effort in reading ingredients and trying to calculate all these things.

01:12:15

I think I'm probably above 33%. I just did the calculation at 3,400 calories a day. It would be 125 grams of fat to get 33% of my calories from fat. And I'm probably eating 150 grams of fat per day, but I mean, I'm not,

01:12:31

above that number just by, I hate this terminology, but quote, intuitively eating. I'm not grossly above that number, but I agree. I think that for myself and probably for a lot of people, there's something to this intuitive feeling that if you go too much below 25, 20% fat, I'm just

01:12:50

I'm just kind of pulling numbers basically out of my subjective experience and other people I know. You're going to be craving fat. And I think you got to listen to that. It's probably too little. And then I think you're right. I'm wondering about absorption of fat-soluble nutrients like vitamin A and all these things in liver and K2 and these critical things, vitamin E. These are important. You need these things.

01:13:09

Synthesis of cholesterol, which is predominantly done from fats. It can do it from glucose as well, but again, fat is energetically expensive. You only get to that if basically after you start actually synthesizing the fats from carbs. If you're eating an extremely low-fat diet, you may have a problem with the synthesis of cholesterol and the downstream steroids from that.

01:13:31

And that can actually trigger a lot of other, you know, probably most of the like sort of like the low libido, low mood, things like that, that go with a low fat, extremely low fat diet can probably be explained by the fact that, you know, fat is needed for the functioning of those organs.

01:13:45

So yeah. Yeah. Anything below 20, I don't feel well on. I can survive on 15, but it requires, first of all, way too much effort on my part. It's like, okay, how much is this here? Okay. How much did I eat? Right. There's stressful days where I just don't have time for this. Right. So I have my sort of like ideal meals that I figured out three or four of those. And I kind of rotate them like every other day or whatnot. And they come down to about 30 to 35% of fat. That's just how it is. I can do it on 20%. Right.

01:14:14

It requires a little bit of effort. I can do that. But if I don't have to do any effort, the George Moldat, the George is about equal percentage. And that seems to be doing okay. I used to be extremely physically active. I basically a lot. These days I walk a lot, right? But I don't do anything.

01:14:32

any direct exercise, but still it burns calories. I mean, I walk about three miles a day on average and that's, let's say what, a hundred calories per mile. That's 300 calories. So not much, but it's most doctors say, oh, that's fine. You know, we like to see, you know, some, you know, that's perfectly fine for us. Don't overdo it. Don't overexert yourself.

01:14:50

I think that's an important point to make before we get into serotonin, this idea that exhaustive exercise is not good for the human organism. I used to run ultra marathons. I've been such a crazy…

01:15:02

in the past, man. Like I know you did, you did, you know, crying. Yeah. Then like running as well. Yeah. Same, same exercise. Yeah. It's just not good for the human organism. So I think people want to kill themselves in the gym and I think that's not good. Um, and though this is just my end of one and I have certain genetics, I,

01:15:21

I try to be really honest with people and tell them like, hey, my physique, and you can see my physique on Instagram, or if you just Google it, like, I'm not a bodybuilder, I don't take any hormones or anything. But I have a good amount of muscle mass as 165 pound, five, nine human male, and I don't really lift weights. It's just, I heard you say this on a podcast, and I thought it was so insightful. Having a good amount of muscle mass is probably an

01:15:45

absence of stress hormones and a good diet of like the micronutrient building blocks. So I heard somebody say on a podcast recently, you can't just give someone, because I've spoken a lot about leucine, optimal amounts of leucine for muscle protein synthesis. They said, you can't just give someone leucine and expect them to grow muscles. And I thought, well, I think you might be able to give someone leucine and they will grow muscles if they don't have high levels of cortisol and stress hormones. You know, I think that the bi…

01:16:13

the body should grow reasonable amounts of muscles with just the nutrients and really, really moderate low-level stress. So like you said, you could just walk. You could probably do five pull-ups a day or 30 push-ups a day or 20 air squats a day. That's probably… I mean, people are going to

01:16:35

go crazy for this climbing stairs like trying to do mostly concentric exercise yeah like just just climbing yeah yeah climbing the stairs at your office could be you know a really reasonable stimulus there's some people out there in the nutrition space who just

01:16:50

who really believe that you need to kill yourself in the gym. And I just don't see that. And I loved your perspective that it's probably adequate nutrients and an absence of stress hormones. And people need to understand that if you overexert yourself, you're increasing your stress hormones. And we're right back to where we started, which is this serotonin cortisol cycle, which we want to stay out of.

01:17:12

I'll give a couple of great examples. First, to the point you made about leucine, this is something that even the leucine opponents don't know about. So the branching amino acids, together with tyrosine and phenylalanine, compete with L-tryptophan for the passage to the blood-brain barrier.

01:17:29

And basically, when you're consuming leucine, you're going to decrease the amount of free tryptophan in the brain, which means you're going to produce less serotonin. Guess what this does? Lowers your cortisol, right? So that's probably one of the most anabolic effects of leucine that almost nobody talks about.

01:17:45

Uh, but several studies have shown that it could administer the BCAAs. It doesn't have to be just like Lucy, but let's say you take all, what is it? Three of them. Lucene, azuleucine and valine, right? Yeah. Yeah. They usually sell them as bodybuilding supplements in capsules. So you take a, take about two to three grams of those. They didn't animals, but they're about to also repeat it in humans. Uh,

01:18:04

In fact, that combination is used in something called acute tryptophan depletion for mood studies. So they mix BCAA with either L-tyrosine or L-phenylalanine because either one of those is a precursor to dopamine, right? And when you feed those, right, but don't feed any tryptophan, they're going to outcompete the tryptophan and basically you're going to have more L-tyrosine or more L-phenylalanine in your brain. And because the enzymes that synthesize dopamine or serotonin, they're actually –

01:18:31

at rest, baseline is actually they're unsaturated. When you give them these nutrients, they're going to synthesize more of what you gave them, which is more dopamine in this case, right? But dopamine has an anti-catabolic effect. Basically, it has an anti-serotonin effect. Anything that is pro-dopamine is anti-serotonin. In other words, anything that is pro-dopamine is anti-cortisol.

01:18:49

So by giving the leucine, I'm thinking a lot of the anabolic effect may come from, aside from stimulating muscle protein synthesis directly, there's a metabolite of leucine called HMB, very popular as a supplement these days. But leucine, I think, has an anabolic effect, which has to do with its anti-serotonin-enhanced, anti-cortisol effect.

01:19:11

That's one. Second thing is basically when it comes to exhaustive exercise, can you show me one person over 40 who continues to kill themselves with these sessions and thrives? I don't know of a single such person. They're all invariably young. The people who do like the really, really growing stuff, they're people in their 20s and 30s. And then the reason actually for them, even for them is not ideal, but actually they do derive some benefit from it. Why? When you're younger, when you're exerting yourself,

01:19:40

the body wants to protect you from the catabolic effects of cortisol. So it's producing a lot of pregnenolone and DHEA in the adrenal cortex. With over time, with aging, basically there are three layers of the adrenal cortex, zona reticulata, fasciculata, and glomerulolist, right? One of them produces cortisol, the other one produces aldosterone, and the third one produces DHEA. The ones that produce aldosterone and DHEA atrophy with age, remaining only the cortisol. So when you're getting older,

01:20:07

And when you exert yourself, you will get all of the negative effects of stress, but none of the beneficial effects of these anti-catabolic hormones, which you were producing when you were younger. So that's why when I said, like, don't over-exert yourself, is that when you're young, you don't care because the body has…

01:20:22

It's means to protect you. When you're getting older, all these defensive mechanisms are starting to malfunction or largely absent. I mean, get me a 70-year-old person that can survive a session of, I don't know, kettlebells or like, what do they call it? Crossfit? Yeah, crossfit, exactly. I want to see that happening. I bet you they'll be doing CPR by the time this person is done.

01:20:44

I mean, they just can't handle stress that well. And I think it's like universal perception of everybody who is like getting over 40 is like, I cannot really do these things that I used to do younger.

01:20:53

And the reason is, as we're aging, basically, there's a graph I can send you later that looked at the changes in the steroid balance as we age. Now, androgens decline, thyroid hormone declines, estrogen don't decline, cortisol doesn't decline, serotonin doesn't decline. So as we age, by definition, we are in a catabolic state. Do not add anything further to make it even more catabolic than that.

01:21:16

And I'm sure like many people have noticed that basically a lot of the Hollywood stars and many athletes are on steroid therapy. In other words, they inject the testosterone or other synthetic hormones. How do these hormones work? Because they do work.

01:21:29

Well, it turns out that the vast majority of the anabolic effect of a steroid, such as testosterone or Tremblone or methanol or any of the other ones that are they ingesting is actually about 80% of the anabolic effect is actually anti-catabolic effect. In other words, if you block the effects of cortisol, you're effectively allowing the muscle to grow if you provide leucine, valine, and all of the essential amino acids that are required for muscle protein synthesis.

01:21:56

So if you don't overexert yourself and your cortisol is at baseline, so you don't want it too low, obviously, right? Because otherwise you're going to hypoglycemia. You can actually die from that. You don't want that, right? But if your cortisol is at baseline, it's in range, and you're eating a decent diet, you should be synthesizing muscle. If you're not, the only other explanation is there's chronic inflammation

01:22:16

going on somewhere or something else producing these inflammatory cytokines or the prostaglandins and whatnot. And several people have found that in very old people, anti-inflammatory drugs have anabolic effects, which shows you that with very advanced age, when these people have lost almost all their muscle, they are very chronic, almost 100% catabolic state. When you give them the anti-inflammatory drugs, it kind of gives them a reprieve and they actually, when they eat protein, it is not to the yoke,

01:22:42

It restores the muscle proteins, not to the youthful level, but about halfway in between. And if you actually give them an anti-cortisol as well, these people start building muscle as if they're in their mid-20s. And people could easily ask, the inflammatory side of it is easier to check. The cortisol side is a little bit tricky for people to check. I think they'll know intuitively where they're at. But the inflammation side is probably pretty easy. I mean, I think a lot of people would be able to tell. I mean…

01:23:07

HSCRP, fibrinogen. Any other inflammatory markers that people could check? Very good one and probably my favorite, erythrocyte sedimentation rate. The ESR, okay. Yeah, yeah. It used to be the one that the doctors would almost check in the early 20th century. Then for some reason it became a biomarker for rheumatoid arthritis. I don't know why they only do it for rheumatoid arthritis because it's a non-specific. It says in the medical books, non-specific inflammatory biomarker, right?

01:23:31

I mean, you can check some of the, depending on how much the insurance is going to cover or the lab will charge, you can check some of the interleukin 1 and 6 are particularly bad. You can check those, right? Some of the very successful anti-rheumatoid arthritis drugs are interleukin 1 and or 6 antagonists, right? TNF-alpha, that can be checked on a blood test as well. But they tend to be more exotic. You can check for blood levels of the prostaglandins and the leukotrienes.

01:23:58

um, those are pretty, pretty, uh, reliable in terms of like, uh, telling you what the inflammatory state will be because about 80% of the inflammatory reaction is driven by the Cox and Lux pathway. You take care of these two chances are, that's why aspirin and all of the NSAIDs that I said had a, anabolic effect in the elderly. Um,

01:24:14

Actually, I think they gave him like ibuprofen. And ibuprofen, I think it only affects the Cox enzyme. So apparently, most of the inflammatory reaction is coming from the Cox pathway. And if you block that, then you're fine. So if you're checking the prostaglandins, you're probably getting a pretty decent idea of what's your chronic inflammatory state. But yes, you had another one. So the CRP, the ESR, lactate dehydrogenase is actually a pretty good one. Mm-hmm.

01:24:38

it's kind of like a sinister biomarker too, uh, because it's an, it's an intracellular enzyme. It's not supposed to be in the blood, you know, uh,

01:24:45

at a beyond a certain level but but basically it's elevated in heart attacks uh various like inflammatory conditions and infections like a meningitis um and because it's composed of multiple families like isoenzymes the blob can do a breakdown and tell you exactly where the damage is so let's say like uh ldh1 is produced in the liver right so if that's elevated that's contributing to the elevation then they have a liver inflammation like hepatitis right but unfortunately if it's let's say like 50 above the upper limit it's usually indication of cancer

01:25:14

It's becoming widely recognized. The cancer for LDH. Yeah. But cancer is inflammatory disease. So yeah, they're not a confirmation that, yeah. I've heard you mentioned soluble CD14. Have you ever seen anyone check that? And that'll for endotoxin. The bio, the endotoxin, the only studies that I've seen checked it is for people with HIV. Apparently it's a very reliable biomarker of future mortality for people who are HIV positive. Interesting. Yeah.

01:25:41

Interesting. I haven't seen anybody test it, but actually, I don't know if even labs offer it. I see it on the menu in LabQuest and Quark, but I don't know how to order it because I went through some of these self-testing labs where you can order tests directly. Not a single one of them offers it. But LabQuark and Quest have it.

01:25:57

But I think a doctor has to order it. Like you can probably prescribe it to somebody. Yeah, yeah, yeah. It's so interesting. I must be, you know, you're a geek and a nerd when you get really excited about the menu at a blood work place. And you're like, what can I check? You know, I'm looking at this menu and I'm like, oh, I can get that. Oh man, I can get all these cool little blood work things. That's how you know you're a total geek. I like that. Let's talk about serotonin, Georgia. We've kind of danced around this a little bit, but you know,

01:26:23

In my rotations in medical school, in mental health, we'd give people SSRIs. And I was like, these drugs are bullshit. There's this book, The Emperor Has No… I forget, there's this book about the SSRI thing. There's all these books kind of exposing this. There was a big study that came out with SSRIs.

01:26:40

And like there's this general zeitgeist that serotonin is good and it's a happy drug. But I've heard you speak a lot about the fact that this is not the way it is. So let's kind of tell people the serotonin. Let's paint the picture of serotonin and kind of tie it into other things we've talked about because we keep mentioning it. I want to make sure people understand serotonin, what raises it. We can even segue into a discussion of gut stuff and endotoxin if you want from serotonin, but wherever you want to go. Sure.

01:27:05

So serotonin is a neurotransmitter, but apparently most of it is now about 90% is produced in the gut, the GI tract. Its old name was enteramin. So basically it was to recognize the fact that most of it is produced in the gut. And it was known, it actually has been known since the 1940s that elevated levels of serotonin are a very bad indication, typically associated with something called carcinoid syndrome.

01:27:26

These people produce a lot of it. And some of the symptoms of very high serotonin are diarrhea, flushing, constant flushing without any reason, without any exertion, right? Mental changes, psychosis, depression, which by the way, should I mean it there? Hold on a second. How can medicine, not medicine, but how can the pharma companies tell me that serotonin cures depression when people with carcinoid syndrome are heavily depressed and psychotic sometimes, right? It

01:27:50

It's just, these two just don't go well together. Well, I mean, basically, so there's plenty of evidence for specific conditions. Serotonin is pretty, pretty bad. In fact, I think I mentioned, as I mentioned earlier on the podcast, the company Pfizer, despite selling you an estriatum, I forgot what the name of their, Paxil, what's their, Lexapro? Yeah,

01:28:11

Yeah, Paxil. Paroxetine, yeah. Yeah, whichever one Pfizer sells, it's still an SSRI, right? But on one hand, with one hand, they're selling you the SSRI, but with the other hand and behind your back, they're doing clinical trials with serotonin antagonists that are curing a lot of conditions that are

01:28:28

They must be caused by serotonin because these drugs are selective antagonists on a very specific serotonin receptor. They have no other known mechanism of action. So the only conclusion is that if you elevate extracellular serotonin, you're going to end up with a fibrotic state somewhere.

01:28:43

heart, lungs, kidney, liver, you know, you name it, right? And now they're doing all these clinical trials with this selective serotonin antagonist called turgoride. What this drug does is basically similar to bromocryptine. It's an agonist of several dopamine receptors, but it's also an antagonist on several serotonin receptors, but most strongly in the 5-HT2B. So there's pretty indisputable evidence that serotonin is a profibrotic drug.

01:29:06

mediator, right? But then, you know, usually when I've discussed with people, with psychiatrists, the defensive minute that comes back is like, well, the dosage makes the poison, Georgie, don't you know that? I'm like, okay. So have you measured serotonin levels in your patients that you're giving these SRI drugs? How do you know that you're not elevating to the point where you may be causing problems there?

01:29:26

Well, there's no way because while they're alive, we cannot measure serotonin in the brain. We can measure its metabolites, such as 5-hydroxyindoacetic acid in, I think, blood and urine, right? I'm like, have you done that? No. Well, why not? Why would

01:29:39

Why would I do that? They don't have carcinoid syndrome. Well, how would you know that this drug that you're giving that is basically known as inhibiting the reuptake of serotonin, which means it elevates extracellular serotonin. We know that it's profibrotic when you have high extracellular serotonin. How do you know they're not causing any brain damage?

01:29:57

It's not my job. You know, if there's any symptom, I'm going to refer them to a neurologist. The neurologist is going to worry about it. And that's just the way it is. Okay. So first of all, multiple studies demonstrated that the S-ride drugs are no better than placebo. The only ones that work, the only ones that work, Prozac is one of them. And I think like Lexapro is another one, a similar one. And there's a new one called, I think, Veroxetine.

01:30:21

Basically, behind the scenes, even though this is not advertised in the marketing literature, but studies have been published, these drugs are actually, despite being SSRIs, they're actually partial serotonin antagonists. If you look at Prozac, very strong antagonist that

01:30:36

at the serotonin receptor 2C. In other words, 5-HT2C. 5-HT2C just so happens to be the receptor through which, as I mentioned earlier, serotonin drives the production of cortisol. When you activate 5-HT2C, you're raising ACTH and triggering the whole downstream cascade. You block 5-HT2C, you can cure even Cushing syndrome.

01:30:55

right so Prozac is actually kind of like a very nefarious drug it's blocking serotonin it's giving you the antidepressant effect right but simultaneously it's elevating extracellular serotonin and causing weakened havoc in all kinds of other tissues right and another drug another effect that Prozac has fluoxetine I think it's like the

01:31:14

the chemical name. It elevates the synthesis in the brain of a very protective neurosteroid called allopregnanolone. Allopregnanolone is a metabolite of pregnenolone, then progesterone, then 5-alpha-dihydroprogesterone, and you get allopregnanolone. So it's basically a, it's a pregnen steroid, but it's a derivative of progesterone, let's say. Allopregnanolone was recently approved by the FDA as a fast-acting and potent antidepressant at even a single dose.

01:31:41

for postpartum depression, but they expressed the opinion, the operating committee, that allopregnanol should work universally for any depression, not just postpartum. I mean, to my knowledge, I don't know if the psychiatry distinguishes between the postpartum versus non-postpartum depression. It's still depression, right? These people are in danger of potentially killing themselves or harming others, right? So anyways, allopregnanol. So Prozac

01:32:04

lowers your levels of cortisol, right? Increases your levels of the protective allopregnanolone, but you pay the price with systemically elevated serotonin, which can lead things like blood clotting, fibrosis, and many other things associated with serotonin. Serotonin and histamine go well together. Histamine is a highly pro-inflammatory molecule.

01:32:24

So, and by the way, whenever you elevate extracellular serotonin, because serotonin and dopamine are inversely correlated, they actually block each other's effects. Serotonin actually inhibits the synthesis of the enzyme tyrosine hydroxylase. So you're going to be synthesizing less dopamine. So it's really just like nefarious state, but it does help. It does help. Like if somebody is about to, you know, become suicidal or whatnot, Prozac,

01:32:47

But it turns out that the good effects are only at microdosing before it starts to inhibit the serotonin transporter. Once you get to dosage levels, which unfortunately is what's usually clinically prescribed, you're getting like a very mixed bag of effects, which is probably why in the large scale, long term clinical trials, the vast majority, if not all of the SSRI drugs demonstrated effectiveness no better than placebo.

01:33:09

And this recent study, which probably is the one you're referring to, coming out of University of Oxford, this lady who's been studying serotonin for her entire career, and she basically said, the serotonin hypothesis of depression is dumb. We need to come up with something else. The evidence is just not there. And if anything is true, it's that serotonin is actually higher in depression than lower. And

01:33:33

Another famous study you can find easily on Google by typing serotonin, upper or downer. Another famous psychiatrist and a clinician published a study two years ago. He said that

01:33:43

Am I the only one who's looked at the evidence and we've kind of realized that doing post-mortem exams on brains of patients who committed suicide and they were clinically depressed, where their serotonin levels are through the roof. Like how is this possible? And I also looked at animal studies and it kind of showing the same thing. What are we doing here, people? Is serotonin an upper or downer? Because I'm hearing upper from the pharma industry,

01:34:04

But then the evidence says downer. Like, which one is it? He concludes that serotonin is actually largely a downer. And him and this lady, the clinician at the University of Oxford, are saying the primary effects of serotonin are actually as a metabolic regulator. So what serotonin really does, it inhibits sort of like the entire oxidative-phosphorylation cascade, predominantly in the brain. And you're getting in a situation where you're basically like zombified. I don't have a better word to describe it. You're really not reacting to your environmental stimuli.

01:34:33

whether they be good or bad, right? So if the environment is really so bad that it's actually depressing you, that may actually be somewhat beneficial. But that doesn't mean it's curing your depression. You're simply blunting the response of the body towards these negative stimuli. And over time, if you're continuing to give these drugs, obviously you're going to get all of the fibrotic effects and all of the other negative effects that we've mentioned so far. And fibrosis in a solid organ is usually the precursor stage to cancer.

01:35:01

I think a number of studies have shown that you cannot get to cancer in, let's say, a liver or kidney or lung or uterus or whatnot before passing through a fibrotic stage first. So if you actually cut out the tumor, you basically see almost like a gradient of more healthy tissue but becoming progressively less healthy to where the tumor is. And around the tumor, there's usually calcification. And the first couple of layers are fibrotic tissue, right? So…

01:35:26

This is most of the fibrosis is driven by serotonin. We basically kind of get like, okay, so we're not curing these people's depression. We are blunting their response to negative stimuli. They look okay, right? They're not killing themselves, maybe, right? But we're paying the price of basically really, really drastically, you know, reduce health and chronic disease down the road.

01:35:48

And why would lowering metabolism sour up mood? Well, basically, your higher cognitive functions, of which mood is one, by the way, feeling upbeat and happy, creative and whatnot, turns out just like anything else, depends on energy. Very simple example, when people are sick,

01:36:06

they tend to be in a pretty poor mood, pretty sour mood. Don't mess with a person who is ill. They're very irritable. They may even become aggressive, right? That's not by accident. Their serotonin is high and maybe because of disease as well, but their serotonin levels are high and serotonin inhibits the ATP levels in the brain. An animal study demonstrated that drop of ATP levels in the brain of just 20% leads to violent aggression, right? So these people are almost like they're not in their right mind. They're almost temporarily insane. I think it's like the legal term which they use.

01:36:35

Serotonin can cause that if it gets really, really too high. Serotonin is now known to be the actual cause of psychosis. So in other words, schizophrenia type diseases. For a long time, medicine said, no, it's dopamine. And here is our proof. We're giving anti-dopamine drugs and these people are doing fine. Guess what?

01:36:52

the most highly used drug, haloperidol, recently turned out that it actually is a non-selective serotonin antagonist at every serotonin receptor. So we still don't have the proof that the serotonin is driving it, but we do have some proof from isolated clinical trials where selective serotonin antagonists cured people's schizophrenia

01:37:14

because these people who were part of the trial for different reasons, but they had schizophrenia or other psychotic conditions, they were given an anti-serotonin drug

01:37:21

and then schizophrenia went in remission. So that's what serotonin really does. By lowering cardinally your metabolic rate, especially in the brain, it kind of basically makes you very tolerant to very inhospitable circumstances around you. That does not mean it's a good thing, right? I mean, it may have its uses, but I will not actually adopt this as a public health practice on a nationwide or even global level. Another cool anecdote, when the Prozac was first approved,

01:37:50

The German equivalent of the FDA had such strong reservations about this drug that they refused to approve it. They said, no way in hell we're going to give this to our people. It's causing people to commit suicide. Actually, it's an admitted side effect, first two weeks of getting on SRI, you're at very high risk of committing suicide. And they said, no, we're not going to do it. Well, something happened behind the scenes that after about two or three years of infighting,

01:38:11

The German FDA approved it, but they slapped a big black box warning. And the first country to ever do that by saying that if you take an SSRI for the first two weeks, you're at a much higher risk of suicide. This only happened in other countries over the last maybe year.

01:38:26

Five to 10 years when some very high-profile suicides happen. But that's really, you know, there's no way to avoid tying this to the serotonin effects of the drug because those are the actually, you know, the official mechanism of action through which these drugs got approved is that it inhibits the activity of the serotonin transporter, which means the serotonin deactivation is slowed down, right? And you get more extracellular serotonin to wreak all kinds of havoc.

01:38:55

Georgie's having to move around to get the light. Okay. So how does… It's such an interesting alternative hypothesis and it's fascinating. And what I saw clinically…

01:39:08

on my psychiatry rotations is when you give people serotonin reuptake inhibitors, SSRIs or SNRIs, anything that affects serotonin raised in the brain, they do kind of, they feel blunted and they say this to you. They don't say they feel happy. They say they feel in a cloud. I mean, zombified is a harsh word, but I think it's kind of true. They're blunted and they just don't, they don't react to things. So the way that mainstream medicine and psychiatry

01:39:37

treats depression is by making people blunt it. That's a horrible idea. It's a type of anesthetic, right? If you have pain, they'll give you an opioid. By the way, you know, coincidentally or not, many depressed people self-medicate with opioids. It blunts their response and the SRI drugs seem to be doing the same.

01:39:56

So what raises serotonin? We talked about how 5-HT2C might raise cortisol. Right. And we talked about cortisol increasing serotonin by changing its synthesis and perhaps favoring tryptophan hydroxylase versus tyrosine hydroxylase. This is really interesting. What raises serotonin in humans? If most of it's made in the gut, what causes excess serotonin physiologically? Well,

01:40:22

Well, if it's mostly some kind of a gut irritation, which in most humans tends to be endotoxin, right? Or you're eating something that's physically irritating the intestine. Spicy foods can tend to do it. Not for everybody, but, you know, if somebody has like an irritable bowel syndrome, which is, let's say, diarrhea type, IBS type, type D, which is since it's diarrhea, it's probably high serotonin. They cannot tolerate spicy foods. It's really wreaks havoc. They're bedridden for like a week afterwards.

01:40:49

So, you know, physically irritating foods. But even beyond that, if you're eating something that gets to the, let's say, so your stomach and your small intestine should be preferably clean of bacteria, unless you have HP lower in the stomach, but it doesn't produce endotoxins, so it's okay. It does produce ammonia though, which may be a problem. So stomach and small intestine should be clear of bacteria. And that's where most of the food should get absorbed. So by the time you reach in the colon, there really shouldn't be that much undigested food. If there is…

01:41:17

which is already kind of like a pathological state. And I think most GI, what do you call them?

01:41:24

I mean, gastrointestinal doctors will probably agree that if you're not absorbing most of the food by the time it reaches the column, that means something is going on. Maybe you're not producing sufficient amount of the enzymes in the pancreas, right? You have like insufficient production of stomach acid, which by the way, depends on CO2, which depends on metabolism. Anyways, once indigested food reaches the column, then your microbiome, which outnumbers your cells, I think in a ratio of 30 to one or whatnot,

01:41:52

Then they're going to start eating that food. And whenever a bacterial colony gets this supply of food, it increases its turnover, which means some bacteria dies, new bacteria. So they start to divide, right? But the dead bacteria, the gram-negative type specifically, in its outer layer has this component called endometriosis.

01:42:09

endotoxin, which is really lipopolysaccharide. It's actually a molecule which is a mixture of a fat and a sugar molecule, right? Now, that molecule by itself is irritated to almost any tissue it comes in contact with, including the intestinal wall. Now, depending on how much endotoxin gets produced, and especially if this is done over time, in other words, if you're eating a lot of resistant starches,

01:42:30

which actually are resistant to the digestion absorption, and they shouldn't be, a lot of them will get to the column. A lot of food for the bacteria, very high turnover of the bacteria. And if you have a lot of the gram-negative species, a lot of endotoxin. Okay, over time, this irritates the intestinal wall and increases its permeability.

01:42:48

So over time, you're going to start to see increased absorption into the bloodstream of endotoxin. Very bad thing because it activates this receptor called TLR4, which the body uses to sense actually external pathogens. So to the body, this is the same as if you actually somebody injected you with like a strain of bacteria directly into the bloodstream. In fact, injection of endotoxin in animal studies is used to mimic a bacteria infection. Right.

01:43:13

because it activates the exact same receptor of TLR4. So it activates TLR4, and the activation of TLR4 triggers a cascade, which is associated with the release of nitric oxide, which basically, by activating TLR4, it stimulates the production of something called INOS, inducible nitric oxide synthase, and then you start producing a lot of nitric oxide from the amino acid L-arginine.

01:43:37

And then also, because you're activating TLR4, that actually directly triggers the activation of the enzyme tryptophan hydroxylase. And since tryptophan is always available, it's a component of your muscle tissue. It's one of the essential amino acids, right?

01:43:54

then you basically, whatever 3 to 5 is floating around in the blood, it's going to get converted into serotonin. And it looks like the cells that express the 3 to 5 hydroxylase enzyme, there's only two regions in the body where this happens, the GI tract and the brain.

01:44:09

So 90% of the serotonin you'll produce will be produced in the GI tract, another 10% in the brain. For a long time, and in fact, I've had this argument with many doctors, and they were crushing me down by saying like, there's no evidence that serotonin produced in the gut of

01:44:24

affects the brain? Well, now there is. Now there is. First of all, it affects the brain through the vagus nerve, right? Second of all, now we have evidence that serotonin actually, preformed serotonin, which was claimed, medicine was claimed for a long time that it cannot cross the blood-brain barrier. It does cross it. Just like they claimed for GABA, could not cross

01:44:45

cross the blood-brain barrier. So taking GABA supplements apparently was useless. Yes, it does. So now, even though you're producing 90% of serotonin in your GI tract, a lot of it, if it starts circulating into your bloodstream, will actually go to the brain and directly start affecting the brain. And just the agnotoxin, just by activating TLR4, so you're increasing nitric oxide, which is itself a free radical. Guess what?

01:45:08

it will directly start attacking a lot of the poofy new tissues and converting, generating all of these toxic aldehydes that we mentioned earlier. 4-hydroxynone now is one of them. There are multiple others, which are now known to be a primary component of arterial plaque.

01:45:23

So basically you're contributing to cardiovascular disease. Also nitric oxide stimulates itself, 3 to 5 hydroxylase. It stimulates something called NFKB, nuclear factor Kappa B, I think it's called, which is like the master regulator of the entire inflammatory cascade. If you activate NFKB, you're activating coxal locks. And if there's sufficient PUFA around,

01:45:45

which there always is, then you're triggering a lot of these inflammatory mediators as well. So just the presence of endotoxin, and by the way, not just endotoxin, but any bacteria will probably trigger a similar thing. The reaction, the inflammatory reaction from like a bacterial presence in the bloodstream very closely, if not identical to endotoxin in the bloodstream. And then what else? Oh, yeah, I wanted to say, so what happens when you eat a lot of fat?

01:46:08

Well, typically tryptophan, when it's floating around in the bloodstream, is attached to something called albumin. But free fatty acids and only free fatty acids are capable of displacing tryptophan from the albumin. And now you have a lot of free-floating tryptophan. And then it becomes a competition between the free-floating tryptophan and the other large neutral amino acids, BCAA, tyrosine, phenylalanine, to get into the brain. Now, if you've eaten some food and it's got this amount of protein in it,

01:46:36

then maybe these other amino acids will outcompete tryptophan. But let's say if you're fasting, if you're fasting, you're increasing lipolysis, right? And if you're increasing lipolysis, then you get these free fat acids in the blood. They're displacing tryptophan. Now it becomes free tryptophan. Nothing to oppose it.

01:46:53

goes right to the brain, right? And it basically starts feeding the production of serotonin locally, right? And then even if that doesn't happen, like I said, now that we have direct evidence that the serotonin produced in the gut can actually translocate to the brain and affect it as if it was produced there.

01:47:11

But Georgie, everybody in nutrition knows that resistant starch is good for you. Yeah, right. So is this the reason that there's this idea, Ray's idea, and this idea that you've talked about to not eat starchy foods? We talked about cornstarch to avoid starchy foods. Is this the reason you don't want to eat starchy foods, that these starches, these resistant starches are getting to the colon

01:47:36

and increasing the production of LPS and the toxin-containing bacteria, and then triggering TLR4, triggering serotonin, and starting the whole cascade. If we want to get carbohydrates, the best place to get them is from the lowest starch foods. Exactly. Honey. Yeah.

01:47:52

The simple carbs. The simple carbs. Don't make it to the column. Now, if you have to eat starch, now well-cooked starches, non-resistant ones, well-cooked starches, such as well-cooked potatoes, well-cooked white rice, especially if eaten with saturated fat, are actually probably okay.

01:48:07

Now, I still don't like them because the starches get converted 100% to glucose and they do trigger a very strong insulinogenic response. We want to limit these extreme spikes of insulin because every time your insulin spikes too much, you'll cause a hypoglycemic response

01:48:25

And whenever there's hypoglycemia, cortisol will get reactivated because the body's like, oh, my God, I'm going to die. The brain is going to die without sugar. You don't want that. So you don't want a hyperinsulinemic response, which is why sucrose, it has a lower glycemic index than the simple starches. And in fact, sucrose should be better for you metabolically, especially if you're diabetic, than actually eating the pure glucose. But if you're eating the starches, it's well-cooked. And why I said mixed with saturated fat, why?

01:48:51

There's a study which showed that eating coconut oil or butter or like any other kind of ruminant fat that's predominantly saturated fat completely abolished the endotoxin response from eating starchy foods.

01:49:03

I don't know how exactly it does that. I think some of the fatty acids, saturated fatty acids, may be an antagonist of the TLR4 receptor. There is some evidence for that. Really, this is not settled yet. But the indisputable finding is that eating starch, well-cooked starch, I emphasize, so it gets absorbed in the upper portion of the GI tract, right? Eating it, this well-cooked starch with the saturated fat is actually okay.

01:49:28

I think like, I mean, a lot of the indigenous cultures out there, that's what they're eating. They're like tapioca, right? They're eating a lot of white rice, the Asian cultures. And they're usually eating it. They would love to eat it with things like beef fat, beef tallow. Kobe beef, it's a very, very yummy dish that the Japanese make. It's basically, you know, they can either boil the rice, but then they mix it with the beef tallow or actually fry the rice in beef tallow. And it's really good.

01:49:54

So yeah, so if you're going to be eating starches, make sure you eat them with a decent serving of saturated fat. I heard Ray even mentioned that you should cook your bananas. And I will say, cooked bananas are freaking delicious. If you haven't tried grilling bananas, they're way better. But it makes sense that you'd want to cook the bananas. So that's amazing. Thank you. Let's talk a little about organs. I've heard you talk about the importance of copper, vitamin A. I mean-

01:50:18

What about liver, man? Should we be eating liver? I think so. I think that you've talked about how important this is as well. And I think it adds to the narrative.

01:50:26

But not just liver, like a lot of other organs. Like, for example, let's say, like, somebody has, like, male hypogonadism. So let's say the doctor says, well, I have to put you on testosterone injections. You don't have to. Eating either, like, animal testicles or heart, actually. And people say, like, well, why heart? Well, heart is the most important muscle you have, right? Well, and there's another one, but I'm talking about the heart, you know? Basically, the heart needs to beat until the very end. If the heart stops beating, you're done. So…

01:50:55

Since cortisol is extremely catabolic to muscle, it's been noticed that even in extremely catabolic animals that have been administered cortisol, the heart actually does not get shredded until the very end, until the animal is about to die. It means there's something in the heart that's protecting the heart from the effects of cortisol.

01:51:12

And it turns out that in male animals, there is a protective factor, and that protective factor is testosterone. So eating hearts from male animals is a really good way of actually getting a decent supply of testosterone. Like an average-sized beef heart will probably give you an amount of like 5 to 10 milligrams of testosterone if you eat the entire heart.

01:51:34

And then if you're eating like kidneys, using kidney extracts and in general eating kidneys has long been used as treatment for actually kidney problems. And probably because the steroids they contain and some of the free fatty acids. Recent research showed that it's not just the steroids. There's some unique fatty acids there that are derivatives of

01:51:53

of the palmitic and I think stearic acid. They're hydroxylated on specific positions and they're present in very small amounts, but these also play a protective effect against acute kidney injury that it can induce in animals with a variety of different toxins, right? So eating organs, so liver is great because you get a very high amount of minerals. Most of the minerals and vitamins you eat because they have to pass through the portal vein

01:52:19

and get to the liver, right? The liver decides what to release in the bloodstream. So this means that the liver, just being like a filter for everything you eat, is going to store a significant amount of what you eat in there and then release it as needed. Fat-soluble vitamins, the highest concentration in the liver. B vitamins, highest concentration in the liver and the brain.

01:52:39

What else? The minerals, zinc, copper, selenium. In land animals, you don't tend to get a lot of selenium. It's mostly present in seafood. But if you're going to get it from food and you're basically at the land, you have two options. You have nuts, which are very high on PUFA. They have a lot of zinc and selenium. Or liver.

01:52:59

So really, liver is kind of like your vitamin supply, and you can eat it once every two weeks, and you'll probably still be okay. It's a very yummy supply of vitamins, and they seem to be present in a manner that doesn't trigger toxicity. The liver, let's say if you give like eight ounces of beef liver, you're probably going to get about eight to ten milligrams of copper in that.

01:53:23

Now, if you're taking that amount of copper as an isolated supplement, like copper chloride or copper acid and all that, I've tried that. It's not a pleasant feeling. It makes me nauseous. It gives me like a toxicity symptom, but not when I'm eating it in the liver. So maybe the balance with zinc or manganese or many of the other minerals, I don't know what is it, but when you're taking it from liver, you're getting a very good supply of vitamins, very good supply of minerals, and they're in a ratio and in a form that the body seems to like.

01:53:53

It's really amazing. I mean, even half an ounce of liver a day, which is like the equivalent of a smaller size than a quarter. It's like almost a little bigger than a nickel size piece of liver a day, depending how thick it is. That's a lot of nutrients in there. And if you put it into chronometer, you'll see your copper go up, your vitamin A go up, your folate, your selenium. I mean, like the zinc, the folate, the riboflavin, it's incredible. And I think liver and heart are my two favorite organs. I'll eat a half an ounce of liver

01:54:22

almost every day, just a little bit. It doesn't have to be a lot. And I will eat heart as often as I can get it. And the last few days, I haven't even eaten any muscle meat. I've just been eating heart, like a pound of heart a day. I mean, what's so interesting, Georgie, and I'd be curious for your perspective on this, is that in the carnivore community, there's people that don't think the organs are necessary. And I just kind of scratch my head and go, I mean…

01:54:46

This is crazy. Look at the way they fill in the nutrients. All the indigenous cultures eat the organs. They're prized. What are your thoughts about potential problems with just eating muscle meat?

01:54:59

First of all, it used to be the food for poor people back in the Middle Ages, like whenever there's an animal that's being butchered and the aristocrats will get the organs and they'll actually distribute the pure muscle meats to the poor to eat it. So they knew what they were doing, right? The primary problem with eating only muscle meat, not that there's anything wrong with it, but eating it, but you have to balance it, basically, right?

01:55:21

And a good way to balance it is to balance it with collagen, which is mostly present in the bones and the skin, right? But there's also this decent amount of collagen, depending on how fibrotic the animal is and how old, because collagen is a component of fibrotic scar tissue. You can get it in organs too, but not as much. So when eating the muscle meats, they're very high in tryptophan, methionine, and cysteine.

01:55:45

And these three amino acids are antithyroid. They actually have a direct inhibitory effect on the thyroid gland, on its production of thyroid hormone. But even worse than that, we already said tryptophan is the sole precursor to serotonin. You cannot form serotonin from anything other than tryptophan, right?

01:56:02

And then in addition, tryptophan is the only amino acid that is directly carcinogenic. It is not a coincidence that if you look in nature, whether it's an animal or plant and whatnot, tryptophan is always present at the smallest amount compared to any other amino acid. And in the composition of whether it's a plant, an animal, any kind of a living organism, tryptophan will be the tiniest amount of them all.

01:56:25

And I can give it like, let's say you get a glass of milk and you get a couple of grams of like some amino acids. Tryptophan will be probably on the amount of the something in the range of like 50 milligrams. So it's two orders of magnitude lower than what the other amino acids are present. And that gives you a good indication that in general, that's not something you probably want to overload with. Right. So now we know it's a precursor to serotonin. It is directly carcinogenic.

01:56:51

And it's also anti-thyroid. It's a glitrogen. You can cause hypothyroidism by feeding too much tryptophan. There are animal studies on that. Methionine and cysteine.

01:57:02

Now, both of them are also anti-thyroid, but methionine has this unique effect. It's a methyl donor, right? It is an essential amino acid. Cysteine can get synthesized from methionine. But some of the studies on lifespan extension initially thought that it was the amount of calories that you're consuming. And if you lower that, then you're basically living longer. They don't know that it's not. They don't know that it's specific nutrients.

01:57:27

tryptophan restriction, methionine restriction, or cysteine restriction, either one of these, or all three combined, much more synergistic effect, actually increase, not average, maximum lifespan, which is what really you want to increase, right? Basically increase it by about 20 to 30%.

01:57:44

So, and actually dwarfed the effects of caloric restriction, right? By restricting the amount of these amino acids down to zero. Recent human study demonstrated that if you lower the amount of methionine down to two milligrams per kilogram body weight per day, which means if somebody weighs a hundred kilos, let's say 200, okay, a hundred kilos because it's easier to calculate. If somebody weighs a hundred kilos, which is 250 pounds, maybe, right? A pretty decent weight. This

01:58:12

This means that if they can consume no more than 200 milligrams of methionine daily, it can cure their obesity. It can cure their type 2 diabetes in a matter of weeks.

01:58:24

guess what? Most people, actually not most, the vast majority of people on a Western diet are consuming several grams of methionine per day. So we're getting way more than what we need. And several studies now, including humans, have demonstrated methionine restriction is very, very highly beneficial. And that study with humans demonstrated when you drastically restrict methionine intake, the metabolic rate starts to climb up, which supports the idea that methionine is a potent anti-thyroid chemical.

01:58:52

which has been known from earlier studies. So that's the big problem with the muscle matrix, that they're very high in these amino acids, but they're very low on the amino acids that oppose those bad amino acids, such as glycine, proline, hydroxyproline,

01:59:09

various other derivatives that are found mostly in collagen. So what this means is that if you're eating meat, muscle meats, you should be eating probably a decent amount of collagen that matches one-to-one ratio, at least one-to-one, the amount of these, like basically, like let's say you get a chunk of meat, you can look in chronometer, how much, what's the sum of methionine, tryptophan, and cysteine present in this chunk of meat? Let's say it's like three grams. Well, I need to eat at least three grams of collagen, right?

01:59:33

in order to balance like the inflammatory and anti-thyroid effects that are there. Preferably more, because three grams of collagen is not much. It's a teaspoon. Right. Yeah.

01:59:43

That's what I was going to ask you about, the ability to balance the methionine with the glycine. Because I know there are some animal studies where they do methionine restriction and they get longevity, but then they also supplement with glycine and they see improvements in longevity too. I think it's going to be… I mean, I'm just thinking like I would have to be completely vegetarian to get 200 milligrams of methionine a day. You know, I'm only eating…

02:00:03

Right now, I'm kind of playing with the amount of meat in my diet. I'll do a pound, a pound and a half, and I'll try and do mostly heart and organs and then a smaller amount of muscle meat. But even with that, I'm getting a couple of grams of methionine in my diet. It's just in there. There are some tricks you can do. Several studies that I've seen show that if you increase the intake of the branchian amino acids or collagen, they actually block the uptake of methionine from the gut.

02:00:29

So you're not going to absorb it, right? And basically, it's going to get excreted. And another aspirin also blocks the absorption of methionine, tryptophan, and cysteine from the gut. So taking a tablet of aspirin, which probably has other beneficial effects,

02:00:45

If it's done on a semi-regular basis, that's probably not a protective way. And finally, there was one study that kind of hinted that you don't have to necessarily restrict methionine, cysteine, and tryptophan. You just have to make sure you eat sufficient amount of these antagonist amino acids present in collagen, and then you're going to get the exact same benefit without going through this orthorexic exercise of like, my God, like this food, I really love it, but it's got too much methionine. No, eat it, but add a tablespoon of gelatin. It's not that difficult.

02:01:12

Exactly. And I think it kind of goes back to this evolutionary perspective that, I mean, I spent time with the Hadza, hunter gatherers like that. They never waste anything. They're going to eat the ligaments. They're going to eat the tendons. They're going to eat every chewy little bit of the steak. They're going to eat all the organs. They're going to eat the liver and the heart and the pancreas and the spleen and the testicles. And I think that I see this happen a lot in popular culture that people will get a steak

02:01:40

And they'll cut all the chewy bits off the steak. If there's a tendon on a New York steak, nobody's going to eat the tendon. You go to a steakhouse and they don't eat the… I'm thinking you have to… You're supposed to eat the tendon. I mean, you don't have to do anything, but that's the reason that there's a tendon there.

02:01:55

to eat. And just because it's chewy, we're not used to it. So people only want to eat the most tender cuts. They want to eat a filet mignon. And I think there's not a lot of connective tissue in a filet mignon. There's always a little bit of connective tissue. That's probably the worst. Even though it's the tenderest, it's the worst for your metabolism. Yeah.

02:02:11

And so, I mean, it makes me think that ground beef might be good in a lot of ways because with ground beef, you've got a lower quality, in air quotes, cut of meat, and they're grinding in tendons and they're grinding in chewy bits. I mean, you try and give, you know, I've got friends who have kids and

02:02:27

sometimes we'll try and make them hamburgers and the kids go, oh, it has a chewy thing in the hamburger. And you think, okay, this is important that the kid eats the chewy thing in the hamburger. That's the tendon. That's like built into a hamburger. But if all that someone wants to eat is a filet mignon or a New York steak, and they're not going to eat the tendon or just a ribeye, even a ribeye has like tendons and sinew in it. And if people are just cutting that out, I think you're going to end up with problems. But ground beef is kind of great because it's cheap. Yeah.

02:02:55

And it has that stuff kind of built into it. And you could even, if you have a butcher that you know, you could even ask them to grind things into your ground beef. I mean, force of nature does heart and liver ground into ground beef, but you could ask your butcher to grind some tendons into your ground beef or anything you wanted, a little collagen in there.

02:03:14

You don't have to ask them. Like the commercial ones, especially like the larger chains, they do it because it's cheaper for them, right? So they'll do it anyways. I think there's a famous proverb, I'm blanking on what the indigenous culture is, but basically, I think the Native Americans were the ones who said, we eat the organs, the meat we give to our enemies.

02:03:30

So like even they knew that basically like eating that lean meat is not good. And another anecdote kind of confirmatory is in Africa, when like the large predators kill an animal, they always invariably go for the organs first. And if they're not very hungry, they would actually leave the carcass for later. Like,

02:03:47

I mean, they'll still eat it, but they wanted the good chunk, the good pieces first. And then basically, like, if they're hungry, they may even abandon it. And then the vultures come in and all the others, the hyenas and whatnot, they eat the rest, right? But they always go for the soft tissue in the abdominal cavity. So they eat all the organs, the intestines, the liver and whatnot. And then they leave the rest for later. So even they are not very keen on eating pure meat, like a building of meat.

02:04:10

It's so interesting. Yeah. I meant to tell you this early in the podcast. To prepare for this podcast, I had a lot of glasses of raw milk with honey and salt. And, you know, I…

02:04:21

I think that I would be very happy eating that with a little liver and heart and never even really eating a lot of muscle meat. It's so interesting how my taste for muscle meat goes down when I'm eating a lot of organs or when I'm just getting a lot of milk with honey and salt and fruit. So like if people haven't tried this,

02:04:40

You know, take raw milk or low temperature pasteurized milk or whatever kind of milk you want, grass fed organic milk, a whole milk, I think. But an add maple syrup or honey and salt. And that's the best. That's so good.

02:04:54

I mean, I can't think of much that's better than that. My usual meal is like I eat some eggs in the morning, but I do take a tablespoon of gelatin. And then at night, I try to eat more soups. And then basically I put two more spoons of gelatin in there too. So basically I'm getting about 40 grams of my protein from gelatin daily. And then maybe the other, I don't know, 50 to 60 grams from other kind of protein because you do need at least a certain amount of the essential amino acids to –

02:05:22

to function properly. But it looks like methionine, even though it's essential amino acid, we actually need very, very little of it, like orders of magnitude less than what we're consuming on a daily basis. And that's so interesting that you can balance it with other things, but…

02:05:35

Yeah. Wow. Georgie, what an amazing conversation. We're going to have to do a part two because I know that if we go more than two hours, people are going to get, are going to get overloaded. If anyone is still here, they're super diehard, but I hope they didn't miss this. Where can people find more of your stuff and follow you and support your work? Best thing is I have a blog. So that's probably the best way to like read the stuff. All I do on the blog is like, I, I,

02:05:59

if I see an interesting study, I'll read the study and then I'll, I'll basically extract the relevant quotes. And I put like a little bit of a commentary and maybe link to other posts that I've done, but I have a blog. And it basically, the website is, uh, H is in Harry, A, I, D as in dog, D as in dog, U, T as in Tom, hey dude, dot M E. So that's me, right? Hey, the dot me. And the same thing feeds into Twitter. Uh,

02:06:24

For some people, it's easier to follow me on Twitter because they can retweet and link and whatnot. And it's basically twitter.com slash Hayden. So that's probably the easiest way to follow on an almost real-time basis my work. And that's pretty much it. Basically, everything that I do, I'm doing my own studies now. We do some steroid testing, which we mentioned. Maybe we can talk in another podcast, basically. So anything that I do research-wise goes on the blog and then goes on Twitter and then people forward it from there.

02:06:52

What is the genesis of this name, Heydut? Oh, I'm originally from Bulgaria. And the Heyduts were the guerrilla fighters that fought against the oppressors at the time, which was the Ottoman Empire. So it's kind of like a guy who's a misfit.

02:07:10

who has his own ideas, right? And many people get irritated by these things, especially in the medical community. And I do my own thing. And basically that's what the halos were like. We don't like this authority. We're going to fight for independence and we're going to go live in the woods away from society. I,

02:07:26

I still live in society, but like, if you think about it, most of the things we discussed today, you know, many clinical practitioners will probably either disagree with or they will basically feel threatened by. And it varies heavily argued like, no, this is how it is. That's how we do it. Right.

02:07:41

And that's my experience in general so far, just talking about health topics. Some people feel intimidated for whatever reason, maybe because their career, maybe because they have something to lose. I don't know what it is, but it's not my intention to attack anybody. It's more like, look, if I see that something doesn't work, I will look for an alternative method. I'm not saying that my method is right, but I'm presenting evidence. And I think that evidence, if it's published in a peer-reviewed journal, should at least be heard.

02:08:05

If we got to the point where people are so set in their ways that are saying, no, I don't want to see any other evidence. My evidence is the best, right? I'm kind of seeing that, and I think that's dangerous, but I have faith that we're going to overcome that because I think we're getting to a point where a lot of doctors are seeing that chronic diseases, we have not made much progress in curing them over the last

02:08:26

100 years. We haven't cured diabetes type 2. We haven't cured cardiovascular disease. We certainly haven't cured cancer. None of the chronic neurological disease like Alzheimer's, Parkinson's, Huntington's disease, ALS. None of these have been cured. So whatever we've been doing so far is not working.

02:08:42

Now, that doesn't mean nothing of medicine is working. Emergency medicine is very good. Surgery is very good, right? Infectious medicine, at least when it comes to bacteria infections, treating bacteria infections and fungal infections is also pretty good. But things are there, very straightforward. I think when it comes to more of the unknown pathways of a chronic disease, that's when you get into the political infighting because certain groups are set…

02:09:04

they have a preference for a specific pathway or maybe they're working on a drug that works on a specific pathway. And as it's very common, I think there's a famous saying, it's like, you cannot get a person to understand something if his career depends on not understanding. Yeah, it's so true. It's so true. But that's such an appropriate name. I love it. There's a character in Edward Abbey's books, the Monkey Wrench Gang, called Monkey Wrench Gang, Hey Duke. And it's kind of the same- Same word. It's the same word.

02:09:35

Yeah, yeah. Hey, Duke. It's kind of like it's spelled a little differently, but I wonder if it has the same epistemology. It's so interesting. It's like rebel fighter and they're going around and monkey wrenching construction companies that are destroying the American West. So thank you for your work, my friend. And I look forward to future conversations. Thanks a lot. Hopefully we didn't bore your listeners. Hopefully they find it useful.

Edit:2024.12.18

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