Transcripts to Minds & Matter Podcast

transcript to transcripts 2hr podcast Obesogens, Oxidative Stress, Dietary Sugars & Fats, Statins, Diabetes & the True Causes of Metabolic Dysfunction & Chronic Disease | Robert Lustig

https://mindandmatter.substack.com/p/obesogens-oxidative-stress-dietary 

Welcome to the Mind and Matter podcast. I'm your host, Nick Jikomes, and today I'm speaking with Dr. Robert Lustig. Dr. Lustig is Professor Emeritus of Pediatrics at the Division of Endocrinology at the University of California, San Francisco.

He has specialized in the field of neuroendocrinology, and a lot of his work has emphasized the regulation of energy balance by the central nervous system. His research and clinical practice has focused on childhood obesity and diabetes, And he's an expert about nutrition and metabolic health generally speaking.

He's written a number of books and many scientific studies that have to do with all of these areas. I believe his latest book was Metabolical, The Lure and the Lies of Processed Food, Nutrition, and Modern Medicine.

He's one of my favorite people to follow who's very public about disseminating information about metabolic health and what is actually causing it. We talked about the causes of obesity and metabolic dysfunction. That included a discussion of obesogens. These are things that cause obesity.

These can be either components of our food like fructose or other things that we're eating that we normally think of as food or they can be other environmental contaminants. Lots of the stuff that is in our household goods and products can also get into our bodies and cause obesity and metabolic dysfunction.

We talked about oxidative stress and mitochondrial biology. We talked about the difference between different types of sugars like fructose versus glucose. We talked about different types of fats like omega-6 and omega-3 polyunsaturated fats versus saturated fats.

We actually broke down the saturated fats even further into even and odd chained saturated fats and talked about whether or not those things actually cause obesity and cardiovascular disease. We talked about scientific funding. and the role that industry plays in driving many popular perceptions of what causes obesity.

We talked about all different aspects of nutrition and metabolic health. We talked about why people who live in colder or higher altitude climates are often skinnier or less obese than people who live in We talked about basically what the true causes of obesity and metabolic dysfunction actually are. This is a really great episode.

If you're interested in this topic broadly of metabolic health and nutrition, I highly recommend this episode. It's one of probably the most information-dense episodes I've done on this general subject area. And as a reminder, I have all of my podcasts on my Substack at mindandmatter.substack.com.

on that sub stack page you will also find my long form science writing and that includes a series I'm writing right now about metabolic health that integrates a lot of the information in this episode together with information from other episodes and you can sign up for my free weekly newsletter as well as become a paid subscriber if you're getting a lot of value from the podcast and want to help me keep going and keep growing

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Click the link in the episode description to learn more and use the code MIND in all capital letters to get $50 off your Lumen device today. And with that, here's my conversation with Dr. Robert Lustig. I'll have an intro written up for you so we don't need to go over your full background and everything.

You're fairly well known and I'll describe you at the beginning for people who don't know you. We're going to be talking about obesity and obesogens today and related topics. I want to start at the beginning of obesity. And as I understand it, that means for any individual before they're even born.

So, what can you tell us about how the metabolic health of our parents and the in utero conditions that we live in when we're little babies before we're even born affect our propensity to develop obesity and metabolic disease?

Well, that's a loaded question, Nick, to say the least. We've learned in the last 30 years about a new aspect of medicine, and it's called the Developmental Origins of Health and Disease, or DOHAD.

The first person to notice this was an epidemiologist working in Southampton, England by the name of David Barker, and he was basically going through records of people who were born uh during the war during world war ii and notice that these people were dying early

and he didn't know why and you know it was years later that he noticed this and he did an enormous amount of exculpatory work that to this day is you know kind of classic epidemiology and he came to the realization that something was going on in utero that was actually changing

These fetuses physiology that was ultimately leading to the ultimate development of chronic disease, cardiovascular disease, type 2 diabetes, etc.

He presented that and people started looking at this question and they found similar stories elsewhere and they started doing animal experiments and sure enough, it looked like what the mother was exposed to ultimately is visited upon the baby later on. Now we had always thought that the placenta was this

Great barrier that kept the mother from the baby. And we had lots of reasons to think that because after all, you know, mom's immune system does not become the baby's immune system and Thank you for joining us.

For instance, cortisol from getting to the baby, unless of course the mother takes something that the enzyme can't work on, like for instance dexamethasone, and then it does go to the baby. So we had this notion that the placenta was all-seeing and all-knowing.

and the ultimate you know suit of armor for for the baby and that mother's diet didn't matter and that mother's medicines didn't matter and ultimately when we learned about microbiome that mother's microbiome didn't matter that turns out all of that is hogwash the placenta is not that great it's it lets a lot of stuff across and it doesn't do what we think it does and so in fact

The fetus ends up swimming in the same cesspool of contaminants and environmental exposures that the rest of us do. And so it shouldn't be too surprising that those contaminants, when they have effects on us, that they would also have effects on the fetus.

Now, one of those that I happen to be particularly interested in, so I've done a lot of work on obesity,

are these chemicals which we now term obesogens that is they are chemicals that drive adiposity drive weight gain drive chronic disease in humans both you know adults and as it turns out also fetuses having nothing to do with their potential inherent calories

so there are a lot of substances that have calories but generate more adiposity than their calories like my favorite fructose and there are plenty of chemicals that generate adiposity having nothing to do with calories like for instance

Polyfluoroalkylated substances PFAS like Teflon okay or BPA bisphenol A which turns out to be an estrogen and you know there's a whole host of compounds phthalates plasticizers PBDEs flame retardants parabens things that are in cosmetics things that are in vinyl flooring things that are in oh oh and by the way air pollution All right.

And so you'd think the placenta would be a great way to keep the fetus away from all of these things, because after all, fetuses don't use cosmetics and fetuses don't breathe our air. But you know what? They're still getting damaged. And that's what we've learned.

And the obesogen hypothesis brings this question of what's really at the at the nidus of this obesity pandemic that is really only about 50 years old. You know, before, you know, 1970, only 5% of the population was above the 95th percentile for body mass index.

you know this has all occurred in the last 50 years and something has to explain it and you know our DNA hasn't changed but our environment sure has and you know people want to say well it's because of the food you know because people are gluttons and sloths no it turns out that there are chemicals driving this

and that's you know part of you know what my research has been about for the last 25 years so there are both food and non-food obesogens substances that we're exposed to that promote obesity and and promote metabolic dysfunction probably in other ways um starting with some of the food obesogens you mentioned fructose yeah that's the big one how now how is it an obesogen how is it punching above its weight compared to say glucose or some other comparable food

right absolutely so this is what i've spent my entire you know obesity career i have two careers you know one was on well working on why boys were boys and girls were girls from the neck up that was what i did for the first uh 20 years of my career and then for the second 20 was on obesity um but uh why is fructose a an obesogen unrelated to its calories

because glucose has calories and glucose stimulates insulin and insulin drives weight gain so glucose should be just as big a problem for obesity as fructose it turns out that the reason is because of the way it is metabolized and also what it does to the brain

So there are three reasons that fructose is worse than glucose in terms of obesity and also metabolic disease like diabetes. And those three things are, number one, fructose is not metabolized in all the organs in the body like glucose is. Fructose is metabolized in the liver. So an entire fructose bolus, like a 20 ounce Coke,

Thank you for joining us, Robert. For glucose, what it does is it tries to turn it into glycogen.

which is a storage form of glucose which is non-toxic and which basically every liver has some and you know marathon runners have more because they're running marathons so they load up with pasta very specifically to drive their liver glycogen stores and that's where you want to put extra energy because glycogen is for lack of a better word non-toxic but fructose does not go to glycogen

Okay, there's no direct pathway from fructose to glycogen. It goes instead down to the mitochondria through the Emden-Meierhoff or glycolytic pathway, which takes you from fructose to acetyl-CoA. And then acetyl-CoA then enters the mitochondria and the mitochondria would then burn the acetyl-CoA through the Krebs cycle to generate carbon dioxide and water and ATP.

And the whole goal of this is ATP. So, fructose overwhelms the mitochondria because the mitochondria are fixed. They have a Vmax, a maximum velocity. They can only, the cycle can only turn so fast. The only way to make the cycle turn faster is to have more mitochondria. By the way, that's why exercise is good.

You make more mitochondria.

that's a good thing i'm not saying exercise is bad but you know ultimately a mitochondrion is a mitochondrion and you know it's not like you can you know sort of pressure test a mitochondrion if you overwhelm a mitochondrion okay it's not going to work better or faster and so what happens is you overwhelm it it can't deal with the load it ends up sending out

um a uh compound called citrate um a uh compound called citrate

and the citrate leaves the mitochondrion through a process called the citrate shuttle and then now that citrate is in the cytosol of the cell and now the cell has to do something with that citrate and what it does is it takes the citrate down to acetyl-CoA the acetyl-CoA gets bound to another acetyl-CoA to make malonyl-CoA and then the cell starts adding two carbon fragments onto that malonyl-CoA and so it builds

from a 2-carbon string to a 16-carbon string, which we call palmitate. And the liver only makes palmitate. And this process is known as de novo lipogenesis, new fat making. This is how your liver turns sugar, fructose in particular, into fat, palmitate. Fructose to palmitate through this de novo lipogenesis.

Once the palmitate is made, the goal is to package it in a form that can be exported out of the liver. And so it gets added to a glycerol molecule to make a triacylglycerol or serum triglyceride. And then that triglyceride gets packaged with ApoB100, a lipoprotein. And now you've got this little Thank you for joining us.

because insulin will work on that VLDL to deposit it in your peripheral subcutaneous tissue and now that grows. Or it can be potentially a driver of cardiovascular disease if it unloads in the arterial wall. But some of the triglyceride will be manufactured and will never make it out. It won't be packaged.

In which case, now you have a lipid droplet Now you have fatty liver disease. When you have fatty liver disease, now your insulin signaling in your liver cell doesn't work anymore. Now you have liver insulin resistance and that makes the pancreas have to make more insulin to make the liver do its job.

And that has its own negative side effects because insulin is a mitogenic factor. It is a growth factor. It causes vascular smooth muscle growth. It causes glandular growth, therefore leading to cancer. So it actually increases coronary vascular disease and it increases cancer risk.

and it basically is the primary driver of chronic metabolic disease plus you're putting so much extra stress on the pancreatic beta cell to make that insulin that you will ultimately burn out now you'll have type 2 diabetes but that's only one problem there are three okay we have we have now described one

Now let's describe problem number two. You like barbecue? Oh, yeah. Yeah, me too. I love barbecue. Why do we paint our ribs with barbecue sauce? To get that nice caramel color and that caramel flavoring, right? That, you know, so good, right? Why do bananas brown?

The point is, this is a reaction which is known as the Maillard or the browning reaction. The browning reaction is the caramelization reaction. This is why if you take sweetened condensed milk and you put it in a pressure cooker, you will get pudding. That's a way to make a very cheap dessert.

But it turns a white substance into a brown substance. Well, we are all browning all the time as we speak. If I was a cardiovascular surgeon and I opened up your sternum, the cartilage ends of your sternum would be brown today. And you're a young guy. Mine are even browner.

okay they started out white now they're brown and the reason is because of this Maillard reaction it's occurring all over your body it's occurring all of the time it is a you know byproduct of life there is no life without the Maillard reaction but the goal is to make that Maillard reaction run as slow as possible and the reason is because every time that Maillard reaction occurs

You are taking that protein and you're making it less flexible. You're making it less functional because there are these glucose or fructose molecules hanging off of it, which change its conformation. And every time that reaction occurs, you are releasing a reactive oxygen species. So this is all like an oxygen dependent thing. Absolutely. Completely oxygen dependent.

Okay, so bottom line is you don't want that Maillard reaction to occur fast. You can't stop it, but you want it to occur as slow as possible.

Well, it turns out because of the nature of the stereochemistry of the fructose molecule, fructose engages in that Maillard reaction seven times faster than glucose, and it generates 100 times the number of reactive oxygen species. So that is the aging reaction. That is the reaction that causes wrinkles. That is the reaction that causes cataracts.

That is actually the reaction that causes cardiovascular disease. So more fructose, more sugar, more cardiovascular disease, having nothing to do with insulin and having nothing to do with energy just because of the stereochemistry of this molecule. So unrelated to calories. And finally, number three, remember I said there were three, Fructose stimulates the reward center in the brain.

So there's an area of the brain called the nucleus accumbens. It is the reward center. It's where cocaine, heroin, nicotine, alcohol, shopping, gambling, social media, internet gaming, pornography, all work. They all generate a dopamine signal. So the question is, fructose does that. Does glucose? And the answer is glucose does not do that.

Glucose activates other places in the brain Mostly the basal ganglia and the cortex, but it actually does not stimulate the reward center. Only fructose stimulates the reward center. So a little sugar means you're going to have a lot more sugar because of that reward.

So it's fructose specifically that is the sort of addictive sugar among the sugars.

Exactly. Fructose is addictive. And in fact, on February 15th, so just three days from today, Dr. Nicola Vina, who is a neuroscientist at Mount Sinai, who actually discovered sugar addiction. I mean, she's the one who basically put it on the map.

and I are going to be at the Commonwealth Club in San Francisco discussing sugar addiction, both from a biochemical and from a public health standpoint.

And when you say fructose is addictive, it's not a metaphor. It's literally tapping into the same mechanisms that a drug of abuse would tap into.

Exactly right. So people who say, oh, I have a horrible sweet tooth, that's sugar addiction until proven otherwise. Fructose is more obesogenic than glucose because the body metabolizes it differently.

And among other things, that tells us the body doesn't treat The True Causes of Metabolic Dysfunction

took a bomb calorimeter and threw some fat in it and exploded it and threw some protein in and exploded it and threw some carbohydrate in and exploded it. And he came to the calculation that fat burned at nine calories per gram and protein burned at four calories per gram and carbohydrate burned at four calories per gram also.

And so he said, well, fat obviously is more energy dense, which is true. That is absolutely true. That is more energy dense. That's why there is fat because it's an easier way to put more calories in storage and Take Up Less Room. That's a good thing, I guess.

But from the standpoint of utilization, that has nothing to do with anything. And it turns out that that fat, just because it's nine calories per gram, doesn't mean it doesn't have value or that it has too much value and it's the target for trying to fix obesity.

because you need certain fats and you don't need other fats and when you basically go fat free which we all did for 50 years okay we actually got sicker because we actually needed the fats and what we did was we loaded up on the carbohydrate remember all the pasta bars from the 1980s you know as everybody tried to go fat free that was the worst thing that we could have ever done

because all it what we did was we took something that was actually good for us in our diet and substitute something that was bad for us in our diet another example which i love is you know as a pediatrician chocolate milk you know they took the fat out of the milk and then the kids wouldn't drink it because it tasted like dish water and what they do they added the chocolate

They took the fat out, which was good, and they put in instead the sugar, which was bad. And because this has nothing to do with calories, and so that is my mantra, kill the calorie, you know, hashtag kill the calorie. And we have shown 50 ways from Sunday why obesity is not about calories.

So you've told us about a carbohydrate obesogen. That was the whole fructose discussion. We talked about how fructose affects the body differently than glucose because it's processed differently. And because of the way it's processed, it's more obesogenic. Are there any obesogenic fats?

And what I'm thinking of here, based on what you just said and some other things that I've discussed on the podcast recently, there's two types of fats I would like to get your take on. So one are basically the seed oils, the omega-6 polyunsaturated fatty acids and the extent to which they're obesogenic.

And then maybe after that, I want to ask you about, we were just talking about milk and other things, saturated fat, because I've been told my whole life that saturated fat is the really problematic one that will drive cardiovascular disease and other bad things.

Right. So let's start with the omega sixes. Okay. And I do believe you had Chris Knabe on your show already. Yes. You know, major proponent of getting rid of omega sixes. And I love Chris, you know, great guy. I'm not sure that omega sixes are obesogenic. Specifically, However, they are pro-inflammatory.

And when you are pro-inflammatory, you generate insulin resistance. And if you generate insulin resistance, then that is obesogenic. So in that respect, they may be obesogenic indirectly as opposed to directly because they are pro-inflammatory. Now, omega-6s, You need them. It's not like you can do without them.

If you didn't have any omega sixes, you would be eaten by the maggots. All right. They are part of your defense system against foreign invaders. And the reason is because omega six fatty acids, which are in seed oils, you know, canola oil, soybean oil is famous for, you know, et cetera. They are the precursors to arachidonic acid.

And arachidonic acid is the precursor to virtually all of the pro-inflammatory cytokines, thromboxane, zycosanoids, missing one, thromboxane. Prostaglandins. Prostaglandins, right, sorry. So you need them, but you don't need too many of them.

and it is estimated that what we need is an omega-6 to omega-3 which is anti-inflammatory omega-6 to omega-3 ratio of about one to one would be optimal but you can only really achieve that if you live on a coast and or you know three to one four to one maybe tops

Our current omega-6 to omega-3 ratio is 20 to 25 to 1 based on how many processed foods you eat.

And that little comment you made about living near the coast, was that alluding to seafood?

Yeah. Basically, seafood has omega-3s. And the reason is not because the seafood makes omega-3s. The seafood eats the omega-3s. The omega-3s are made by algae. Algae make omega-3s. The fish eat the algae. We eat the fish. So we get our omega-3s third-hand, and they are anti-inflammatory.

We're talking about three omega-3s, ALA, alpha-linolenic acid, ALA, and that you can find in vegetables, but alpha-linolenic acid, ALA, has been shown to have cardiovascular protection, but not neural protection. It doesn't get to the brain. The next one is EPA, eicosapentaenoic acid.

That gets to the brain and that improves neural transmission and it is absolutely essential for brain health. The problem is that EPA is the one that smells fishy. So it's not in a lot of processed foods.

So fresh EPA smells fishy. It's not just oxidized.

Well, more oxidized EPA will smell fishier. Got it. No question. I mean, there's a little bit of a smell, but not nearly as much. And then finally, the last one is DHA, docohexyenoic acid. DHA is necessary for neuronal structure. Now, The problem is that ALA does not really get converted to EPA or DHA.

The percent conversion of that in the body is extremely low, like less than 1%.

So if you tried to get all of your omega-3s through a purely plant-based diet, would that be problematic for that reason?

Yes.

yes and so people who are on plant-based diets really do need to take some form of omega-3 supplementation because ala alone is not enough so they can take fish oil but then they're not vegan anymore because it came from fish they can take algal oil and stay vegan and that's okay but algal oil is primarily dha not epa so it still becomes a little bit of a problem

So personally, I think the right, the best diet, if someone asked me what the best diet was, I would say pescatarian because you can basically have the best of both worlds in terms of what you're eating and effects on the environment. That would be my personal choice. But, you know, it is what it is.

I still like barbecue. So, anyway, omega-6s are highly inflammatory because they are the precursors to these inflammatory cytokines. We need to get those down. And Chris Knabe has basically argued, I think effectively, that those omega-6s are driving multiple different diseases as well, including, in his case, acute macular degeneration or AMD, and, you know, for good reason.

So, omega-6s are an issue.

And probably if we just had to put it in one sentence, the best way to reduce omega-6 intake is probably just to reduce processed foods generally.

In general, yes, absolutely. Because that's where they're hiding. And then finally, you asked about saturated fat. Yeah. Now, we have been told for time immemorial that saturated fat is the bad guy. I am here to say that saturated fat is not the bad guy. Saturated fat is cardiovascularly neutral. It's neither good nor bad, but it is necessary.

You need saturated fat in order to be able to make a decent membrane, decent cell membrane.

So there's actually an analogy here maybe with the omega-6s, which is you don't want too many omega-6s, but they are essential. Can we think a similar way with the saturated fats?

Yeah, pretty much. Saturated fat has certain advantages. Number one, because it's saturated, you can heat it to any level you want. All right. And it won't cause the isomerization at the double bond to turn cis fatty acids into trans fatty acids. And trans fats are the devil incarnate.

Trans fats are the single most poisonous thing you can put in your body that we call food.

I see. So trans fats are very, very bad. And tell me if this is a fair statement. Anytime you heat an unsaturated fat to a high enough temperature, you're running the risk of creating some trans fat.

Correct. That's exactly right. So we want unsaturated fats. We have demonstrated the benefit and value of unsaturated fats, like, for instance, olive oil. Olive oil is oleic acid. Oleic acid is the endogenous ligand of a transcription factor in the liver called PPAR alpha, proxosome proliferation activated receptor alpha. It's one of the things that runs the liver.

It's a fuel gauge on the liver cell. It's a good thing.

and you know I'm for olive oil and I got a lot of it upstairs but but olive oil has a relatively low smoking point of 310 degrees Fahrenheit so cooking with it could be a problem so depending on how you cook cooking with olive oil especially if you put in a frying pan and you heated something up you know to fry something in olive oil could potentially be a problem because you could be making trans fats at home

And the more double bonds that any given fat has, the more risk you run of creating trans fats at home.

So this is why deep frying in omega-6 polyunsaturated fats is so problematic.

Exactly. Exactly. But of course, that's what every state fair has.

so what what are you gonna do so the so saturated fat gets away from that saturated fat will not isomerize because there's nothing to isomerize and the smoking point of saturated fat is much higher so you will not get into any trouble now saturated fat got a bad rap because of all of this

Very bad epidemiology that was done back in the 1950s and 1960s. A guy named Ancel Keys, who's sort of famous in the literature, he was a hero, even appeared on the cover of Time magazine. Okay. And now he is a villain and has been appropriately vilified.

He was the one who basically correlated saturated fat consumption with mortality due to cardiovascular disease back in the 1950s. However, when you look at the data. He cherry picked it. He cherry picked it. Okay. He published a volume

a very long volume about an 800 page volume called the seven countries study jeez i don't know it's that big yeah it's pretty big and on page 262 of that volume and i know because i took it out and i made you know like a slide of it okay he basically said that the reason that um

uh sucrose sugar consumption was associated with cardiovascular disease was because of the association of sucrose with saturated fat in other words donuts and all the countries that he picked in his seven countries even though there were 22 he picked the seven that made his case the seven that showed the highest incidence of mortality from cardiovascular disease were all donut eaters

and the countries that were not were not donut eaters so it was obscuring uh the story you told us earlier about fructose exactly exactly those people were not just eating high saturated fat they were also eating high sugar and what he did was he basically dropped it out I don't I don't want to spend too much more time on Ancel Keys because everyone's talking to death about him is it established fairly well that he intentionally cherry-picked this data

Well, intent is complicated as we have learned in the last two years. I'm not sure, I never asked him. I don't know that anyone ever asked him if he intended, but there were 22 countries and when he published it, there were only seven. We have the data on the other 15 and they don't fit.

So I don't know, you tell me, did he or didn't he?

Okay, one more question about saturated fat that I think is important. We're talking about saturated fat, but are there multiple types of saturated fat that we should be distinguishing and thinking about, analogous to the way that we talk about omega-6s versus omega-3s?

Well, in fact, that's right. So, you know, we've learned a calorie is not a calorie. And by the way, an amino acid is not an amino acid.

and we've learned a carbohydrate's not a carbohydrate we've even learned a fiber is not a fiber and of course a fat is not a fat so there are two types of saturated fats not one two there's red meat saturated fats and then there's dairy saturated fats and they are not the same either even though dairy comes from

A animal that also provides red meat. So like, why is that? But it's true. So it turns out red meat is filled with even chain saturated fatty acids, C-16 and C-18, palmitate and stearate. And those, as I've said, are cardiovascularly neutral.

Got it. Red meat saturated fats, even chained, those are cardiovascularly neutral.

Neutral, neutral. Not good or bad. Not good or bad. Neither good nor bad. Dairy saturated fat, so like in milk,

turns out to be odd-chain saturated fatty acids, C15 and C17, and those odd-chain saturated fatty acids have a specific phospholipid signature on their tail end, which is why they stay in solution, because after all, fat is in milk, right?

I mean, yes, the cream rises to the top, but there's still fat in milk even after the cream rises to the top. The phospholipid allows both the fat The oil and the water, if you will, to mix. And so they turn out to actually be protective against cardiovascular disease. Protective. Protective.

Dairy saturated fat is protective against cardiovascular disease.

So are you telling us that there's no saturated fats that are clearly negative across the board?

That's right. There are no saturated fats that are clearly negative.

They're neutral if they're even-chained like red meat, and they're actually protective if they're odd-chained like from dairy.

Exactly right. So you also have to know that the reason everybody made a brouhaha over saturated fats was this molecule that came out of your liver called LDL. Now, we've already talked about VLDL. Well, LDL and VLDL are not the same either. What makes VLDL? Sugar. What makes LDL? Dietary fat, dietary saturated fat.

Okay, so there's no question that dietary saturated fat increases your LDL. And there's also no question that in large population studies, LDL levels correlate with cardiovascular disease. That is also true. Okay, the hazard risk ratio for high LDL and coronary heart disease is 1.3.

So if you have a high LDL, you are 30% more likely to die of a heart attack than if you don't have a high LDL. Okay. That's real, and I'm not even saying it's not. I totally subscribe to that.

1.3.

Turns out the public health community has identified 1.3 as sort of what's necessary for a public health effort. So if it was 1.29, we wouldn't even be having this discussion because we'd be below the threshold. But we're at 1.3.

That VLDL that I told you about before, the hazard risk ratio for high triglyceride and coronary heart disease is 1.8. So if you have a high triglyceride, you are 80% more likely to die of a heart attack than if you have a low triglyceride. So which one is worse? The LDL or the triglyceride? Well, clearly the triglyceride.

So why are we spending all this time worried about the LDL when we're not even focused on the triglyceride? And the answer is because we had a medicine for it.

So that's why when my mother, my late middle-aged mother, recently went to the doctor and her LDL was high, but her triglycerides looked fine, the doctor was immediately like, you should be on a statin.

Well, that's what the guidelines say. And the guidelines suck because they're not taking into account this whole issue. In addition, there's not one LDL.

There's two. And we don't normally measure the VLDLs when you go to the doctor. Is that accurate?

Number one, you don't. Well, you measure serum triglyceride when you go to the doctor. But there are two LDLs. So the LDL is its own thing, but there are two LDLs.

There's one called Large Buoyant or Type A, and there's another one called Small Dense or Type B. And it's been shown that the Large Buoyant is the one that dietary fat raises, but the Large Buoyant, and by the way, Large Buoyant is 80% of your LDL concentration in your blood.

But it turns out the large-buoyant are cardiovascularly neutral. That's why I said, you know, for the most part, they're cardiovascularly neutral because the large-buoyant LDL do not contribute. Number one, they're large. They're so large, they don't fit under the surface of the endothelial cell to start the foam cell formation process to actually drive the plaque.

and they're buoyant they float so they take they go through laminar flow in your arteries and arterioles and they basically don't set up a chance for those particles to be able to actually get under the endothelium to cause problems so large buoyant are Cardiovascularly neutral because they're not contributing to the pathogenetic process of heart disease.

Conversely, small dense, they're small. Okay, they're, you know, I mean, from an angstrom standpoint, they're about 10 angstroms smaller than the large buoyant, you know, 273 versus 283 microns or so, or angstroms, sorry, angstroms. And they are small enough to get under the surface of the endothelial cell. And They're dense. They don't float.

So they fall out of laminar flow so that they can approach the endothelial cell surface so they can get underneath. And then they oxidize. And now you've got oxidized small dense LDL. And now you've got a pathogenetic substrate for heart disease. No ifs, ands, or buts. So the bottom line is a fat's not a fat.

An LDL is not an LDL. Okay. And, uh, you know, this whole concept that we should go fat free to solve the problem actually only created two more. It created both obesity and type two diabetes.

Yeah. It created those problems and it did not solve the one that we thought it would.

Right. So, you know, we need to rethink how we did this and where we came from. And basically, you know, when you, when you make a mistake, you admit the mistake and you write the ship. We have not admitted the mistake and we have not righted the ship.

And so that's what I spend all of my time basically trying to get the medical community to sort of get with the program.

So given what you told us about statins and LDL and all that, in your opinion, what characteristics does someone have that justify a statin prescription?

So, statins stop you from making your own LDL, okay? That is true. And by the way, full disclosure, I have been on a statin for 33 years, okay? I went on my, actually I take it back, sorry, 31 years, 31 years. I've been on a statin since 1993.

And the reason is because everyone in my family has heart disease. My grandfather died at age 44 of a heart attack. My father had his first heart attack at age 61. Everyone in my family has rampant heart disease. My sister, 40 years ago, when I worked at Rockefeller, she was a research subject in Jan Breslow's lab.

And my colleague and good friend, Elliot Britton, did a heparin test on her to demonstrate that she had familial hypercholesterolemia. So I am a heterozygote. Oh, really? Okay. I already know.

You have a specific genetic reason for this.

I have a specific genetic reason. So I have been on a statin for 31 years, and I've also tried myself off the statin more recently, and my LDL popped up from 70 to 300 again.

And how common is this condition? How common are people like you? 1 in 500. 500, okay.

Okay, so I'm not against statins. They probably, you know, the reason I'm still sitting here talking to you, okay, for the right patient. And if you have familial hypercholesterolemia, either homozygote or heterozygote, you need them. Okay, so I'm glad they're here. I'm not anti-statin. I want to make that very clear.

However, having said that, of the people who are on statins today, which is a whole lot of people, turns out probably four out of five people who are on them don't need them. They were put on them for what we call primary prevention. That is, they went to the doctor, they got their labs drawn.

Doctor said, oh, your LDL is a little high. Let's put you on a statin. And the reason is because the guidelines say so. So if you don't put somebody on a statin, you're not following the guidelines. And the guidelines are based on this hazard risk ratio of 1.3. So the question is, for primary prevention, do statins work?

We've been using statins for over 40 years now. For primary prevention, do statins work? And the answer is,

Many meta-analyses have been done and they all show that for primary prevention, that is not having had a heart attack yet, just having a high LDL, no event, the mean increase in lifespan for being on a statin is four days. Four days.

Now, when you think about the fact that 20% of people who go on statins end up with some level of rhabdomyolysis, you know, the muscle breaks down, they end up with severe inflammation and 20% have high blood glucose. They have hyperglycemia because statins interfere with mitochondrial function. That's why they work to get your cholesterol down. Okay.

You know, that's not a good thing. So you were putting people at risk for four days of increased longevity and incurring this huge side effect profile.

So let's just restate this explicitly. When you say you're putting people at risk with a statin, at risk for what's the list of things?

For rhabdomyolysis and hyperglycemia.

Hyperglycemia and muscle loss basically.

Yes. So bottom line, if you've already had a heart attack, if you've already declared yourself, or if you have familial hypercholesterolemia like I do, then you absolutely need a statin. And then the data on statin use and longevity is very, very strong and very robust. So for secondary prevention, Totally. Absolutely. Sign up. You need it.

And if it's primary prevention and you don't have FH, I think this is a real travesty.

Let's say you have type 2 diabetes, no personal history of heart attacks, and no family history that's abnormal. It's average family history with respect to cardiovascular disease. What would your general position be on if statins are a good idea for a diabetic?

No, so if you have type 2 diabetes, the first thing to do is get rid of the type 2 diabetes. Everyone assumes that type 2 diabetes is this chronic, unrelenting, progressive,

destructive degenerative process that will never get better and you know you're going to be on medicine whether it's insulin or oral hypoglycemics you know for the rest of your life that's the general gestalt amongst the uh cognoscente in uh in medicine garbage absolutely not true absolutely not true

Numerous studies now show that a ketogenic diet can actually reverse type 2 diabetes. Virta Health, 77% of people who go on a ketogenic diet reverse, not ameliorate, reverse their type 2 diabetes. Just by getting rid of the offending agent. And what is the offending agent? Well, what is type 2 diabetes? It is extreme carbohydrate intolerance.

So if you're intolerant to something, what's the best way to deal with it? Get it out of your diet. That's how you deal with an intolerance. If you are lactose intolerant, get the lactose out of your diet. If you have peanut allergy, get the peanuts out of your diet.

Whatever it is that you have an intolerance to, get it out of your diet. If you get carbohydrate out of your diet, you are on a ketogenic diet. And it turns out a ketogenic diet will reverse, reverse type 2 diabetes. There are other ways to do it too.

It's not like you have to be on a ketogenic diet, but that is one way. And what it does is it is the test case. It is the theory of the argument that if you fix the diet, you can fix your type 2 diabetes.

I have family members who are type 2 diabetic. They're on statins. They're not given clear dietary guidelines by their physician except to cut out basically junk food, which by that they mean like candy and things like that. But they're told, for example, eat as much fruit as you want. Does that make sense to you?

It's complicated, but let me try to explain fruit. Okay, so yes, get rid of candy, but there's a whole bunch of other things you have to get rid of too in order to, you know, make that right. I guess, you know, the question is, okay, get rid of candy. Sure, sure. Is Cheetos food? Is Cheetos food?

Yes or no? Probably not. It's got calories. It's got calories. Is Cheetos food? So what is the definition of food? That's what we need to know. So go to the dictionary. I've got one up here if you want. I'll read it to you. I've memorized it.

The definition of food is substrate that contributes to either the growth or burning of an organism. That is food. Growth or burning. So the question is, Does Ultra Processed Food Contribute to Growth? My colleague Dr. Efrat Monsenigo-Ornan at Hebrew University Jerusalem has now looked at this and shown actually that ultra-processed food inhibits growth.

It inhibits skeletal bone growth, it inhibits trabecular bone growth, it inhibits long bone growth, it actually reduces calcium in cortical bone. It changes epiphyseal function. Okay, so it is inhibiting growth and we also know it hijacks growth for cancer, you know, because it basically, fructose in particular does not need to be burned in the mitochondria, right?

I see. So it sounds like you're saying there's an inhibition of natural or good growth and there's actually, it's actually stimulating pathological forms of growth.

Correct. How about burning? Mitochondria burn, right? Fructose, which is in all virtually all ultra processed food. I mean, you know, it's been added to 73% of the items in the American grocery store on purpose. Okay. It inhibits three separate enzymes necessary for mitochondria to do their job.

It inhibits AMP kinase, which is the enzyme that drives mitochondrial biogenesis. So you get make more mitochondria and fresher mitochondria. It inhibits ACAD-L , which is necessary to cleave the two carbon fragments to engage in beta-oxidation in the mitochondria so that you can burn in the first place.

And finally, it inhibits CPT-1A , which is the enzyme which regenerates carnitine. The carnitine is the shuttle mechanism by which the fatty acids get from outside the mitochondria to inside the mitochondria. So basically, you can't even import the fatty acids. To Burn. So, ultra-processed food does not contribute to growth and does not contribute to burning.

So, is ultra-processed food food? Is Cheetos food? I knew what I was asking when I asked it. Bottom line is we think it's food because it has calories. Can you name something else that has calories that's not food? Alcohol. Alcohol is not food.

There's no dietician on the planet who will say that alcohol is food, but alcohol's got calories. It's got seven calories per gram. How about trans fats? Trans fats are nine calories per gram. Are trans fats food? Trans fats used to be food. And in 2013, the FDA said, no, actually they're poison.

So just because something has calories doesn't make it food.

and that's the key that's that's what we have to impress upon the population and that's a different message than they have been getting for the last 50 years so you know i originally wanted to ask you about obesogens and in my mind i had food and non-food obesogens but it sounds like the way you would frame it is actually none of them are foods really we there's just some that we normally think of as foods and then the ones that we already don't think of as foods that's right

So these are all, you would just call all of these obesogens or contaminants or even poisons.

Absolutely. They happen to be in our food, but that doesn't make them food. That's exactly right. So then let's go back to the question you asked me at the beginning that started this diatribe. Fruit. What about fruit? Because fruit has fruit sugar, fruit has fructose. So is it not food? The answer is no.

Fruit is okay and the reason it's okay is because not only does it have the poison But it also has the antidote, which is the fiber. The antidote is the fiber.

No, I fully recognize this and I accept the argument here. I think it makes sense for a healthy person. But let's say you're talking about someone with type 2 diabetes whose goal should be to reverse that. My inclination would be to say, why don't you just cut out all of the fruit?

So yes, the fiber will prevent you from absorbing it as quickly. But wouldn't a better strategy be to just cut it out completely until you reverse the diabetes? I agree with that.

If you have type 2 diabetes, almost assuredly you also have fatty liver disease. The correlation between fatty liver disease and type 2 diabetes is extremely tight. It's almost for sure that the reason for your diabetes is because your liver is not working right.

And because your liver is not working right, your pancreas had to make extra insulin to make your liver work right. And now your pancreas is burned out. And so you got to give your pancreas a chance to regenerate and work properly. And the only way to do that is to make your liver work properly.

So you got to burn off that liver fat. You got to get rid of that liver fat in order to fix the problem. And ketogenic diet will do that. And the reason is because the LDLs that the liver makes out of your dietary fat don't get clogged. Only the VLDL that comes from sugar gets clogged.

The LDLs get exported right out. The VLDLs sometimes don't. So if you're clearing LDL and you're not making VLDL, Your liver has a chance to be able to heal itself. And so that to me is where it starts.

So if you have type two diabetes and you have fatty liver disease, which if you don't know it, I'm telling you, odds are you do. Best thing to do is give your liver a rest. And the best way to give your liver a rest is don't challenge it. And fructose is a primary challenge.

And so if you're asking me, if you have type two diabetes already, best not to eat fruit until the diabetes is resolved. And then you can probably add it back in reasonable amounts.

What are some other, so the caveat of everything we just talked about with the definition of food, I want to talk about non-food obesogens. You mentioned some earlier. What are one, two big examples, things that are all over the place that people are using commonly? And what do we know about the mechanisms here?

Well, there are a lot. There are a lot of obesogens. There are a lot of mechanisms. Bottom line is they're all around us. And for the most part, we put them there. They're all For the most part, part of our Anthropocene. They're part of the man-made environment that we have created for ourselves.

They can act through multiple different pathways. There are multiple receptors in the body.

that can transduce these obesogen signals but they're all basically receptor mediated signals so it can be the estrogen receptor it can be the androgen receptor it can be the glucocorticoid receptor it can be the aryl hydrocarbon receptor it can be la lxr or fxr in the in the liver okay it can be the ppr gamma receptor there are a bunch of different

compounds and there are a bunch of different receptors all of those receptors that i just listed all are part of the evolutionary process of a fat cell they will create at a oh i've got thyroid hormone receptor that's in there too um they will create adiposity when stimulated and so different obesogens will stimulate different receptors so the aryl hydrocarbon receptor

grilling your food will activate the aryl hydrocarbon receptor so remember i said i love barbecue well you want to get rid of that you might have to get rid of the barbecue well that's a problem what is it about the barbecue is it is it the like the charred the chart yeah the charred part yes so i don't know how to make barbecue without charring it's part of the part of the process

Unfortunately, that's one of the reasons why everybody says eat raw too. Number one, the fiber is still there and you haven't created any of these dietary advanced glycation end products. That's another thing that drives this phenomenon.

So the glycation that we talked about before the Maillard reaction, it can occur in the body or can occur in the can before you even eat it. If it occurs in the body, it generates the reactive oxygen species directly.

If it occurs in the can before you eat it, then what happens is that dietary advanced glycation end product will bind to a receptor for advanced glycation end products on your cells called RAGE, R-A-G-E, receptor for advanced glycation end products and activate the NADPH oxidase generating reactive oxygen species also.

So they're everywhere, including in the canned or packaged foods to start with. If the food's been heated before you got it, there's a good chance there are dietary AGEs in the food before you even put it in your mouth. Air pollution, as I mentioned, is an inflammatory reactant which has been shown to increase adiposity.

and that has nothing to do with calories. It has to do with the air. PM 2.5, particulate matter at 2.5 microns or smaller so that it gets into your bloodstream and drives an inflammatory response. BPA, Bisphenol A, which activates the estrogen receptor because the estrogen receptor just needs two hydroxyl groups 22 angstroms apart and you're an estrogen.

So, you know, there are a lot of estrogens in our environment.

and BPA is everywhere if you've ever opened up a can and there's a whitish lining to it that's BPA so it just it just happens to be the estrogen receptor has a structure that is sensitive to things uh that many uh components of modernity are made out of yes exactly exactly um

Years ago, many, many, many, many years ago, I was taking care of a kid in Wisconsin, a five-year-old girl with breast development. So everybody thought she had precocious puberty. And we looked at her, we assessed her, we did every exam, every lab test under the sun, and everything came back negative.

And then I sent her urine for a tox screen, thinking maybe she was getting into mom's birth control pills, but mom swore she didn't have any birth control pills. So where would she be getting them from? But I sent the urine for the tox screen anyway. And what came back was genistein. What is genistein?

Genistein is a plant estrogen. It's plant estrogen. And that was what was driving her breast development. Where does that come from? So I asked the mom, I said, you've already told me about her diet. What do you bathe her in?

She looked at it, she was on the phone at home and she said, well, I use this Victoria's Secret bath gel. And I said, what are the ingredients? And then she looked at it. She says, not for use in children.

And the reason is because the reason it's Victoria's Secret Bath Gel is because it's loaded with plant estrogens to make your skin silky smooth. So this kid was absorbing the estrogen through her skin from her bath.

Got it? Her mom was inadvertently giving her a sex hormone therapy.

Yeah. Without knowing it. So environmental estrogen can also be an environmental obesogen because after all, estrogen lays down subcutaneous fat as an example. Parabens, things that are in cosmetics like lipstick. and Hair Care Products. Tributal Tin is what they use to paint the bottoms of boats to keep the barnacles from attaching to the hull.

Okay, so all our water supply is filled with tributyltin and my colleague, Dr. Bruce Blumberg at University of California, Irvine has shown that this particular compound is so egregious and also has epigenetic effects going forward.

So you can expose an animal to tributyl-10 and their great, great, great grandchild will be obese because of what you did to the great, great grandmother.

If we're using it on boats, is it in the tap water?

Yeah, it's in the tap water.

and we're in the tap water at you know levels that are that concern us yeah yes absolutely so you know you're never going to get away from these pfas you know polyfluorylated alkylated substances you know the whole teflon thing if anybody wants to watch the movie dark waters came out in 2019 with mark ruffalo it's all about um dupont and how they hid the teflon story from you know the the from the populace for 20 years

Okay, you know, this is, this is, and these are forever chemicals, they are not going away. Another example, DDT. So DDT is a plant, sorry, is an insect estrogen. Okay, it is an insecticide.

Okay, it's what we've sprayed on all of the crops during World War Two, you know, to basically get rid of the, you know, insects, malaria and what have you. Okay, but turns out DDT

is a an estrogen you know two hydroxyl groups 22 angstroms apart that's why it was a good insecticide you know it was basically contraceptive you know for the insects but we can measure dde levels in in pregnant women's urine today and it predicts obesity in the child at age five okay it's been gone for 50 years but we can still measure it

So, given everything that you're telling us, the question is simply going to be, how does an ordinary person react to learning all of these things? And I can think of a number of reactions, but none of them seems particularly palatable.

Reaction one could just be you become Ted Kaczynski and you move to a shack in Montana and try to destroy civilization. Let's assume we don't want to go down that path. Reaction 2 could just be to say, fuck it, whatever, I don't care, this is what we live in, and that's basically what people do.

Reaction 3 could be to just become completely neurotic about all this stuff and become an uber health nut, for lack of a better term. Most people probably aren't willing to do that, don't want to have the anxiety and the stress that come with that as well. Is there another path? What is the path?

Yeah, so Nick, you're absolutely right and you've identified three of the four paths. There's a fourth.

okay so you're no question we've got people who you know are lunatics in part because of you know what society has wrought upon them we have the people who have basically chosen to ignore it because it's just too hard that's a lot most of the population i would say uh we have orthorectics you know who basically now you know

Question every single thing they put in their mouth and are dysfunctional because of it. It basically feeds into OCD to make them very miserable. Or there's a fourth, which is actually do something about it. Number one, vote.

you know this is a voting issue this whole obesity thing the whole food thing the whole environment thing is a voting issue now a lot of people think that there are other reasons to vote but this is one of them and you you know you should you should actually you know want to do something about this another is explain this to your doctor because your doctor doesn't understand any of this

and they need to and the reason is because doctors went to medical school to learn two things the two p's prescriptions and procedures and i know because i'm one and i that's what i learned there's a third p prevention does doctors learn prevention Not currently. And why is that?

Because 80% of the medical school costs are underwritten by Big Pharma.

So I'm going to put this in a way that isn't going to seem defeatist. So let's take those in reverse order.

So I like the idea of talking to your doctor about these things, but how does an ordinary person talk to their doctor about these things in a way that doesn't make their doctor just roll their eyes and say, who are you to lecture me?

I went to medical school okay so yes but no I mean it's true okay some doctors are very uh provincial and some doctors are very um uh paternal

and i know a lot of them and you know a lot of them live in the ivory tower you know where i used to practice as well so i know what i know what i know from whence that question comes and i and i and i you know identify with it to a great extent having said that no doctor actually wants to do harm okay you have to basically show them how what they're doing is doing harm the easiest way to do that

is to show up at your doctor's office 50 pounds lighter, having not taken their advice. And then when the doctor says, well, what'd you do? And then the patient says, well, I actually got the carbohydrate out of my diet. I actually changed what I had in my pantry. And you know, this is where we are.

And then the doctor says, really? That's what happened. So they need to see the results. You can't explain this to them. You have to show it to them. Let me give you another example. I am working right now with a food company. I take no money from them, but a food company offshore in the Middle East.

This company is the Nestle of the Middle East. They make all sorts of problem foods. They make flavored milks, frozen yogurt, ice cream, confectionery, tomato sauce, biscuits, okay? Like all ultra processed food to the highest degree, all bad stuff. And their CEO at age 48 weighed 350 pounds and had type two diabetes and back pain.

And he went to his UK physicians and they put him on insulin and oral hypoglycemics and he got worse.

and he said this is not working and so what'd he do he went to Dr. Google and he started researching it for himself and he found two people online he found Jason Fung who is a nephrologist in Toronto who is a great believer in intermittent fasting and has written several books the obesity code the diabetes code if it's a code the cancer code if it's a code it's his okay that's his code and me and so

CEO started doing what we said to do and lo and behold in nine months he dropped 100 pounds his type 2 diabetes resolved his back pain disappeared and he thinks we hung the moon okay great and then he has his aha moment his moment of epiphany where he said wait a second if i did this to myself eat my own crap what am i doing to the rest of the middle east

And so they came to me four years ago, this company, and they said, we want to move into the 21st century. We want to be a metabolically healthy company. We want to change the food to contribute to the health of our population, not hurt it. Wow. How cool is that? And we've been doing that.

And we actually published a paper last year in March of 2023 in Frontiers in Nutrition called The Metabolic Matrix, Reengineering Ultra Processed Food to Protect the Liver, Feed the Gut, and Support the Brain. And it turns out any food, if it does all three of those things, protects the liver, feeds the gut, supports the brain, is healthy.

Any food that does none of the three is poison. And any food that does one or two but not all three, it's going to be somewhere in the middle.

And so you can actually set precepts and you can set protocols for being able to actually determine what needs to be done and what needs to be in ultra-processed food to actually make them healthy. Now, can people do that at home? And the answer is absolutely yes, they can. Okay, well, they need some education.

They needed tools to be able to help them do that. And we have developed one just for them. Okay, and for your audience, it's called Perfect, P-E-R-F-A-C-T. It is a recommendation engine. It is not AI, very specifically not AI, because in nutrition, you know, the AI only knows what the internet knows.

And when it comes to nutrition, the internet is replete with garbage. You don't want AI to be making your decisions for you, but you want a scientist who actually knows something about metabolic health to be making your decisions for you. So go to http://perfact.co and you will find a Recommendation Engine.

And what you do is you click on it and it will show you all of the items at Walmart, Amazon, and Target, all the food items. And you can apply different filters, like for instance, no added sugar filter, or a keto filter, or a peanut allergy filter, or a oxalate filter, or no ultra-processed food filter.

And so it will only show you that which you can buy to make yourself metabolically healthy so that the store becomes a store instead of an obstacle course.

We talked about these four different reactions that people can have to the whole obesogenic situation that we are embedded in. The second one that we talked about was the one that just says, fuck it, this is what we have. That's probably where most people are.

I want to ask you about how difficult it's actually going to be to get people out of that given the The Unholy Alliance Between Different Factions in Our Society You've got the big food, big ag side, which makes the voting thing difficult because everyone we vote for is completely plugged into all of these special interests.

And then you've got, I think, both sides of that equation there promoting things like the so-called body positivity movement, saying, hey, this is the way we are and you should love yourself the way you are and therefore you can just keep consuming all of these things.

How do we break the sort of alliance of forces there that seems quite strong?

Nick, I couldn't agree with you more. There are many stakeholders in this and they all have their own angle. Agreed. And you can't fix those until you give them a better answer. It's like the Arab-Israeli conflict. Too many stakeholders, too difficult to come up with a single answer that helps everybody. But you know what?

There actually is a way. There is a way to do this.

and it it it requires everyone coming to the table at once and that's what i'm trying to do that's actually you know part of why i do what i do is trying to bring the doctors and the nutritionists the dietitians and public health and the food industry and politicians

you know and and the public you know to the table all at the same time but you have to be working off the same set of facts and as you've learned as we've learned you know people have their own facts whether they're right or not is a different story and that's one of the reasons why I'm happy to do this podcast with you now is to try to deliver you know the shall we say the truth somebody will say no that's Lustig's truth but you know I can document everything I say

so um nonetheless um how do you do this here's how i think about this problem and i you know am welcome to you know suggestions in the last 30 years we have had four count them four cultural tectonic shifts in america okay And here they are. Number one, bicycle helmets and seatbelts. Number two, smoking in public places.

Number three, drunk driving. Number four, condoms and bathrooms. Now, 30 years ago, If a legislator stood up in a state house or in Congress or in Parliament or the Duma or anywhere else in the world and proposed any legislation for any one of those four, they'd have gotten laughed right out at him.

Nanny state, liberty interest, get out of my kitchen, get out of my bathroom, get out of my car. Okay. Now, None of those are problems today. We have solved every one of those four. Okay, you don't hear anybody bellyaching about those. Oh, you hear about other bellyaching.

I mean, vaccines, perfect example of, you know, how, you know, new things have come into this, quote, nanny state issue. Okay, but the bottom line is those four are solved. Now, how did we solve them? We taught the children. The children grew up and they voted. Remember voting? And the naysayers are dead.

That's why this is a generational shift. But that's also why it takes 30 years. Now, the good news about this is we're about 10 years in. All this started around 2013. We already see signs of it working. We already see documentation of the public being educated. And I can actually prove that the public is being educated.

The food industry actually generated the data for me. There's a public relations arm of the food industry called IFIC, International Food Information Council. It is just a PR arm of the food industry, but they publish a report every year and every year they ask the public a question.

And in 2011, they asked the public the following question, what food stuff is most likely to cause weight gain? And in 2011, 11% of the population said refined carbohydrate and sugar, and 42% said a calories a calorie or I don't know. They asked the exact same question seven years later in 2018, the exact same way, no change.

And now 33% of the public said refined carbohydrate and sugar, and the exact same number reduced from a calories a calorie or I don't know. In other words, we taught those people the real story. So you can do it, but it's a generational shift because there are a lot of people who will never get it.

And I've given up on trying to get those people to get it. I got to get the people who are receptive to be able to get it because they'll live longer.

because they did the right thing and then we'll actually see the change i have no qualms about the fact that this problem is going to outlive me you know i'm just a cog in this wheel this is going to go way past my lifetime But the fact of the matter is you got to do something.

Yeah. I mean, the piece about this that I think I like the best is whether we like it or not, these things are generational. They do take generational periods of time to change. And that means no matter what your position is, an effective strategy probably has to involve educating the young. That's right.

And that's what we're trying to do. I am the chief science officer and co-founder of a nonprofit here in the Bay Area called Eat Real. So you can find that at eatreal.org. And our function is to get real food into K-12 around the country. Okay? All these public schools right now, they don't even have food preparation facilities.

They were taken out. Back in the late 70s, early 80s, they were taken out because The food industry started supplying all of these schools with ultra-processed food, calling it, quote, nutritious, unquote. And I put that in air quotes for very specific reasons, okay, because it wasn't nutritious. It was calories, but it wasn't nutritious because it wasn't food.

and that's when the grades started going down and that's when the obesity start you know pandemic started you know rearing its ugly head and you know it's only gotten worse and if you go to any standard school in America today it's a disaster so I have a question for you I have a quiz for you Nick what is the largest fast food franchise in America I mean my guess would be McDonald's our nation's public schools oh

If you add up McDonald's and Burger King and Wendy's and Subway, that is only half of our nation's public schools. Jesus. Okay? And every school in America uses ultra-processed food to feed their kids. And the reason is because they don't have any place to make food.

Because all of the food preparation facilities and all the blue herds, you know, with the hairnets and stuff, you know, that they used to make the food, they're all fired and gone. So the question is, how can you get real food into schools today when there's no infrastructure to support it? Well, that's our genius.

That's what Eat Real does. So we have multiple different paradigms. We have multiple different ways to do it, depending on the district, depending on the infrastructure that's there, depending on the geographics, depending on the food procurement availability. So there's not one way to do it, but let me give you our first way, the way we started.

We worked with the Mount Diablo Unified School District right across the bay in Otracosta County over in east of San Francisco. And they had an enterprising food services director. And what we did was we helped him purchase a dilapidated factory, which he then repurposed into a food preparation facility, hired all the people to work at that facility.

They would create 27,000 meals per day.

and because they were making so much food and they were able to buy at scale and they were able to buy local and they knew what was in the food so they were able to keep all the bad stuff out of the food and then they would use trucks to basically ship it to all of the different schools each day

And so we got every kid not just a hot meal, but a truly nutritious meal, a metabolically healthy meal. We lost 100,000 pounds of sugar out of the kids' diets in one year. And guess what? Their grades got better.

and the kids ate the food and you know we're not going to have time to get into yeah we're not going to have time to get into this but do you think that the grade's getting better part do you think that's basically because um a better diet is literally going to help your brain function better better mitochondrial function absolutely duh this ain't rocket science

I want to shift gears a little bit and I want to ask you about something that is very striking. Other people have pointed this out. I mostly don't hear good answers to this and I think it might sort of tie back to things that we talked about earlier but didn't necessarily explicitly put together.

So before I ask the question, this paper on obesogens you put out recently, it basically goes through the four main models of obesity that scientists and the thinkers on this stuff have used to explain obesity in the past.

And you basically come to the conclusion, if I read you right, that the model that you like is an integration of the obesogens model and the oxidation reduction model. So contaminants and stuff causing oxidative stress in the body.

Right. So this paper that you're referring to, which is in the International Journal of Obesity, January of 2024, first author for those who want to look it up is Heindel, Jerry Heindel. So this is a conglomeration of four authors, Jerry Heindel, who used to run the Endocrine Disruptors section of the National Institute of Environmental Health Sciences.

myself i'm the second author sarah howard who runs heeds healthy eating and endocrine disruptors and finally barbara corkey who is the banting professor uh venting award winner sorry at the uh at boston university school of medicine who's done more on hyperinsulinemia than anybody else and we published this paper called obesogens a unifying hypothesis on the pathogenesis of obesity

That sounds a little too, shall we say, full of ourselves, but nonetheless, we think we've gotten there. So the standard model that everyone believes, which I hope I've already debunked just from doing this podcast, is the calories in, calories out model or the energy balance model. If you eat more than you burn, you'll gain weight.

If you eat less than you burn, you'll lose weight.

Yeah. And I should just emphasize to people, even like I I did my PhD in Neurobiology in the Department of Endocrinology, Diabetes and Metabolism at Harvard Medical School. And even people studying the neurobiology of people with fancy degrees doing fancy experiments, we would often just default to the energy balance model without even thinking about it.

Absolutely. And I know that. And I cannot tell you how many arguments that I have had over my career with really smart scientists. who basically just say, yeah, but a calorie is a calorie. Yeah, but it's calories in, calories out.

Okay, I can document who in my career have basically thwarted this notion that there might be something else going on. So this is well thought out.

you know ensconced you know it's calcified in the minds of most of the uh intelligentsia and the fact that it occurred in the division of endocrinology at harvard medical school is no surprise and you know i won't call out your your your bosses but i know who they are anyway bottom line if the energy balance model is right then how do you explain obesogens

If the energy balance model is right, then how do you explain obese newborns? If the energy balance model is right, how come body temperature has gone down 1.5 degrees centigrade over the last 150 years? If the energy balance model is right, why are animals in captivity gaining weight over the last 25 years.

All of those say that the energy balance model is bullshit. Plain and simple. Now, there is no question that calories play a role. But just because calories play a role does not mean the energy balance model is correct. And I will give you four reasons right now that the energy balance model is bullshit. Okay.

Let's start with fiber. You like almonds? Yeah. I love almonds. Almonds are great. Okay. Except for they take a lot of water. Okay. But you eat 160 calories in almonds. How many of those calories do you absorb? 130. You ate 160, you absorbed 130. Where'd the other 30 go?

The fiber in the almonds, the soluble and insoluble fiber formed a gel on the inside of the intestine, an impenetrable secondary barrier. So the insoluble fiber acted like a fishnet The soluble fiber plugged the holes in the fishnet. And you can actually see the whitish gel on the inside of the intestinal lumen on electron microscopy.

And so what's happening is that it's preventing those 30 calories from being absorbed early. And so they go down the intestine where the microbiome is, and then they get chewed up by the microbiome for its own purposes. So even though you consumed it, even though it passed your lips, you actually didn't get it because your microbiome did.

We always tell pregnant women, you're eating for two. Well, we're always eating for a hundred trillion because we have to feed our microbiome. They end up consuming 25 to 30% of all the calories that we eat.

Well, if they consume 25%, but if you can change the microbiome so that they consume 30% of what we eat, you've just gotten thin. just by changing the microbiome from 25% to 30% without changing anything that passed your lips. So this calories in thing is just bullshit from the beginning, has been forever. Number two, protein.

So if you are using an amino acid to build muscle or build anything in the body, then the amino acid goes straight there. Okay, fine. If you're using the amino acid to turn into energy,

you have to take the amino group off okay because you can't burn an amino acid you can burn an organic acid but you can't burn an amino acid so you have to deamidate the amino acid you have to take the amino the nh2 group off the amino acid right that ends up costing more energy

then say phosphorylating a carbohydrate getting it ready for absorption so there's a net loss in burning protein for energy than there is in burning carbohydrate for energy even though they're both four calories per gram so a calorie is not a calorie because if you're burning an amino acid versus burning a carbohydrate you're losing energy there's a net loss so calories not a calorie

Number three, fatty acids. We've already talked about this. We have, you know, omega-3s over here, heart healthy, save your life, anti-Alzheimer's, anti-inflammatory, best thing you can put in your body. And over here we have trans fats, you know, devil incarnate, you know, consumable poison. It will kill you. They're both nine calories per gram.

One will save your life, one will kill you because a calorie is not a calorie. And finally, fructose and glucose, and we've already done that one. Okay, fructose makes adiposity because of the three things it does, the de novo lipogenesis, the Maillard reaction and the activation of the reward center.

Glucose doesn't, but they're both four calories per gram. So calories in calories out never made sense. In addition, I did work that basically showed this to me back in the 90s. I took care of these kids at St. Jude Children's Research Hospital in Memphis, Tennessee that became massively obese after their brain tumor.

So this is a form of obesity called hypothalamic obesity because your hypothalamus is damaged. And these kids gained weight like crazy. As soon as the tumor was diagnosed and treated, they started gaining weight at a kilo a month nonstop ad infinitum.

Now, George Bray, the father of obesity research in America at UCLA Harbor years, years earlier, 1975, took eight of these kids, admitted them to his clinical research unit at UCLA Harbor, Locked them up, threw away the key, and fed them 500 calories a day for a month. What do you think their weight did, Nick? Went up.

How do you gain weight on 500 calories a day?

Well, if you're basically, if we're talking about an obesogenic, if they're very obesogenic calories, then that would be the answer.

It's because these kids made enormous amounts of insulin. These kids would rather store it than burn it. These kids had catecholamine levels at zero in their urine because their sympathetic nervous system was in absolute zero default mode. And their insulin was driving everything they ate into fat. And the reason was because Their fat made leptin.

We didn't know about leptin back then, but their fat made leptin, but the leptin didn't work at the level of the brain. The brains thought they were starving because those neurons were dead.

I see.

So the satiety signal wasn't getting through. The satiety signal and the energy sufficiency signal wasn't getting through. And therefore, these kids released enormous amounts of insulin to try to store more energy to get an energy signal through. But it would never go through because those neurons were dead from the tumor or the surgery or the radiation.

So it was up to me to figure out what to do to help these kids. Now I knew from my neuroendocrine training that there was a connection between the hypothalamus and the pancreas that ran through the dorsal motor nucleus of the vagus nerve. So I knew that there was a vagal output that was driving that insulin.

And you could show that in animals very easily. And if you cut the vagus nerve, the animal stopped gaining weight, even though they had a hypothalamic lesion. So I said, well, I can't cut a vagus nerve. I'm not a surgeon, but can I do something as good? Can I give them a drug that will suppress insulin release?

So we did a pilot trial. In these kids, eight kids, where we gave them a drug that suppressed insulin release called octreotide. And lo and behold, they lost weight. And most importantly, not only did they lose weight, but they started exercising spontaneously.

And how obese were they? Were they extremely obese?

300, 400 pounds. Oh, wow. And they lost weight just as fast as they were gaining it.

and they would say things like this is the first time my head hasn't been in the cloud since the tumor and the parents would say I've got my kid back because these were kids who sat on the couch ate Doritos and slept they chose not to engage with society because they felt like crap because they had no energy to burn and now because we blocked their insulin they did have energy to burn

One kid became a competitive swimmer. Two kids started lifting weights at home. One kid became the manager of his high school basketball team, running around collecting all the basketballs. These are kids who were lumps on a log. We changed their behavior because we changed their biochemistry.

We got the insulin down and they started losing weight and they started burning energy faster.

And so I guess the wider lesson there is, you know, these are kids who had, you know, tumors and, you know, it required a physician to come in and fix the problem, which is to get the insulin lower. But for everyone else, our insulin is often high because of our diet and we can take changes that...

Thank you. Thank you. Exactly right. So, you know, people say, well, you know, that was great for these kids, but what are you going to do about everybody else? Well, everyone else has super high insulin. Our insulin levels are two to four times higher than they were 50 years ago. And it's because of our diet.

So if you fix our diet, you get the insulin down and now you have it to burn.

and that's why body temperature's gone down is because our insulin is high because if you're storing it then you're not burning it and therefore your body temperature goes down so the second model is the carbohydrate insulin model okay carbohydrate drives insulin insulin drives weight gain irrespective of total calories

So the energy balance model and the carbohydrate insulin model, they've been fighting it out. And by the way, they've been fighting it out right at Harvard Medical School. And I used to be a proponent of the carbohydrate insulin model. I was on that train as well.

And the reason was because of this work I had done with the kids, because I knew that the insulin was the driver. But you know what? That model doesn't explain the epigenetics. It doesn't explain the obese newborn. It doesn't explain the things that change in utero. So there was still something else that needed to be added.

And so this paper that I have referred to, the Heindel paper, what we've done is we've assembled all of the models that currently exist. The energy balance model, the carbohydrate and insulin model, another model, a third model, which is very important, called the redox model. So oxidation reduction, so reactive oxygen species.

So every cell has an energy pathway, has to, because you got to make ATP. Every cell has enzymes that regulate that energy pathway. And every energy pathway checkpoint is a kinase. In other words, it has to be phosphorylated.

And so it is subject to reactive oxygen species and it is also subject to pH to determine whether or not those kinases are phosphorylated to direct energy one direction or direct energy in another direction.

It turns out when you look at the data that's in the literature, when cells become depleted of energy, the kinases change in order to re-replete energy.

and if you all if you block that then it doesn't happen so those and those are intracellular so it has nothing to do with hormones it has to do with what's happening inside each cell but it turns out that all the different organs have different responses so the brain has a different response that causes

more food intake and more insulin release the liver has a response that causes more de novo lipogenesis more fat making okay the pancreas has one that releases more insulin so all of the different phenomena that occur in each of the different organs are all lined up to promote adiposity together or not or the opposite or to burn the energy and not eat together so it looks like the behaviors

are all conglomerated the gluttony and the sloth are conglomerated together but they're actually all because of changes in cellular physiology that are occurring simultaneously due to the changes in these biochemical checkpoints which are subject to reactive oxygen species and as long as the reactive oxygen species stay low

you can burn when they start getting high that tells the cell it's got a store because it can't handle it so it actually makes physiologic and teleologic sense that this would be a control point and then the obesogen model is the fourth model and it turns out that Almost all the obesogens generate reactive oxygen species.

So that's why those two fit together so well. They fit together very well. And so they so the the the redox obesogen together model

actually explain both the carbohydrate insulin model because it's driving the insulin and it also explains the energy balance model too because of the eating and burning so in fact it's really a unifying hypothesis that brings all the models together but it actually identifies the ROSs as the thing to target and so now the question is can we set up a research experiment to answer that question and we're in the process of doing that now

I want to, in just the few minutes that we have left, I want to ask you about a striking relationship that I've heard people attempt to explain, but I'm wondering if you have a better explanation that might involve things like reactive oxygen species, mitochondria, and obesogens.

And that is the striking correlation, at least in the continental US, between geography and in particular altitude and obesity rates. Everyone looks at Colorado, which I believe has the lowest obesity rates or among the lowest. And typically the default answer there is

Well, you know, people move to Colorado because they love the outdoors and they go hiking a lot.

Yep.

What's going on?

Right. So everybody thinks Colorado is less obese because they have a great lifestyle. Garbage. Colorado is less obese because it's cold and high. And every place that's cold and high has less obesity. The heat map on altitude and obesity are virtually identical. Another example is Switzerland versus Germany.

Same, you know, sauce-laden food, you know, you know, what is it, , you know. Bottom line, Germany's obese and Switzerland's not. It's not because of skiing, it's because of altitude, okay, because Switzerland's high and Germany's not. So what's happening?

Well, because you are in a rarefied atmosphere, because you are mildly hypoxic, you have to push your mitochondria harder to generate more ATP.

because the oxygen tension is lower so you need more mitochondria so in the same way exercise generates mitochondria which is true it does and i'm not saying exercise is bad it's good okay altitude generates mitochondria and exercise on altitude well that's great you know then then you're an alpine skier Okay, and that's fine.

Okay, but for the rest of us mere mortals, okay, altitude basically does what exercise does in terms of generating increased mitochondrial capacity. And that's why Colorado is less obese. Also, because it's colder, so you have to generate more body heat. in the first place. So it's not that Colorado is not less obese. It is.

The question is, is the reason because of an active lifestyle? And the answer is no, it's not because of an active lifestyle. It's because of the geography, the altitude.

Another way of saying that would be you could transport someone from somewhere else, say Louisiana, into Colorado, change nothing about their lifestyle, nothing about their exercise or eating habits, and you would expect them to actually lose weight.

Yeah, exactly. You expect them to lose weight. This concept of hypoxia reducing energy utilization and actually contributing to longevity has actually been shown in animals. So if you actually expose animals to hypoxic regimens, like instead of 20% oxygen, 11% oxygen, they live three times longer.

This was work done by a colleague here at UCSF by the name of Isha Jain. You know, looking at the role of hypoxia and longevity. And the reason is because of reduction in reactive oxygen species formation. So, you know, it's all internally consistent. Ultimately, you got to make your mitochondria work better.

Yeah, so much of it comes down to the mitochondria.

I think knowing everything I know today, if I had to go back and go through school again and go through the academic science track, I think I would probably study something about mitochondria probably in the brain because I think that's just a fascinating area and an important one right now.

I couldn't agree more, Nick. I've become a self-taught mitochondriologist and it's hard, it's complex to be sure, but the data coming in from various directions and different places in science demonstrating that mitochondrial function is perhaps the

single most important nidus for understanding the diseases that ail us you know that this is really where the where the rubber hits the road i i refer you to a colleague at university of california san diego by the name of robert navio and a v i a u x and he has done enormous work on reactive oxygen species external atp to the cell and the inflammatory response and how mitochondria fit into all of that it's uh you know this is this is uh

We've just got a couple minutes left, so I'm going to do a very simple question that is very practical for people. So, health and nutrition and metabolism, it's sort of an inherently difficult area. I don't just mean the subject matter is complicated, but there's a lot of motivated reasoning.

There's a lot of conflicting opinions, even among credentialed experts. When you couple that to the proliferation of information that our technology has enabled, you can go watch a podcast with any number of people and there's going to be some level of mutually contradictory information out there.

When it comes to metabolic health and the science of that general area, who are two or three or four names for people that are out there that are on podcasts, on the internet, writing books or whatever that you think are mostly right or directionally that are worth following for people?

I think David Perlmutter, he's gotten a bad rap and I think it's totally undeserved. Neurologist who wrote Grain Brain, but is totally on board with this notion and mitochondria being sort of the at the, at the, you know, Focal Point of Cellular Physiology.

Rick Johnson, Richard Johnson at the University of Colorado is also, you know, totally on this and has written about fructose and Alzheimer's and he wrote a book called White Nature Wants Us to be Fat. And the last person that I would refer you to is Christopher Palmer right there at Harvard. He's at McLean.

He's a psychiatrist, and he is going to explode the field of metabolic psychiatry. There are other metabolic psychiatrists, Shabani Sethi at Stanford and Georgia Ede also at Harvard. So there are other people in that field too, but Christopher's just done the most. And he's the one who's shown that basically a ketogenic diet can reverse bipolar

because it is a biochemical problem, not a behavioral one. It's really quite remarkable when you see the data and when you hear the stories. It's so uplifting.

Anything else you want to reiterate for people that we talked about?

You can't fix a problem if you don't know what the problem is. We've gotten the problem wrong for the last 50 years because we were told it was fat. Thank you very much for your time. Oh, thank you for having me, Nick. Appreciate it.

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transcript  to 95 min podcast Drugs, Addiction & Neuroplasticity: Psychedelics, MDMA, Opioids, Cocaine, Amphetamine (Adderall), Nicotine, Marijuana & Alcohol | Robert Malenka | #162 

https://mindandmatter.substack.com/p/drugs-addiction-and-neuroplasticity 

Robert Malenka 2:32

Well, I'm a neuroscientist and a psychiatrist who has spent my career at institutions in the Bay Area at Stanford than a place called UCSF and back to Stanford, and my lab. Initially, I've had a lab for a long time for 35 years. My lab initially focused on a topic that we call synaptic plasticity, which is a catch all term that encompasses how synapses, the connections between nerve cells, how they change in response to experience. And that experience can be a form of learning and memory, that experience can be administration of a drug or the experience of a drug, a stressful event. And Most neuroscientists believe that part of the way we encode new Acts experiment we encode experiences and remember them and their impact on our brains, and therefore how our brains adapt to experiences and change our subsequent thoughts, feelings and behavior. Most of us believe that changes in the properties of synapses play a very critical, important role. So really, probably for the first 2025 years of my career, a lot of my work focused on how to these changes in synapses, in response to changes in the patterns of activity in the brain. How does that actually happen? Which proteins at the synapse, which receptors, and I apologize, I'm not sure, who's listening to this, I don't know if I need to define the terms such as receptors, but the proteins in the membranes of nerve cells that respond to chemical messengers that we call neurotransmitters, anyhow, how these changes in synapses actually happened at a pretty at a fairly molecular level. And then that led me to start doing work in the behavioral relevance of the of these various forms of synaptic plasticity. That is, I'm studying synapses and how they change in very reduced systems and I became very interested in Okay, If this is really important, I should be able to correlate these changes with behavioral changes in my favorite experimental species, which is a mouse, or mice. And then gradually, over the decades, while I continued to study the molecular mechanisms of synaptic plasticity, that led me into all sorts of different research topics, including how a neuromodulator, we call dopamine, how it works, what it does in the brain, studying changes in what we call the reward circuitry in the brain, which my guess is we're going to end up talking about in the next hour, hour and a half. That led me to studying another neuromodulator that goes by the name of serotonin, and some of its important functions in the same reward circuitry. And then finally, that led me to studying certain psychedelic drugs. But there was actually a natural progression of how I, my research led me from studying pretty molecular mechanisms to the behavioral effects of psychedelics, there's actually a thread throughout my scientific career.

Nick Jikomes 6:22

Interesting. Yeah. And hopefully we sort of trace that thread to some extent. And, and I think we will, when, when you were just getting started back in the early days of synaptic plasticity, and some of the early discoveries of the initial mechanisms that we discovered, when we think about things like NMDA receptors and long term potentiation. And we can we can briefly define those things, but but I've talked about them on the podcast before a lot of people listening will have some familiarity with those terms, when those things are being discovered the mechanism through NMDA receptors by which you know, this coincidence detection, synaptic strengthening happens. What was the thinking, like leading up to that, that people have a notion for how that would work? Or was it completely surprising what what was that initial sort of set of

Robert Malenka 7:06

discoveries like, it's a fun scientific story. So, you know, it sounds like here, listeners, and you certainly know that the major form of plasticity that I have studied and others in the field of study is called long term potentiation, or LTP, which is shorthand for long term potentiation of synaptic transmission. It's been studied primarily in a region of the brain called the hippocampus, which made a lot of sense, because we know the hippocampus is critical for the storage of memories, the storage of new information, it was also studied in the hippocampus, in terms of trying to understand the underlying mechanisms of LTP. We use the hippocampus because we could cut slices of it, and put them in a dish. And it offered a lot of experimental advantages. And so the big breakthroughs in LTP, were sort of a natural progression, that some of the basic properties were elucidated initially, in some classic papers by some European neuroscientist, and then a critical critical of observation was, as you alluded to the finding that NMDA receptors this subtype of receptor for the excitatory neurotransmitter glutamate, was critically required for the initiation or triggering of the biochemical events that lead to LTP. And what was really interesting about that discovery, and was a very simple experiment, just bath applying an NMDA receptor antagonist to a hippocampal slice. And the key finding there was that this antagonist to NMDA receptors blocked LTP, but it did not seem to affect what we call basal synaptic transmission or basal synaptic strength. And that was at the time, pretty bewildering. So how could a drug have this, you know, a blocker of NMDA receptors have this very clear effect and LTP but have no detectable effect on basal synaptic transmission. And that remained a mystery. It's been so long, I can't remember how many years it took. And then two different groups started studying NMDA receptors at a biophysical level. And they made the very important discovery and I hope this isn't too much scientific detail, that the NMDA receptor was a very unusual ligand gated ion channel that responds to the neurotransmitter glutamate because it was voltage dependent, that when glutamate bound to the NMDA receptor, when the cell was was just hanging out at what we call its resting membrane potential. The NMDA receptor didn't pass current and past very many ions. And it turns out that's due to the fact and again, this may be too much detail that a DI valence can ion called magnesium sits in the, the poor of the NMDA receptor. And it actually isn't quite true that no current or ions can flow in and out of the NMDA receptor channel, but it's pretty much blocked. But when the cell gets depolarized, gets activated by other synaptic inputs or for whatever reason, the magnesium is expelled out of the ion channel. And now when glutamate binds to the NMDA receptor, ions can flow currents are generated and the cell can respond, and most important, so there was a voltage dependence to the response of the NMDA receptor. And then the other key finding from two different groups was that unlike many other glutamate receptor channels, the NMDA receptor was permeable to calcium. So when the cell was depolarized, calcium and activated by glutamate, calcium could enter the cell. And so that, that those biophysical findings, let me just remember my history here were made in the 80s. And two different groups, the group I was involved in when I was a postdoc with Roger Nico, and a guy named Gary Lynch sort of looked at these papers, and realized, well, if what makes the NMDA receptor so special, is that calcium can enter through its ion channel, maybe Calcium is a critical trigger for LTP, but the calcium entering through the NMDA receptor. So then Gary Lynch's lab did an experiment, that very simple into, you know, in today's world, but back then it was a very clever experiment, I hope I'm remembering this correctly, where he recorded from individual hippocampal cells, and loaded the cells with a compound that sucks up the calcium, it's called a calcium key later and prevents the calcium from binding to other proteins and doing its magic. And if I'm remembering correctly, that blocks to LTP. And so that was, although the finding actually didn't get as much attention as maybe it should have. And then work I did with another postdoc, and Roger Nichols lab, Julie cowher, and Roger Nichols lab and this was worked on at UCSF, we showed not only that, we replicated that observation, that if we calculated the calcium by loading or the postsynaptic cell, from which we were recording synaptic responses, which are called IX, e PSPs, excitatory postsynaptic potentials, we could block the generation of LTP. And then very importantly, we showed if we use some very cool molecules that we could load into the cell, and they held on to the calcium but when we flashed a light, calcium was released in the cell, we showed that could cause an LTP, like if effect, so we had both necessity, meaning if we blocked the key later, the calcium prevented it from doing its thing, we blocked the generation of LTP back shows necessity, then we showed sufficiency by showing if we just released the calcium independent of activating NMDA receptors, when we could cause an LTP like effect, we could strengthen synaptic transmission. So that then, really, I think, opened up the field because now there was a very clear explanation for the initial triggering events of the LTP and why it required depolarization of the cell. And in the real brain, we think that happens by the coordinated activity of different inputs onto that sandwich starts act depolarize in the cell making it more excitable, so then when another synapse is activated, in a temporally coincident manner, the cells already depolarized the glutamate that is released from that synapse activates the NMDA receptor, because the cell is depolarize. Calcium can enter that specific cell naps trigger a cascade of biochemical events that lead to LTP. And so everything came together in a very beautiful scientific. I mean, it's how science should work. I mean, when it took, I mean, the truth is, I mean, LTP was first described, I hope I'm remembering this right? In 1973. And it really took 15 years till the late 80s. to elucidate what is really a relatively simple mechanism. It's a combination of the initial description of LTP, the discovery of NMDA receptors and their role in LTP, the description of their biophysical properties. And then labs, like the work I did in Roger Nichols lab with Julie Carr, and Gary, putting it all together and saying, testing the hypothesis, that LTP was triggered by depolarization activation of NMDA receptors and the entry of calcium. And then that led, if we're, you know, to all sorts of additional experiments before then you needed to know.

Nick Jikomes 16:09

I mean, it's, it's a, it's a fascinating story. And, you know, for those who don't know, like, the mechanism is sort of beautifully simple. It's probably one of the most beloved mechanisms in the brain that

Robert Malenka 16:21

books, it's now just standard textbook knowledge. But

Nick Jikomes 16:24

if we, so if I sort of reiterate some of what you said, we've got this sort of special receptor, this protein complex, the NMDA receptor, and it doesn't really pass much current through under normal baseline conditions. But if a cell becomes excited enough, because say, multiple neurons are simultaneously activating it, it can suddenly pass more current. And there's a couple of interesting ions involved here. On the one hand, you've got this magnesium, so like, when we when we eat magnesium in our food, some of this magnesium is being used to block this channel, so that nothing is really going through it. But then when the neuron becomes sufficiently excited, now calcium can go through it and get inside the cell. And calcium. You know, most people probably know calcium, when they think about, like, you know, their bones and their teeth. But it's important in neurons, it sounds like you're actually getting into the cell to trigger the things inside the cell that are necessary for strengthening the synapses. That's

Robert Malenka 17:16

exactly correct. Very well put, as we may get to, calcium can also decrease synaptic strength, and cause the opposite of LTP. So like everything, once you start delving into the details, the biological processes involved get more complicated and more flexible.

Nick Jikomes 17:40

And so long term potentiation. That's what we just described, that's at least one way that synapses can get stronger. Are there other? Is that the primary mechanism? Or are there like a whole bunch of ways you can shrink the synapse that work and strengthen

Robert Malenka 17:55

there? You know, it's a very good question, I have to go through the Rolodex in my head, it turns out that added some cells, including the hippocampal cells, that are the main source of of the scientific information we have about how synapses change, you can actually if you act depolarize, the cell repetitively with action potentials, you can probably load the cells with calcium via what are known as voltage dependent calcium channels, which is just another source of calcium, that when they are these calcium channels are repetitively activated to a sufficient degree, that can lead to the strengthening of synapses. Now, whether that actually ever happens in the awake behaving brain remains unclear. Let me just think, are there other example? Yeah, it turns out at certain synapses, there's a very different way of strengthening synaptic transmission. So what we just talked, and then I hope, we're going to talk about the weakening of synapses, which is, could be as important depending on the circuit in which those synapses are embedded, but at certain sets of synapses in the brain, which are embedded in certain circuits. In specific brain regions. There's a form of LTP that rather than being triggered by post synaptic activation of NMDA receptors is triggered presynaptically due to certain repetitive activation of the presynaptic terminals that release the glutamate. And, you know, historically that was first described that a set of synapses in the hippocampus called mossy fiber synapses. And so it's a very different form of synaptic strengthening, called mossy fiber LTP interestingly at all So involves the key triggering mechanism is the entry of very high amounts of calcium in the presynaptic terminal through these voltage dependent calcium channels. But I think most of us in the field believe it's NMDA receptor dependent LTP, which we were talking about previously, which is what I would call the prototypic form of LTP. And synaptic plasticity, it occurs at many different excitatory glutamatergic synapses throughout the mammalian brain.

Nick Jikomes 20:40

different brain regions, exactly.

Robert Malenka 20:42

This this other form I was describing, which is this presynaptic form of LTP, we call mossy fiber LTP. I mean, it's only so far, it's only been found at a few, a very small number of kind of specialized synaptic inputs in the hippocampus at the mossy fiber synapse, and at a certain synapse in a region of the brain called the cerebellum, which is important for motor movement for controlling motor movement. And maybe one or two others that I'm not just remembering at the moment. And then that beyond NMDA receptor dependent LTP, mossy fiber, I'm, I'm sure, when we're off this, I'll think of one or two others, but there's not a lot.

Nick Jikomes 21:32

So the sort of classic NMDA receptor LTP is a major, major way that's an emphasis or strengthened across.

Robert Malenka 21:40

Most neuroscientists would agree with that. Absolutely. You know, and that's why, at least historically, it's not a very popular topic, currently, now that we're in 2024. But in the 70s 80s, and 90s, it was a very popular topic to study that received a lot of attention.

Nick Jikomes 22:04

And so sort of the flip side of this is, as you've alluded to earlier, you know, you not only want to strengthen synapses in the brain, you want to weaken, and sometimes get rid of synapses in the brain. How does that happen? Okay,

Robert Malenka 22:16

so that that phenomenon is called, you know, I guess we're not neuroscientists are not that imaginative. It's called long term depression of synaptic transmission, or Ltd. And, you know, it's an interesting history, once LTP was described in the early 70s, you know, all neuroscientists started thinking, Well, you know, it might be advantageous for several different reasons to have the opposite phenomena. That is long term depression, some people argued, you don't want to have a permanent strengthening of synapses, you want to have a way of weakening them, perhaps that's a mechanism of forgetting, which I actually am not sure it is, I think it's more complicated than that. Other people just posited that circuits and circuits within the brain would have a lot more flexibility and power, if they could utilize the bi directional control of synaptic strength, that is, if synapses mediating information processing and this or that circuit, could both strengthen the synapse and weaken synapses. If you do simple minded computational modeling, the flexibility of how that circuit functions is enhanced enormously by having both LTP and LTD. So and the let me get my memory, right. You know, in the 70s, and 80s, there were, you know, there were papers published, reporting phenomenologically, various forms of Ltd, primarily in the hippocampus, but they never really gained traction, I think primarily because experimentally, they were a little bit ephemeral, they were hard to induce different labs couldn't maybe couldn't get the same reliable generation of Ltd. Whereas LTP once you know what you're doing, most people, even very novices in the field could generate LTP, relatively easy, let's say in a hippocampal slice. So then in the early 90s, a colleague of mine who's now at MIT Mark bear, developed a very simple protocol based on some theoretical work he had been involved in for inducing Ltd in the hippocampus at the same set of synapses, at which LTP had been studied for decades. And then Mark continued to study this form of Ltd and then I I noticed it, because he was a friend. And he told me about and I said, Hey, do you mind if I work on this? And so we started studying Ltd app in the hippocampus, as I said, at the same set of synapses. And very, because we knew how to study synaptic plasticity mechanistically, from all the years we had been studying LTP, we were it was very easy to very quickly elucidate some of the basic triggering mechanisms of this other form of plasticity synaptic plasticity. And interestingly, what we found is that Ltd and was NMDA receptor dependent just like LTP. But it required a different pattern of activity at the synapse. And the simple model we followed, which was actually first proposed by a neuroscientist named John lisman, at who was at Brandeis, Unfortunately, he passed away several years ago. And what John lisman had proposed in a theoretical paper is that LTP involves an NMDA receptor dependent increase in calcium in the postsynaptic cell, but it had to be a very large increase in calcium beyond some critical threshold, let's say the threshold was 10 micromolar, it had to be above that. And that perhaps, Ltd could be triggered if a much lower level of calcium was achieved via the NMDA receptor may be in the range, I'm making this up of one to two micromolar. So we actually test it that kind of thinking and hypothesis. And all of our results were consistent with it. And to be honest, I think it's now kind of dogma in the field, I believe it's in textbooks that there is a there is an NMDA receptor dependent Ltd, due to the increase in calcium in this narrow window, and then I don't know if we're going to talk about the biochemical cascades activated by calcium, but a certain set of enzyme calcium dependent enzymes are activated by a low level of calcium, that trigger Ltd. and then LTP NMDA receptor dependent LTP requires when I said a much higher level of threshold, and then that led to people looking for different forms of Ltd all over the brain. And there, there are probably many more forms of synaptic depression or Ltd, than there are forms of LT P. And why that is and how the nervous system and circuits in the brain utilize these different forms of synaptic plasticity is still an active area of research.

Nick Jikomes 28:05

So it sounds like there's a lot of ways to make synapses weaker. Yeah,

Robert Malenka 28:09

I know that I said that I have to now be I can I have to start going through the Rolodex in my head. And I think there are several Yes.

Nick Jikomes 28:18

So why do you think that might be? Why is it so important to weaken synapses? What have we done experiments where we prevent the brain from from doing Ltd? And does that impact learning?

Robert Malenka 28:31

A very good question. And I you know, I haven't worked on these phenomenon Oh, my God in a long time. Yeah, I mean, actually, I think the home one hallmark example, is in is in the cerebellum. There is a form of Ltd. That requires a god and I have to, it's been so long since I read these papers that involves two different inputs onto the major a major cell type in the cerebellum called the Purkinje cell. And if the timing of these two synaptic inputs is appropriate, there's a weakening of the synapse between a set of axon inputs called the parallel fibers. And then there has been quite a bit of work, proposing theoretically and then experimentally demonstrating that this form of Ltd seems to be required and involved in certain forms of cerebellar dependent behavioral plasticity. And so that's one example. I'm trying to think of other examples it's going to take me a while to but basically,

Nick Jikomes 29:47

there's multiple mechanisms of synaptic plasticity. Synapses can get stronger, they can get weaker. There's a number of ways each of those can happen. Calcium is critical for all of this calcium getting into neurons is super important. Pretty

Robert Malenka 29:59

much except there's another form of Ltd, which has gotten a lot of attention. And again, calcium is sort of always directly or indirectly involved. But this is a very interesting form that involves got, it gets a little complicated the release of these endogenous brain modulators called endocannabinoids. I don't know if we want to get into that. But this is the brain's natural marijuana or their its natural THC. And it turns out that at certain, in certain cells, and at certain synapses, strong repetitive postsynaptic act depolarization of cells are spiking of cells can in a calcium dependent way, so calcium is still involved, cause the release of these substances called endocannabinoids, that then leave the postsynaptic cell, and then attach to receptors on what we call the presynaptic terminals, and reduce the amount of glutamate or neurotransmitter that is released. That's called endocannabinoid mediated Ltd. And that scene, you know, that scene in the hippocampus, that scene in a part of the brain known as the basal ganglia, or the striatum. And there's, there's some evidence that it's important for certain types of behavioral phenomena are real plastic, really,

Nick Jikomes 31:37

I guess, I guess what the basic idea here be that you know, if a neuron is getting too much input, it's it sort of sends an endocannabinoid backwards to the cells talking to it and says, quiet down a little bit,

Robert Malenka 31:49

I think I think that's a nice way of putting it a very nice way. And again, you know, I think describing these synaptic plasticity phenomena has been very important. And people have studied them in many different brain regions in the hippocampus, initially in the cerebellum, in various cortical areas. A larger experimental challenge, you know, which people have been taking on and working on for decades, is how are these synaptic plasticity phenomena actually used in the intact, awake behaving brain to mediate all the wonderful plasticity that happens in you know, as we experience the world, or as our mice experience, the world and there you know, there's hundreds, if not 1000s of papers on this topic,

Nick Jikomes 32:48

is when we think about neuroplasticity, and the brain's ability to change itself in response to experience. Is that is it all about synaptic plasticity? Or are there other forms of plasticity that exist outside of the synapses changing? Um,

Robert Malenka 33:05

it's a very good question. And I think there are certainly other forms of plasticity. I think, most neuroscientist would agree that synaptic plasticity is a major contributor to neuroplasticity. I mean, the term neuroplasticity especially among laypeople, and especially among certain cadre of neuroscientists is used very loosely, because it basically means any change in the brain is a neuroplasticity phenomenon, anything so, but to answer your question, so, synaptic plasticity is certainly really important, but it is very likely that there are forms of plasticity that involve longer lasting changes in what we call the intrinsic excitability of cells. You know, cells have voltage dependent channels that generate action potentials are spiking in the cells. And there are there is evidence that again, in response to certain patterns of input activity, the cell can chant, you know, or in response to certain neuromodulators. The cell can change, its spiking behavior that is, for a given amount of input into the cell, it may spike more, it may spike less, and that could be a very powerful form of neuroplasticity. And then there's forms of plasticity neuroplasticity, which are probably connected to synaptic plasticity, where new synapses new connections can be formed. So that's structural plasticity and synapses. can be taken away, they can disappear. And then most of us in the field believe that these forms of structural plasticity, the formation of new synapses, the disappearance of existing synapses are probably to, to a large extent, triggered by LTP. And Ltd. So and there's actually experimental evidence pretty strongly to support that proposition. And let me just think, and then it sort of depends on how you define neuroplasticity, because there are long lasting changes in gene expression. And that's a form of neuroplasticity, what I have always pointed out, and I don't want to say argue just pointed out that when there are long lasting changes in transcriptional, regulation and epigenetic changes and transcriptional changes, they still have to in order to affect neural circuit function, neural activity, they still have to eventually influence something about the physiology of the circuits, they have to eventually change the spiking behavior of the cell, or, or how synaptic inputs are influencing that cell. Otherwise, they're not really having a myth. They're not influencing the functions of the brain. That is our thoughts, our feelings and behavior. So I hope I'm answering your question. So there are many different forms of neuroplasticity. And

Nick Jikomes 36:44

there's also this concept of meta plasticity that others have discussed, we might loop back to this when we talk about things like drug addiction and psychedelics, but what's meta plasticity as opposed to just plasticity?

Robert Malenka 36:56

You know, it's been so long meta plasticity is the plasticity of plasticity mechanisms.

Nick Jikomes 37:05

So, how easily a cell can use employ those mechanisms? Yeah,

Robert Malenka 37:10

I mean, so I have to remember. So it can be for example, you know, we talked about the triggering mechanisms for NMDA receptor dependent LTP. And Ltd. Meta plasticity would be in response to some experience, that the actual patterns of activity that trigger LTP and LTD had had have changed. So the mechanism LTP and LTD may still be the same, but the patterns of activity, because of changes in the circuit have changed. It also can be that the biochemical mechanisms triggering NMDA receptor dependent LTP and LTD have been modified over the course of days or weeks. So it's really the plasticity of plasticity. And it even can be that additional mechanisms, that before this behavioral experience, that triggered LTP, that the mechanisms have been modified somewhat, so you need an additional, you need additional activation of a different subtype of receptor or something like that. Um, so it's it's a term that is sort of generally used, as I said, to default to say it's the plasticity of plasticity mechanisms. And

Nick Jikomes 38:39

so, an area where you've done a lot of work on synaptic plasticity is in the so called reward circuitry of the brain, the music limbic dopamine reward system, which is very important for learning and memory and responding to natural rewards. And it's also important for drug addiction and the response to various drugs of abuse. I want to talk about that stuff a little bit, very briefly and concisely. Can you just give your sort of definition or perspective on what actually counts as a drug addiction or an addiction behaviorally?

Robert Malenka 39:10

Well, I mean, you know, clinically, the definition is the continued pursuit and ingestion of a substance. And this is the key phrase, despite severe adverse consequences. So people often ask me, you know, can I be addicted to coffee? Well, not by that definition, you never hear about people robbing, you know, you know, their family members committing a crime. You know, a marriage breaking up because they need that coffee in I mean, so you can have a strong of an end so people use it loosely, but the medicals and diagnostic definition is what I said. pursuit and ingestion despite severe adverse consequences.

Nick Jikomes 40:04

So it sounds like there's there's a difference. And it might be a matter of degree, but there is a difference between really wanting something and compulsively seeking it out.

Robert Malenka 40:12

That's exactly right. And again, you know, like many diagnoses, especially in the psychiatry realm and mental illness, there's a continuum. But it's Yeah, exactly. It's this compulsive seeking despite adverse consequences. But you know, I'm very grumpy in the morning if I don't get my coffee, but I would not, you know, I run the bank to get an addict by that definition. Yeah.

Nick Jikomes 40:39

Yeah, I talked to Christian Lucia. And he made the distinction between the pendency, which is, you know, you're waking up with a headache and being grumpy in the absence of the caffeine. And the compulsion side of it, he basically said, you have to have both to qualify as addiction in the clinical setting.

Robert Malenka 40:55

You can be Yes, basically, dependency goes along. But yes, I mean, I think Christians point is very well made and well taken. I'm dependent. Yeah. A little bit. And, and you can have withdrawal symptoms without being addicted. You know, when people talk about, if they don't get there, they can get headaches if they don't get their caffeine, because they're so used to it. But that doesn't mean they're they don't meet the definition, the medical definition of addiction.

Nick Jikomes 41:28

And so there are many addictive substances out there. I'm sure we'll maybe use some as examples. Nicotine, opioids, you know, amphetamines list goes on and on. Is there. To what extent are they all acting through unique mechanisms? And to what extent is there sort of a common core element in the brain and what's going on in terms of plasticity that they all share in common?

Robert Malenka 41:51

Yeah, I mean, so, you know, a big breakthrough in our understanding of the neurobiology of addiction was the realization and and I'm forgetting. Let me just think, I think in the 80s, that it seemed that all these different drugs with high the term I like to use is addictive liability. So drugs have different addictive liability. So you know, a very a drug with very high addictive liability is fentanyl or opioids, psychostimulants like cocaine, methamphetamine. Other drugs may have slightly less addictive liability, but they all seem to cause the release of this neuromodulator dopamine in a key component of the classic reward circuitry in the brain called this horrible name of the nucleus accumbens. And I'm sure if you talk to Christian Lucia, he, he described this, and what's really so that was one major breakthrough. And then the other was that these different substances, opioids versus psychostimulants, like cocaine, methamphetamine versus nicotine, could all cause the release of dopamine in the nucleus accumbens, but at a receptor level, and at a circuit level, they do it via different mechanisms. But this realization of the key triggering phenomenon mechanism that leads to addiction being this unphysical illogical release of dopamine really opened up the field to a more mechanistic neurobiological description of how addiction develops, and has maintained it.

Nick Jikomes 43:41

So nicotine, cocaine, all of these different drugs of abuse, they might act in through different mechanisms touch different receptor systems and things in the brain. But ultimately, they're converging on elevating dopamine and certain key brain regions, beyond sort of what a natural reward would do.

Robert Malenka 43:58

And that's, that's the whole key is it's beyond a, quote, natural reward. So I have I really like donuts. And I guarantee you, when I'm hungry, and I eat a doughnut, I get a spike of dopamine in my nucleus accumbens, but it's not even remotely to the same degree. As the spike of dopamine, I would get in a target region like the accumbens, if I, you know, smoked or injected fentanyl is a different beasts. And that's, you know, the whole one of the major reasons we have somewhat of an addiction epidemic in our country is our brains evolved to respond to natural rewards, because it was really important to have a mechanism in our brain to tell us, this is really good. I need to remember where this food source was or where this sexual partner was. So our brains evolved for natural rewards. But then, you know, really for the for the modern drugs, which are things like morphine, fentanyl, psychostimulants, those who didn't even exist till the 20th century. And our our brains weren't ready for them. So and the connection to synaptic plasticity, to bring it full circle was, and you know, I will take a little credit for this is that I was studying LTP and LTD, and the hippocampus and figuring out the mechanisms. But I was interested about connecting up these forms of synaptic plasticity to some form of behavioral plasticity to put because even in the 80s, it was really hard to directly demonstrate that the phenomenon of LTP in the hippocampus was, in fact required for hippocampal dependent memory. So I started thinking about other brain areas to study synaptic plasticity. And I started, you know, reading literature and all sorts of different fields. And this is probably in the late 80s, so that we didn't really do the key experiments till the 90s. And people who had been studying the actions of drugs of abuse, and were working on the neurobiology of addiction. They had started proposing the idea that may be synaptic plasticity mechanisms like NMDA receptor dependent LTP. But in a different key region, in particular, in an area of the brain called the ventral tegmental area, another horrible name to remember. But it's the home of the dopamine neurons, of the neurons that send projections, or axons, to other key components of the classic reward circuitry. So my colleagues in the field, were proposing that maybe drugs of abuse triggered an LTP, like event onset synapses on dopamine neurons. But nobody had ever done experiments to directly test that hypothesis. So then, in the god, I have to in the late 90s, and early 2000s, with an ex postdoc of my lab, in my lab, a guy named Antonio bunchy, we actually tested that hypothesis. So we administered drugs of abuse, we started with cocaine, and then we expanded to other drugs of abuse. And this became important, and then using some what are now standard methodologies, but at the time, you are a bit clever, I would say. And it's because I had a background in understanding how to study synaptic plasticity, and how to measure synaptic strength in brain slices. So the experiment we did is we administered a drug to a mouse and that first cut first drug was cocaine. And we studied glutamatergic excitatory synapses on VTA dopamine neurons, and we made a measurement that correlated with synaptic strength. And we showed that cocaine cost and LTP like change. And then we showed in a subsequent paper done primarily in my lab, that other and this was key, because the question was, Is this LTP like effect on dopamine neurons as an only occur in response to envy, in vivo, meaning in the real mouse, administration of cocaine or to other drugs of abuse caused the same change. And then we showed that nicotine alcohol, I'm trying to remember, I think morphine all caused a similar LTP in these midbrain dopamine neurons, that then open the door for all sorts of different synaptic and circuit work on looking at how synapses and circuits that are part of the reward circuitry, how they change in response to drugs of abuse, and which changes lasts long enough that maybe they contribute to Addictive Behaviors, probably more than you needed to.

Nick Jikomes 49:35

So so so no matter what drug of abuse we're talking about, they can act through very different mechanisms, but they sort of all converge by causing an unnaturally high level of dopamine release in certain key regions of the brain. And that's tied into the strengthening of synapses through LTP. And that's ultimately going to be required for for addiction to set in.

Robert Malenka 49:59

Yeah, and In the hypothesis that at least one of the initial triggers is LTP, at synapses on the dopamine neurons, there are other mechanisms. It's that's not the only mechanism just to be clear.

Nick Jikomes 50:13

So there's, there's more than one way that the dopamine release can initiate the strengthening. Yeah,

Robert Malenka 50:19

it's a combination of a number of different biochemical and synaptic changes in response to a drug of abuse, then lead to the cascade of events that we define as addiction.

Nick Jikomes 50:35

And I like what you said earlier about addiction liability. So instead of thinking of drugs as being addictive, or non addictive, we should think of them as existing on a spectrum of addiction liabilities, ranging from very low to very high and everything in between. Absolutely. When we think about something that's usually considered to be pretty addictive, like a psycho stimulant, like cocaine, say, and we say that it has, you know, a certain addiction liability. What does that mean, in terms of, you know, does everyone have the same percent chance of becoming addicted upon repeated exposure? Or are some people likely to become addicted? And some people sort of immune from becoming addicted? How do we think about that the population, I

Robert Malenka 51:13

think, you know, like, like, everything in medicine, and everything in our human behavior, and how we react to our environment, it's complicated. And, you know, what I, you know, I teach this topic, you know, at Stanford University, the undergraduates, and, you know, what I always say is, you know, you can, you cannot become addicted to a substance, if you never ingest the substance, right, by definition. So if you're thinking of trying fentanyl, or trying methamphetamine, just be aware of that, you if you don't take it, you can't become addicted to it. But then the truth is, you know, there are people have different responses to these substances. And that's probably has to do with their underlying genetic, you know, genetic makeup. And so, let me just give you another example from my own experience, alcohol. You know, when I drink a few drinks, I, you know, I like to drink, I find it is a social lubricant for me. I have actually been in need reIated over my life. But a lot most of the time, I get sleepy, and I don't, it's not unbelievably rewarding to me. I mean, it's fun. But it's not like, but then you talk to certain people who really developed, you know, what we would call out what we used to call, they became alcoholics, we now say they had an alcohol use disorder, they will tell you the first time they had a martini or drink, it was like the best feeling in the world best feeling they had ever had in the world. And there's something genetically different, because my actual physiological response was different. And you can talk to people with the same kind of difference and continuum of responses to the use of cocaine, some people actually don't like it, they find it a little bit adversive. And other people just say, Oh, my God, first time I use Coke or meth, it was just like the best feeling I had in the world. So there is this continuum and spectrum of individual responses, which probably has a genetic contribution to it. And then in addition, as we all know, I mean, I shouldn't say we all know but I think if you think about it, your relative position in society, and what other forms of rewarding experiences you have, influence your addictive the chances of you developing a substance use disorder or an addiction. So I mean, just you know, I don't mean to lecture your audience. While it is absolutely true, that you can be affluent and come from a loving family of high socioeconomic status with high educational attainment and become addicted. And we know famous Hollywood stars who have substance use problems, or have died from their addictions. But it is also true that the prevalence of substance use disorders and addiction is much higher in individuals from lower socio economic strata. And the simple way we think about it is, you know, first Certain people, the substances because of their ability to release dopamine and the reward circuitry can be highly reinforcing. That is rewarding. And if you're living in a situation in an environment where there are no other sources of reward, you know, there's no parks to play in to get reward from playing sports, you're at the edge, the schools you go to are lousy your teachers allows the, you're coming from a home environment where there's no you're not getting, you know, emotionally support it, you're not getting that kind of reward. If there's drugs in your environment, that's a major source of reinforcement. And you don't have that much other choice. So I hope this is. So it's this combination of your individual response to the drug, the environment in which you live in. And your access to the drug. I mean, this has nothing to do this. These are, you know, social issues, they're not neurobiological issues. It's, I mean, so the type of addictions that just substances that are most prominent in different countries and different societies vary enormously. So in Islamic society where alcohol is not allowed, there is not an alcohol problem. There is an opiate problem. But there's not an alcohol problem. Whereas, you know, in Western societies where alcohol is extremely available, and is not socially prohibited, we you know, alcohol use disorder is a major problems. So probably more than you needed to know.

Nick Jikomes 56:51

No, this is great, this is great. There's also drugs, some of some of which you've studied that have little to no addiction liability. This includes the psychedelics, some of them have little to no addiction liability, some of them are even being studied right now as a way to potentially treat addiction to other substances. Before I want to preface this question with with another little question or comment, which is, right now there's there's kind of a battle going on in the literature over the term psychedelics, and what that means. And so I'll let you define the term and the way that you use it. But what is it about psychedelics things like the serotonergic psychedelics like psilocybin and LSD that make them different from classical drugs of abuse in terms of their addiction liability. So first,

Robert Malenka 57:37

you know, especially in the lay press, but even among my academic colleagues, I think, you know, the term psychedelic is used very loosely. And most of us in the field would prefer to use more precise terms because the the group of drugs or substances that underlie the use of the term psychedelics actually have different mechanisms of action and different behavioral and psychological effects in human beings. So I think mostly people loosely when they say psychedelics, they're mostly, but not entirely, referring to what I would define as classic hallucinogens, which are drugs like LSD, psilocybin, maybe mescaline, that have the common action that they activate certain subtypes of serotonin receptors. And as you know, serotonin is a major neuromodulator. Most of us in the field, believe there's pretty good evidence that at least part of the hallucinogenic property is due to activation of serotonin to a receptors. So when you really want to get really, you know, more refined in your definition, you can actually talk about serotonin to a hallucinogenics. So that's what I use the term psychedelics a bit this, you know, I grew up in the 60s and 70s. So I'm usually thinking of the classic hallucinogens LSD, psilocybin, mescaline, people now include drugs like MDMA, which has gotten a lot of attention because of the application from Lycos to use it as a treatment for PTSD. I prefer to use the term for MDMA of an intact origin. Because while there's a little bit of overlap with the effect it has in human beings, it's pretty I think, most people would say it's qualitatively different. And even though it's influencing serotonin mediated events in the brain, it makes kinetically works in a pretty different way than classic hallucinogens. Then people sometimes include ketamine as a psychedelic, I personally do not ketamine, those of us in the medical field define it as a dissociative anesthetic. So, I think scientifically, you have to use more defined terms, but even in the lay press, and as these agents become tested for their therapeutic efficacy, I do think it's useful to have use the term in a more precise way. Let's leave it at that. So then to answer your question, so I think the major reason classic hallucinogens like LSD, psilocybin, maybe mescaline are not addictive in the classic sense is that they don't cause this massive release of dopamine. They're serotonergic agents. And in fact, I have not done this experiment myself. But I have to actually check the literature. But I would predict and bet a lot of money that if you gave a mouse LSD or psilocybin, and you measured increases in dopamine, you wouldn't detect much increase maybe a little bit, but nothing like what you get with morphine or fentanyl or methamphetamine or cocaine.

Nick Jikomes 1:01:28

Yeah, I'm pretty sure those experiments have been done. And the answer is, is what what you just said it's little to no extra relief.

Robert Malenka 1:01:33

I mean, so you know, that's the excitement of studying these drugs. neurobiologically is we can actually start understanding how they really work. And it actually makes some sense.

Nick Jikomes 1:01:47

More recently, you've been studying MDMA, and the mechanisms by which it actually works to trigger its effects in the mammalian brain. You said MDMA is not a classic serotonergic psychedelic, it is a stimulant? I think it would be classified as a psycho stimulant. What is the addiction liability of MDMA? And how much is it tying into the dopamine reward system? Yeah,

Robert Malenka 1:02:08

it's a great question. And, you know, there it's, you know, that's a little bit of a controversial issue, I would argue, but some of my colleagues in the field would disagree with this, that because it is an amphetamine derivative, by definition, it has addictive liability. I don't think it has as much addictive liability as the classic psychostimulants, meth amphetamine, Dextroamphetamine. Cocaine, but it does cause and here you have to get I'm gonna get a little technical, the MDMA that is being tested in clinical trials. And the MDMA that presumably is used, it is an illegal schedule one drug in the United States. So the one that is used illegally, by that has been used by millions of people at parties at raves is a received MC mixture call, which is composed of two different we call them a Nancy immerse probably too much information. There are mirror images, it's our s MDMA.

Nick Jikomes 1:03:15

No, this is great because unlike ketamine, where I think there's quite a bit of not that people do recognize that there's an SN N R isomer. I often find that people don't know this about MDMA, but there's

Robert Malenka 1:03:28

and and we have actually done studies testing this as have others, and MDMA causes a massive release of serotonin in a way because usually this I'm going to anticipate a question in a way that is dramatically different than traditional anti pinch depressant drugs like Prozac, also, which is called a specific Serotonin Reuptake Inhibitors SSRIs. And people often get confused on why does MDMA have this very profound pro social effect and some would argue and pathogenic effect. And we actually just published a paper showing that in mice, it MDMA actually enhances what I would argue is a behavioral measurement of empathy. But I'm going off target here, so but so MDMA, acts on the serotonin transporter causes a massive release of serotonin to a smaller degree, it also causes the release of dopamine to a much greater extent, than classic hallucinogens like LSD like psilocybin, which don't cause it in Greece. It we have not done this directly, but my guess is MDMA doesn't cause as large or as rapid a release of dopamine as methamphetamine. Not sure about cocaine, but it certainly releases As dopamine, and I mean, one of our papers was to try to just associate what I would the what I would define as the pro social effects of MDMA, from what I would define as its addictive liability. And the hypothesis we came up with, based on our own work and other people's work in the field is pretty simple, and perhaps obvious, which is the addictive liability. And it's it's rewarding. It's rewarding. Ask aspect, because at high doses, MDMA is rewarding. People like it, they have fun on it. Mice like it is more due to the release of dopamine and the release of serotonin. Whereas the release of serotonin in the same target structure really seems to be mediating its pro social effects. And the reason I go into this level of detail is while I certainly believe that MDMA the RS form of MDMA has therapeutic potential, as especially as an adjunct to psychotherapy, and the way it was used in these PTSD trials, I also do think it has some addictive liability. And if and when it gets approved in the United States by the FDA, I think there will be off label use that may cause some individuals to have problems. The reason I'm going to this level of detail is based on this potential addictive liability. And the fact that MDMA comes in two flavors are MDMA and smcma. And this is public, I'm not, you can just go to their website, there are companies pursuing the R enantiomer of MDMA are MDMA as a potentially better form of MDMA, to use as a therapeutic agents. And the the neurobiological basis of that is that it appears, you know, more work needs to be done that our MDMA preferentially releases serotonin more than dopamine, whereas es MDMA, probably we have not tested this. This is the theory has higher affinity for dopamine mechanisms, what's known as the dopamine transporter, and probably is releasing more dopamine and serotonin. So enough said so if the if it's the serotonin releasing properties of MDMA, that is really accounting primarily, perhaps not solely for its pro social, and perhaps it's in pathogenic actions than the our MDMA forum enantiomer may have really good therapeutic potential with a higher safety margin way to put it.

Nick Jikomes 1:08:10

So most of the MDMA out there, the stuff being used by Lycos therapeutics for their PTSD trials, as well as what people are buying on the street for recreational use is, is a mixture of the RNs, isomer, of MDMA, and therefore, it's getting a mixture of these effects. I think what you're saying is there's some evidence that the R version of MDMA, the R isomer, is more tied to the serotonin release mechanisms and the pro social effects, whereas the ES one might be a little bit more for the heightened release of dopamine and might be more might have a higher addiction liability. That

Robert Malenka 1:08:42

is the hypothesis. And again, the brain, unfortunately, is always more complicated than we want it to be. And, you know, it will be very interesting to see as some of these companies begin testing are MDMA in clinical trials, probably, you know, I don't prop, whether it's going to be in PTSD or in other third for other therapeutic purposes. It will be really interesting to see what happens, because it may be you want a form of MDMA that releases a little bit of dopamine to get a little bit of that psychostimulant feeling while still causing the big release of serotonin to get the, what I would call the pro social effect. And I will say, at least in mice, and whether this translates into human beings remains to be determined. My lab has generated a lot of evidence, you know, which has been a little bit replicated by other labs. That it really is the release of serotonin. In this target structure, the nucleus accumbens, that at least in mice can account for its pro social effects. For its its effect on wanting one mouse to hang out with another mouse in a non aggressive fashion for showing a behavior that we would say indicates that it's enhancing empathy in that mouse. But you know, the proof will be when this our MDMA form enantiomer of MDMA is actually tested in a phase two clinical trial. And we'll see whether it works or not.

Nick Jikomes 1:10:30

So it sounds like you know, the racemic, MDMA that's most common the mixture of the two isomers certainly has some addiction liability, it's nonzero, but probably not as much as like clear,

Robert Malenka 1:10:41

that's my personal opinion. Okay. I don't think you can argue that it has zero addiction liability. So it would be surprising. Yeah, that would be very surprising, because because of its actions on dopamine, we'll be very surprised.

Nick Jikomes 1:10:57

But which, you know, we don't see people out in the real world, behaving with respect to MDMA, the way they do with fentanyl or methamphetamine again,

Robert Malenka 1:11:05

and that's why I like this way of conceptualizing psychoactive substances as having different levels of addiction liability, because in my view, that should influence how society regulates the access to these drugs. And that's why for somebody like me, as a neurobiologist, and a clinician psychiatrists thinks it's important to really understand this and make these distinctions.

Nick Jikomes 1:11:36

One of the things that people are really excited about with respect to psychedelics and related compounds, MDMA, ketamine, and so forth, is that, you know, there's some evidence that they can be therapeutically useful. And, and not just useful, but useful in ways that overcome a lot of the shortcomings that a lot of traditional psychiatric medications have. You know, there's evidence that you can just give a small number of doses to see remission of things like PTSD, that you don't need to keep taking it chronically for months and years at a time. So they're fast acting in that sense. They also have the effects or the side effects, depending on your perspective of, you know, the the induced subjective effects hallucinations, in the case of classical psychedelics, the the stimulant and pro social effects in the case of MDMA that associated to effects for things like ketamine, and there's some debate right now in the field, in terms of whether or not the subjective effects are just epi phenomenal, or the require for the therapeutic benefit, based on your whole career and standard plasticity and experience dependent plasticity. How do you think about this? I think

Robert Malenka 1:12:43

that is perhaps the critical question, in the whole field of psychedelic research. And in the context of using these drugs as therapeutic agents, everybody in the field wants to know the answer to that question. My personal intuition is that it's going to be very difficult, if not impossible, but it's a personal opinion not based on real data, to dissociate the subjective experience in response to these drugs from their therapeutic efficacy. That doesn't mean so I beat really believed. And it's a little tricky. Do you need the trip for the therapeutic efficacy? And, or is or is it you can't associate them, but you actually don't need to TripIt and as you so I'm not explaining this very well, as you know, I'm sure there are companies, startup companies biotechs, working really hard and developing analogs of these classic psychedelics, not only psilocybin LSD, but including drugs like Ibogaine, with the assumption that molecularly, they can dissociate, they can make a drug that's, for example, still activates the serotonin to a receptor but does not cause the trip or activates the to a receptor. And maybe there was just a paper in Nature about the potential importance of a different subtype of serotonin receptor. As I said, my belief is it's going to be pretty difficult to separate the two. And, you know, and we're actually not going to really know the answer until these drugs that biotechs are creating are actually tested clinically. Because we, you know, we have very simple minded models in mice to tell us whether a drug is hallucinogenic or not.

Nick Jikomes 1:14:59

But we only only don't know until a human being you really

Robert Malenka 1:15:03

don't know till the human babies, the mouse can't tell you what it's experiencing. And let me just think, is there any clinical evidence out? Oh, the point I wanted to make. So that doesn't mean, let's just say I, my intuition is, is reasonably correct, you still need some subjective experience to get the therapeutic action, that that statement does not mean, there is a lot of negatives there, there is not a lot of room to improve upon the classic hallucinogens in turn, maybe you don't need to. I mean, currently in the clinical trials, let's say for psilocybin or even LSD, the doses that seem to be have, in early trials seem to have some therapeutic efficacy, you have this subjective, subjective experience, that is the trip for, you know, six to 12 hours, which means you have to you're sitting, this patient or subject is sitting there in a room with somebody sitting there with them in case they start having what's known as a bad trip. And that's, you know, that's a hard model for the clinical delivery of the substances. And companies working on, can you shorten the duration of the subjective experience, and still get the same therapeutic efficacy. So as you probably know, there are a hallucinogenic compounds such as DMT, or three methodic, three, a, and I always forget methoxy DMT, that cause a much shorter trip or subjective experience. And there are companies pursuing those as potential therapeutic agents, there are biotechs, again, figuring out ways of modifying these classic hallucinogens, to shorten the duration of action. So there's a lot of room even if the subjective experience is required for maybe making the substances more user friendly in terms of their therapeutic efficacy. But just to be clear, their therapeutic efficacy is far from firmly established. There's a few clinical trials out there that really suggest good effects, but how long the good effects last remains to be to German. And if you actually look at some of the what I would view as the best done clinical trials, it, it doesn't cure everybody, in still the case that there's a percentage of papers, papers, patients, who don't respond in a therapeutically beneficial manner. So you know, I'm a believer that these drugs, these substances, absolutely should be studied. And they do have great therapeutic potential, but they need to be studied ethically and rigorously. Without the Evangelica without an evangelical attitude towards them. That's just my personal view.

Nick Jikomes 1:18:20

On the opposite side of the spectrum, when we think about the most addictive drugs, things like synthetic opioids like fentanyl, what makes them so addictive? Are they just causing the most a dopamine release and those synapses we described earlier? I know

Robert Malenka 1:18:32

it sounds so simplistic, but that is probably the case. It's, and it's a little more complicated when we when we talk about the dopamine release, what there's actually evidence from human brain imaging studies, a lot of it done by the director, not all of it, but some of it done by the director of NIDA, the National Institute on Drug Abuse nor Volkoff. And there's actually reasonably good evidence that the addictive liability of a drug correlates pretty strongly with two aspects of the dopamine release in this target structure, the nucleus accumbens. It's the magnitude of the dopamine release, but it's also the kinetics, how fast does that dopamine go up? And how fast does it come down? And that's probably the case because it's not only the substance that makes it addictive. It's the route of administration. So what are the reasons smoking meth is actually more addictive than ingesting meth? Because remember, the standard treatment for kids with ADHD is giving them amphetamine or taking amphetamine orally. So that that drug has has to be absorbed by the GI system, then it takes, I'm making this up 10 to 30 minutes to get into the brain, and the kinetics of the drug delivery, let's say an amphetamine, taken orally, as it gradually gets into the brain gradually decays from the brain. So the effect on dopamine levels is very gradually increase in a very gradual decrease. If you smoke or inject methamphetamine, it gets into the brain instantaneously, especially when you smoke it. And I don't know if you're old enough to remember the crack cocaine epidemic. And the reason crack cocaine was so addictive, is the route of administration people were smoking it, it gets into the brain instantaneously, it causes a very rapid, very large increase in dopamine, which dissipates, which disappears over the course of minutes. And that's why if you talk to people who really were smoking meth, or crack cocaine, it's theirs. As you know, as a neuroscientist, there's this famous experiment done by James olds, showing that if you put an electrical a wire into an animal's reward circuitry, and you allow it to press a bar to activate electrically, the reward circuitry, the animal will just sit there and repetitively press the bar for hours on end. And you know, smoking crack cocaine or methamphetamine is as close to an electrical stimulation of the reward circuitry as you possibly can can get. So you get this very rapid release this this jolt of dopamine, this highly reinforcing event, then it's gone through two to eight minutes later. And then what you're the individual is experiencing this is then left with this overwhelming craving or wanting drug. And it's very, it's so it's a very powerful, intermittent reinforcer. And just to go off on a complete tangent here, you know, the gambling industry has taken a lot of pain, a lot of attention to the neurobiology of addiction, and the neurobiology of compulsive reward sinkings seeking, so it's not an accident that, you know, slot machines on a Vegas casino floor. They deliver rewards on a partial reinforcement schedule, to make people I hope this is making sense. So they're

Nick Jikomes 1:22:48

engineered based on our neurobiological knowledge to give rewards on exactly the most reinforce exactly,

Robert Malenka 1:22:53

and so on for I mean, even so, I imagine with a drug like fentanyl, I'm not sure if the imaging studies have been done. But because it's such a powerful opioid, it you know, in online, I think a lot of people smoke it, I actually, I believe that's a pretty common root of as

Nick Jikomes 1:23:13

far as I can tell, in Seattle, they, they appear to be doing that. So it's just

Robert Malenka 1:23:18

like smoking, methamphetamine, and maybe even worse, so it's getting into the brain rapidly. So I really think it might be, of course, other things are growing, but it really might be that simple. And, you know, it's a little frustrating because we you know, we kind of understand the underlying neurobiological mechanism, but that still hasn't allowed us to develop, you know, a treatment that is as effective as we would like,

Nick Jikomes 1:23:50

as, as a psychiatrist and a synaptic plasticity expert. How, you know, thinking about amphetamine, which, you know, goes by the name of Adderall, when we think about the ADHD medication. How concerned are you that we are giving so many young children at such a young age, a psycho stimulant like that?

Robert Malenka 1:24:08

You know, I don't know, the clinical literature on I'm concerned, but modestly concerned, because, you know, I always say, you know, drugs are not inherently good or bad. There are drugs, and every drug, even aspirin, or what are known as NSAIDs drugs like ibuprofen, or, you know, a leave or nap person. Every drug has some part, most drugs have some positive aspects to them and some negative aspects. So in the case of giving Adderall to kids with ADHD, you know, the benefit is it really does help some of these kids focus function better in school, socially interact in a more adaptive way. And that's It's really important because if you're not able to function in school, you're not able to socially interact, when you're in elementary school or junior high school, that is going to have an impact on the rest of your life. So there's, you know, so I want to make it clear these are, you know, there's a lot of benefit. But it's balanced by there is some risk profile, that a certain percentage of these kids are getting exposed to a drug with addictive liability. And I actually don't know the literature, I think there is a higher, I may be wrong on this a higher light prevalence of subsequent substance use problems in kids who were treated with Adderall early on. But that's, I seem to remember seeing some of that data. I don't think it's profound now. So I hope I answer your question. So it's a it's a balance, I think, you know, as a you know, if you're a subscribing physician, you just want to be thoughtful and careful and balanced the risks versus the benefits. And, you know, talk to the parents of the kid and make sure there's an understanding.

Nick Jikomes 1:26:20

Earlier we briefly mentioned, the role of endocannabinoids and certain forms of synaptic plasticity, that that are really interesting and fairly well studied. Then, you know, we're understanding that that we have an endocannabinoid system that ties into some of these plasticity mechanisms. It's not a big leap to imagine that that's why things like THC, these exogenous cannabinoids that some people consume, affect learning and memory on the addiction question in terms of how exogenous cannabinoids like THC work, are they tapping into the dopamine reward circuitry and what is their addiction liability? Because you see the full spectrum of opinions out there about marijuana, I

Robert Malenka 1:26:59

think. I think cannabis products do have a addiction liability. I do think it's much less than klat opioids or psychostimulants. I think the you know, there, it's actually useful to not really to talk about cannabis use disorder, because in general in Devitt, and then I'll answer your dopamine question in a second. And I'm making gross generalizations here. And, you know, obviously, you know, I know from, you know, I grew up in the 60s and 70s, there are millions of people who can use cannabis products, I look in a way that they use alcohol, with no significant damage done, meaning just use it kind of socially on occasion. And it's really not doing any disruptive things to their life. There's also certainly the case that a percentage of cannabis users do develop a cannabis use disorder, and whether that's 5% of users or 15% of users. I am not sure. But it's not zero. It is a it's a little bit different in the sense that usually these individuals kind of have, you know, develop, for lack of a better term and a motivational syndrome, where they're just, you know, they're not motivated to work as hard. They do they, they develop some cognitive issues, some learning and memory issues. There in general, and it's interesting, and it has to do with the other actions of the drugs. They're not craving the drug who quite to the same degree in the sense that you don't often hear about people committing violent crimes because of their cannabis use, or getting in automobile accidents is I'm not going to even comment on that. I'll bet you there are a lot of automobile accidents due to the use of cannabis. But violent crimes really aren't associated and that's because of the other effects of cannabis of, of marijuana and stuff. You're not you know, you're chilled out. You're just sort of real, you know, whatever the you know, you're high. And you you're not really and you're not particularly aggressive or violent. So in terms of the dopamine, I should know this, I don't, I think it does cause some dopamine release. I think animals like mice, which can be taught to self administer it. But I'm pretty confident if you gave a choice to let's say, a mouse or a rabbit or a rat and they itself administer amphetamine versus, you know, THC or an opioid, like morphine or fentanyl, or they would always choose the former, the substance. So I hope I'm answering your question. So, again,

Nick Jikomes 1:30:15

it sounds like it sounds like this is a drug where there's definitely some addiction liability. And it's certainly not zero. But it's not going to be as high as the things that we normally consider to be the most I mean, put

Robert Malenka 1:30:26

it this way, I think the addiction liability of alcohol and nicotine are substantially higher than cannabis. That doesn't mean cannabis is zero. But, and we're going to see this as cannabis products become more and more legalized, at least in the United States, there is going to be you know, you're going to see more and more people with cannabis use disorders, I predict it's never going to be as high as the number of people who we used to call alcoholic. And now we say have an alcohol use disorder. And I don't think it will ever be as high as people with a tobacco problem with a cigarette problem. And that again, I think can actually really be explained by the neurobiological actions of nicotine alcohol versus, as you pointed out the the psychoactive substance in cannabis, which is THC.

Nick Jikomes 1:31:29

Is there anything that you want to reiterate for people or, or any final thoughts you want to leave people with about synaptic plasticity or addiction and the topics that we we discussed today?

Robert Malenka 1:31:40

I'm not really I you know, synaptic plasticity is a group of phenomena in the brain that makes the brain different than the hardware of a computer. It's why our brains are constantly changing. From the day we're born to the day we're die, I mean, your listeners, their brains have their physical properties of their brain, the biochemical processes going on in their cells and their synapses have changed as a consequence of listening to this podcast. And the hardware of a computer doesn't do that. So. But I would also, you know, remind the listeners that there is, or there are adaptive forms of plasticity, the types of plasticity that we use for learning and memory, we use to, you know, learning and memory, that allow us to remember bad events in our life, good events, but they're also maladaptive forms. So one thing to just gently point out to your listeners is there's a lot of excitement, about psychedelics being special plasticity promoting agents. And I think that is probably the case that they can promote different types of plasticity in the brain very rapidly. But I would also gently remind them, that by that definition, cocaine and opioids are also plasticity promoting agents, they just promote bad forms of plasticity, by definition. So it's a little simplistic to talk about psychedelics as psychotic plastic antigens, which is a very popular term, but because a little bit by that definition, cocaine, fentanyl, morphine, alcohol, are also psycho plastic surgeons. So again, everything in the brain is not simple. You have to be able to think about these phenomenon in a little bit more sophisticated way. And that applies not only to our understanding of psychedelics and synaptic plasticity, I'm giving now I'm going to get a little political there. It also applies to how we think about societal problems in the United States. So I encourage your listeners to have a sophisticated view of how to solve societal problems, including addictions. That that's it. All

Nick Jikomes 1:34:15

right. Well, Dr. Robert Milanka, thank you very much for your time. That was fascinating. We covered a lot of interesting stuff, and I think people are really going to get a lot out of this one. Well,

Robert Malenka 1:34:23

I hope I explained things adequately and it was a lot of fun to talk to you. So thanks for having

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read transcript to 93min mp3 Mind & Matter - GLP-1, Weight Loss Drugs, Ozempic, Obesity, NMDA Receptors, Metabolism & Brain Health _ Christoffer Clemmensen _ #161

https://mindandmatter.substack.com/p/glp-1-weight-loss-drugs-ozempic-obesity 

Whether food, drugs, or ideas, what you consume influences who you become. On the Mind and Matter podcast, we learn together from the best scientists and thinkers alive today about how your mind body reacts to what you feed it. Before starting mind and matter, I spent 10 years in academia doing scientific research. I got a PhD PhD in neuroscience where I focused on neuroendocrinology and the neurobiology of behavior. And before that, I specialized in molecular, developmental, and evolutionary genetics.

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So if you like what I'm doing, please share your favorite episodes with family and friends. The purpose of the podcast is to provide you with information obtained largely from primary sources, the people doing the research and producing new knowledge. This content is never meant to serve as medical advice. And with that, enjoy the episode. Yeah.

Thank you for having me on once more. Can you just remind remind everyone, especially those that did not already listen to our first conversation from last year, who you are and what your lab studies and what you guys are interested in? Yeah. So I I run a lab at the University of Copenhagen in Denmark at the so called Novo Nordisk Foundation Center For Basic Metabolic Research, and we can already kind of, try and tackle the name right now because I think a lot of of people associate our research center with the Novo Nordisk, the company, but it's actually it's different. It's a foundation that is related to the company, but they donate money to the University of Copenhagen that then established this research center.

So it's one out of several Novo Nordisk Foundation funded research centers at the University of Copenhagen, and our center focuses on on basic metabolic research. But in my lab, we're not only interested in the in the basic metabolic research, but also in translational metabolic research. And by that, I mean, trying to take the knowledge that we that we kind of decide for and learn and and develop new pharmacotherapies for for treatment of metabolic disease. Most notably, we're interested in obesity. So we're doing a lot of kind of preclinical work with new potential weight loss, medications.

So I've been running a research lab in Copenhagen since 2017. Before that, I spent quite a few years in in Germany and Munich, and I've also been in the states that, in Cincinnati working as, doing my PhD studies. And my lab is currently, I think, comprised of 14 or so individuals, a mixture between bachelor, master students, PhD candidates, and and postdocs. And next to that, I have a small biotech company, where we also try and and develop further develop or commercialize some of the things that we work on in the academic lab in collaboration with the University of Copenhagen and the cannabis technology transfer unit at the university. So a lot of lot of stuff going on.

In your view, what causes obesity? Is it all about energy balance? Is it, is it exposure to contaminants in the environment? What are the major drivers of obesity? That's a it's a tough opening question.

I think the best the the safest short answer is we we have no clue right now. I think that's and that's kind of interesting if you look at also some of the the the kind of, summarizing review work that is coming out these years. I think researchers are more and more open to newer theories, as opposed to just 5, 10 years ago where it was kind of oftentimes more clearly stated that the modern environment with its readily available, highly palatable, energy dense, cheap, food is the primary driver of the model of these 2 epidemic. It must be. Right?

But then this evidence coming in, kind of suggesting that it may be more complicated than that, in which includes, I mean, in this right of of of different work here. And you've also had, I think, John Speakman on your podcast who has, done work in, on basal metabolic rate, using doubly labeled water over decades to show that there seems to have been a quite weird but interesting subtle decline in in basal metabolic rate over the last 30 years or so. But actually no decrease in in energy expenditure from physical activity, which is a little bit counterintuitive what we often times say like that it's the decrease in physical activity. And at the same time, they've done work showing that it's there's no obvious correlation between, density of fast food, full service restaurants and obesity numbers. So there's kind of these pervasive ideas that it's the it's the fast food and it's like a physical activity that is driving the epidemic that is not necessarily 100% supported by by evidence.

So I think, I mean, we must acknowledge that something in the modern environment, but but it's not necessarily, I think, exclusively something to the food environment, but a combination of factors at which and that's the safest answer, right? Something in the modern environment. So it's the safe kind of gene environment interaction. Right? But there's definitely something with the modern environment that is very, that has very negative consequences in the interaction with our genome that elicits that many of us develop excess body fat mass.

Yeah. I mean But narrowing it yeah. Narrowing it down further than that is is really, really it's really difficult. Yeah. I think, you know, from talking to John Speakman and Robert Lustig and a bunch of other people on the podcast and and thinking about this, To sort of re summarize and build on what you just said, the naive assumption or explanation for what causes obesity is, well, we live in the modern world.

We have a surplus of highly palatable cheap foods. People are simply eating more calories and they're moving less. Right? So we're lazier and we're more indulgent. Therefore we're getting bigger.

But as you pointed out, and as others have pointed out in different ways, that can't be the full picture because actually we're not moving less than we were a few years ago. We're actually moving a little bit more, and our metabolic rate is going down and no one really knows why. And we're actually not, you know, we're not all eating more than we were 5, 10, 15, 20 years ago. So the the eating more, moving less hypothesis can't be the explanation. Certainly the amount of calories we eat, the types of calories we eat, and other things in our environment have to feed into the explanation for why obesity is moving in the direction that it has been.

But the simplistic answer that most people would think of from a common sense perspective, we're just eating more and moving less is not the explanation. We we know that for sure. Yeah. And at the same time, it also kind of conflicts with this notion of that body fat mass and body weight is homeostatically regulated. Right?

So if we if we trust that we are equipped with these homeostatic systems that ensures a stable body temperature, stable blood pressure, water salt balance, they're actually also similar mechanisms in play. Right? To ensure that we have stable body fat mass and body weight. So most of us or some of us go through our lives decades without counting calories or worrying about how much we exercise, But our body weight is remarkably stable. Right?

So many of us can rely on this kind of on on these homeostatic mechanisms to ensure that we match our intake with expenditure. But still then, there are now individuals then that develop, obesity. So there's something what is it that the environment that triggers this sudden imbalance that over time develops to become a a quite large expansion of body fatness. I think that's still a a mystery. Right?

Yeah. I mean, so so, you know, as you said, body weight and and food intake, these systems in the body, just like other systems in the body are homeostatically regulated. So we normally normal animals, most people for much of their lives don't have to think about this. Right? The, the sort of, the sort of cartoon model I think the average person has in their head is, oh, well, you're metabolically healthy when you're young.

And at some point you become quote unquote old and your metabolism quote unquote slows down, and then you start gaining weight. And that does in fact happen for a lot of people, but a, it doesn't happen for everyone. B, it happens for different people at different times. C, it's starting to happen even for children more and more. So it's not like you just get old and magically you're supposed to just start gaining weight at some point.

It's that these homeostatic mechanisms are becoming broken at some point due to, you know, x, y, and z. Then we don't know exactly what is breaking them or what causes them to break when you're 40 years old or or 5 years old. No. Then adding to the complexity is something that we oftentimes put in different box at biology, and that's the socioeconomic status. So if there is one predictor, if I if I were to ask people about one thing in order to predict their body body weight or BMI, I could only ask one question.

I would ask about this their socioeconomic status, basically. I guess that's 2 questions. That's education and income. And that is by far the the best or worst if you want predictor for your your your your body weight. So there is again something with our income and education that predicts whether we have a higher risk for developing obesity.

And then again, how does that fit with this idea of homeostatic regulation? And then even in the in the areas of the world where we have the highest prevalence of obesity, you still have individuals despite they live surrounded by by people in their family and their friends have, BMI plus 35. They're individuals that are completely lean without worrying about or thinking about their body weight. So they have a they're wired differently, right, in terms of homeostatic protection or defense against their weight. So, yeah, the complexity is, is is is is, is very large.

We're gonna spend a lot of time talking today about some recent research that relates to these new and and very popular, weight loss drugs, these anti obesity drugs like Ozempic, and these are GLP 1 drugs. And I want to start out by giving people a sense for some of the basic biology around GLP 1 here. So to start, can you just describe what is GLP 1 and what is it doing endogenously in our bodies? Yeah. So GLP one is one out of several hormones that are produced by our gastrointestinal system.

So it's produced by a a a cell type called the l cell in the in the gut. And, and typically, these hormones, they are peptide hormones, meaning that there are specific size in terms of, they have a specific number of amino acids. They're produced in response to ingestion of meals. Right? And they are sensitive with respect to macronutrient and even macronutrient micronutrient distribution.

So we know that historically, they were discovered for glucose ingestion. You see a secretion of this glucagon like peptide 1 GLP 1. And, it was then identified that this would affect the beta cell of the pancreas to stimulate insulin release. So the first kind of loop discovered in the middle of the of the of the eighties was that glucose ingestion elicits GLP one release from the gut that signals in the pancreas to potentiate insulin secretion so we can remove the glucose from the plasma. So it's a part of kind of this, glucose regulating endocrine system.

And, so this was referred to as the incretin effect. So that means if you give the same bolus of glucose orally versus, intravenously, you'd have a much, a much more pronounced insulin response to the oral load because you get the if effect from the hormones. And by the inking hormones are comprised of the GLP one and it's a close sister GIP. So so these hormones were identified, in the seventies eighties and, in addition to GLP 1 and GIP, the most well known blood hormones are peptide yy, pYY, or, this hormone called neurotensin, CCK, and and a few other, more well known peptide hormones secreted from the gut in some type of mixture in response to to ingested meals. Right?

So the in endogenous function is typically referred to as this incretin effect to potentiate insulin secretion so we can remove nutrients from the bloodstream and and get it deposited into muscle and fat and liver tissue typically. So so every time we eat basically a, cocktail of different hormones gets secreted and they're meant to, affect different tissues in the body so that our body can, effectively utilize whatever it is we've, we've put into it. So if you eat a meal with 1 nutrient composition and then a meal with a different nutrient composition, that might necessitate, higher or lower levels of glucose uptake or other nutrient absorption. And so when everything's working properly, these gut hormones get secreted in some combination that's suited to, enable our bodies to uptake what we've actually ingested. Exactly.

Yeah. And so so GLP one, has to get secreted and then it has to activate GLP one receptors where I'm assuming that these things are located on many different cell types and tissues throughout the body. What are the major tissue systems that respond to GLP one that express the receptor? Yeah. So initially, we were we were we've been focusing on the on the endocrine pancreas that have these, the they have these, islands of endocrine producing cells that produces insulin, the the beta cells of glucagon, the alpha cell, and they are decorated with these, GLP one receptors.

So that's also why this well known effect on insulin secretion has been been early characterized. Then there are also local neurons sitting in the proximity or vicinity of actually where the where the peptide is produced in the gut. So for example, vagal nerve, projecting to the, to to the brain stem, probably picking up locally produced GLP one signals and transmitting it through a nervous signal directly to the brain. And then this, GLP one receptor is pretty densely expressed in the hypothalamus of the bottom of the sitting just around the 3rd ventricle of the brain and the bottom of the brain and also in the brainstem where the vagal nerve is projecting around these two nuclei called the area of the streamer and the nucleus of the solitary tract. So so especially specifically in the context of obesity and diabetes, it's the GLP one receptors expressed in the hypothalamus and in the brainstem we're interested in and in the, pancreatic beta cells for the insulin secretion.

And and then it's expressed to a lesser extent in in in other in other tissues, and we continuously try to kind of, discover kind of smaller, or, or more subtle levels of expression on other, for example, the immune immune type of cells, etcetera, to try and understand what effect the peptide can have on other cell types and systems. But mostly, it's expressed in the beta cells of the pancreas and in these two areas of the brain. I see. So it makes sense that it's expressed in the pancreas because if GLP one is related to, food uptake and nutrient acquisition and and the insulin response, it makes perfect sense that you would find it in the insulin, which is where in the pancreas where the insulin is secreted. It's also found in the nervous system.

So it sounds like you've got the vagus nerve, which reaches down into the gut, so it can sense the GLP one there, relay that information back up to the brainstem. It's you also have these GLP one receptors you said in the brainstem and the hypothalamus. How are they sensing that GLP one? Is it crossing the blood brain barrier and getting into the brain or is it getting to those areas in some other way? Yeah.

So so yeah. So this is the the intriguing part. So these areas often referred to as kind of circumventricular organs or sites. So they are they are kind of the, just surrounding the 3rd and the 4th ventricular system. The blood bearing barriers is often referred to as being less fenestrated or more leaky.

So and that system is is, is quite, advantageous in the sense that this is where the brain, is capable of communicating neuroendocrine in a neuroendocrine fashion with the rest of the body. So especially in the hypothalamus, the, the the the most, lowest region called the arc nucleus, is decorated with receptors for circulating hormones, peptides, and proteins, including insulin, but also leptin produced from the adipocytes. So, that area of the brain can actually see, peptides and proteins in circulation and is less protected than the rest of the brain. So it's a kind of, a neat design in terms of brain body communication rights. So the brain can pick up on what's happening in terms of, nutrient status and the endocrine, kind of, factors that signal also nutrient status.

I see. So so the most of the brain is protected by the blood brain barrier. So so Yeah. There's tight regulation of what goes into the brain. We don't want bacteria getting in.

In. We don't want toxins getting in. We wanna control exactly what's going in because the brain is is sort of the master controller of everything. So we've got this blood brain barrier that's that's tightly regulating what gets into the brain. It's preventing a lot of things from getting into the brain, but a couple parts of the brain, special pieces, including the hypothalamus, they are in direct contact with the blood.

So they are the hypothalamus is basically directly sampling what's in the bloodstream. Exactly. Yeah. So if there's been if you do labeling studies in rodents, you put a fluorophore or something on on a peptide, GLP 1 peptide, you can see it that it up concentrates in those regions of the brain, but it doesn't get further into the brain typically. Mhmm.

So for a neuron in the hypothalamus, say, what happens when GLP one binds to its receptor? Does the neuron become more excitable, less excitable? What actually happens to neurons when GLP one, gets released? Yeah. That's, that's a good question.

And at the neuronal level, you see increased excitability, but it is a g protein coupled receptor. So you don't have this kind of immediate depolarization necessarily with the so it's perhaps more sensitization of the neuron in in those cells. So one of the neurons that expresses the GLP one receptor is called the POMC or the pom c neurons, which is kind of the primary is is kind of satiating or satiety hormone in the bottom of the hypothalamus. We talk about this yin yang hormones, in a little bit simplified fashion where the AGRP, neurons and these are because they produce these neuropeptides express agrp or POM c. So the agrp neuron is the hunger promoting neuron and the POMC neuron is the satiety promoting neuron.

And the POMC neuron, respond to to, 1 third of them expresses a GLP one receptor and will then signal, or at least sensitize in response to GLP one and will, have a little bit, be excited have increased its excitability. I see. And same goes for some of the neurons in in the brainstem. I see. So so the neurons in the hypothalamus and elsewhere that have the GLP one receptor, they're sensitive to GLP one.

GLP one is basically making them more excitable, which may or may not translate into causing those neurons to fire more directly, but will make them more sensitive to their inputs. So Yeah. So you've got these 2 populations in the hypothalamus in, in one nucleus. You have a European neurons, which promote hunger basically, and POMC neurons, POMC, which promotes satiety basically. So if the pom c satiety neurons have GLP 1 receptors and GLP 1 goes up, you would expect the, you would expect to promote satiety More more satiation, less hunger.

Exactly. And they are also then a lot of indirect communication. So there's a recent work where they where they're using a method called fiber photometry. So you can actually in the Vivo, in the live mouse, you can read the activity of neurons. Once they fire, they get you get like a calcium signal that you can pick up on with the optic sensor, the fiber.

And then you can see if you give these analogs GLP 1 hormones that you also can see a suppression of the ADRP neuron. It's not direct because it doesn't have the receptor. So there's a lot of cross communication going on between these neuronal systems. Right? So so so again, and we can talk about this later.

Also, we see also that, activity deeper in the brain with some of the the these type of gut based hormones, but it's not because they we just talked about. They don't reach deep into the brain, but they will have feed forward or they will have activated neuronal signals that will then kind of signal further into the brain and and kind of promote even effect, for example, the mesolimbic, hedonic reward pathway. But those are not because the peptide is direct signaling there, but it's through feed forward, pathways. I see. So so the the hormone GLP one can promote satiety at the level of the brain by acting on specific neurons in the hypothalamus.

Exactly. Yeah. And probably in in combination with the with its effects in the in the brainstem. Right? So there's been there's a study from 2018 where they did, where they made a, GLP one receptor knockout animal where they only ablated or, knocked out the GLP one receptor includes a matrixic neurons.

So they used a a marker for glutamateric neurons called the v glued cream mouse, and then they crossed it with a GLP one receptor flux mouse. So you only log out the receptor in neurons that expresses expresses this marker for glutamatertic neurons. And then they, tested one of the earlier long acting versions of the GLP one drug, and they saw that in mice that didn't have GLP one receptors in the glutamatergic system. The drug didn't work on on body weight lowering and food intake lowering. So based on that study, for example, you can pinpoint that the pharmacological benefits on body weight and food intake is mediated at least through glutamatergic system in the brain.

They did the same for the the GABAergic system, and they didn't see, any, any, loss of effect of the drugs. So those type of combination of these mouse genetic works with the pharmacology can then teach us more about the central modes of action. And so because we've got these circumventricular organs that can directly sample the bloodstream of the brain, the parts of the brain stem, the hypothalamus, that means these GLP-one agonist drugs, the Azempic's and and the related drugs, they are actually acting on those areas of the brain directly. Exactly. And we haven't this is something we should probably touch upon now because the endogenous hormone is very, very short lived, less than 2 minutes.

So it's debatable whether the endogenous produced GLP one ever reaches the brain in a sufficient concentration to signal satiety. I see. So it's so we we exploit the system with the pharmacology because we can recreate these super long lived versions of the hormone that are protected from insomitic cleavage in the bloodstream. And through, lipidation or fatty acid side chain, they also bind to albumin. So they stay in blood circulation for many, many, many days.

And in that way, we kind of they've been engineered to signal in the brain as opposed to the endogenously produced GLP 1. I see. So that was actually gonna be my next question is how these GLP 1 drugs differ from endogenous GLP-one. It sounds like one major way is they've been engineered so that they last longer. They're in circulation for longer and therefore, they can promote satiety with a a longer time course.

Yeah. And that is the primary difference from the endogenous one. So it's a substitution of a few amino acids to prevent them from being degraded by an enzyme called DPP 4. So they don't have this in somatic, breakdown. And then through this, lipidation or this fatty acid side chain that is kind of a well known modification in in medicinal chemistry now because it then enables, your peptide to bind to albumin that circulates, in large quantities of the body and that is then, again, you you retain the peptide longer time in circulation.

So this is also why, significant breakthrough in this area by the pharmaceutical companies was from going through the once daily to the once weekly version that that is now on the market. So the the the predecessor to semaglutide was called liraglutide, and it was a once daily GLP one receptor, agonist. And through further refinement of this side chain, it was made into a once weekly, drug basically. So so yeah. So so through these kinds of modifications, it's a once weekly drug because it's been engineered to, basically stay in circulation for longer.

The body can't break it down as quickly as it can break down the natural GLP one hormone. Exactly. But other than that, they signal in the same way, bind to the same receptor that signals the same, this g protein coupled GS pathway. So so other than that, they work the same way as the endogenous hormone. Mhmm.

And so when GLP 1 or these GLP 1 drugs like Ozempic are working when they're doing their thing, what are the effects on the GI system that are related to the satiety signal? So, so the, the brain is being signaled satiety, but what's happening to the GI tract? Is food moving through the GI tract less? Are other things being secreted like other gut hormones? What is the GI system basically doing in response to this hormone?

Yeah. So so one of the world most well described, effects is a slowing of gastric emptying. And whether that contributes to the weight loss, I think is not a 100% clear, but I to my knowledge, some of them of the earlier versions that has, was were less efficacious on body weight also had the same storing of gastric emptying that maybe speaks against this as a major contributor to the to the weight loss. But in general, they slow they they are slowing gastric emptying. So so basically food moves slower through the GI system.

If the drugs affect secretion of other inocrine factors from the gut? I think I to my knowledge, I don't know. I wouldn't think so. There's also in many in many home own system, it's well known that when if you you kind of introduce some hormone replacement type of therapy that you kind of shut down the endogenous production. And to my knowledge, that's not reported for the GLP one system, which is also quite fascinating.

So then I don't believe you shut down the endogenous production with the drugs. Okay. Interesting. How well do these GLP one drugs work? Can you give us a sense for that in terms of the magnitude of the weight loss that people are seeing when it works, as well as the percentage of people that it actually works for?

Yes. So the first generation of these drugs were, approved by the American authorities, the FDA in 2014, and marketed it under the name Saxenda. And this is the drug we just talked about called liraglutide. This was a once daily injectable, and it had approximately 8% weight loss over 1 year in individuals with the BMI above 30. So what we classified as individuals with obesity.

And then there was the this development with going from the lyric type to the same archetype with the once daily to once weekly. And, I think it was a little bit, I mean, it's just, I think it was unexpected that the weight loss was so much potentiated with that modification. So the the once weekly drug in individuals with BMI above 31 year trial, you see weight loss of 15% approximately, plus minus. There's now been so many trials, but, up to 17% with this type of best in class GLP one receptor monoan agonist. And typically, then we talk about the normanoidis compound semaglutide, which is kind of the leading one when we talk about the monoagonist drug.

But there's also then the dual agonist that are now entering the market, and maybe we can also talk about them later. Yeah. We'll get to that later. So so, so so the the drugs that are out there, the once weekly injectables, the the, the Novo Nordisk version, we're talking on the order of 15% loss of body weight. On average in individuals with obesity, BMI above 30.

And then out of those 15, percent average, there's, of course, a large variability in how people respond to these drugs. So typically, around 15%, we classify as non responders, meaning they have get less than 5% weight loss. But it also means that, of course, there are people in the other side that lose a lot of body weight up to 30% weight loss on these drugs. And that's, like, still it's something we don't know why that is. People respond so differentially to these compounds.

Why is yeah. Is is there a relationship between how obese they are and the magnitude of the effect? Do the most obese people tend to lose the most? Yeah. Good question.

I believe so. So most of these trials are done in in in rather homogeneous population. So typically in in in obese in in individuals with obesity. So I haven't seen any trials with, with individuals that are rather more lean. So so that's more anecdotally right that you see, people with less obesity respond less.

And then there's also the another kind of complexity is that people with comorbid obesity and type 2 diabetes, they also actually have less of a weight loss response. So there's something with the type 2 diabetes that weakens the effect on the weight loss that we also don't know why. I see. So people with obesity and type 2 diabetes tend to lose less weight with these drugs than people who have obesity but not type 2 diabetes. Exactly.

So if the most beautiful data from the phase three trials is typically in in obese, patients with obesity without type 2 diabetes because that's where you get most most weight loss typically. I see. And so so so when you so earlier, you said about 15% of people, about 1 or 2 out of every 10 people that's obese that takes this drug is not going to see a significant response. It'll be 5% or less body weight loss. Does that include those people type 2 diabetes potentially?

Is that one of the things feeding into that 15% number? They should probably not. I think that they've already been been selected out of these type of trials, so it shouldn't be a I see. So so about 50% of nondiabetic obese people will not see a lot of weight loss from these drugs. Mhmm.

Yeah. Okay. But still that means a vast majority do see some, and many of those see quite substantial weight loss. Yeah. And that's also why we see they're so popular.

Right? So I think finally, probably it's the first safe and efficacious weight loss that has entered the market. I mean, up until now. Right? And this is also why they've been so popularized probably.

Yes. And I wanna come back to the safety question in a minute. First, I wanna ask you about the weight that they're losing. So for people that lose weight on Ozempic and similar drugs, what are they losing? Is it primarily fat?

Is it primarily muscle? Is it a mixture of both? Yeah. So I was actually just trying to look up on these data because in the first, many of the clinical trials, it's not they haven't done body composition on all of the the patients, which I think is also, it does it's just doesn't, it's it's just too difficult of a measure to as compared to body weight to do, but it's been done on subset of patients and then some of the follow-up trials. So typically, it's data suggest that 25 to 40% of the weight loss stems from loss of, of lean mass or, of fat free mass, so to say.

And then again, how much of the fat free mass is muscle mass is then probably 50% and the rest is comprised of the rest of the organs. Right? But if we just talk about fat free mass because the if you do DXA scanning that cannot differentiate necessarily between muscle and so it would just say, let's just say fat free mass, non fat mass. And then up to 40% of the lost weight, in some of the studies from with the GLP one agonist, is is is coming from fat free mass. And historically, if you will look at dietary or diet restriction, I think typically the numbers around 25% with kind of normal, low calorie weight loss type of studies.

I see. So with these drugs, you're seeing a higher loss of fat free mass than you would with just a raw food restriction. Is that what you're saying? I think we we don't have the data yet. And at least, so I've seen ranges from 25 to 40%.

And I also looked at Eli Lilly's truck, which is we can talk with this dual GLP 1 chip, agonist. It seems as if it's also around 25% in that one study that they reported. So I think the jury is still out, but it's, of course, it's a very hot topic. It's something that is being discussed widely. Now is is this kind of risk with the loss of muscle mass?

Yes. So what so regardless of what, you know, the the numbers actually are, there's some loss of fat free mass. Yeah. Is that okay? Is that not ideal?

Is that dangerous? How do how do how should people think about that? Should they want to preserve that fat free mass or is it okay to lose it? So I think there's 2 ways to view this. First of all, this this will be very individual.

Right? Both depending on on your, sex or gender and your age and, starting point. So I think if you're old and somewhat frail, you want to for at any cost, you want to preserve your lean mass because we know that's directly correlated with how long and how well you live. Right? You want to be able to walk up the stairs and grocery shopping, etcetera.

So I think once you've acquired fat free mass at old age, you want to preserve it at any cost. But for some individuals, I think it's expected. If you we know if you have a higher body weight with elevated body fat mass also comes elevated fat free mass. So typically individuals with obesity will have more fat free mass also compared to. Yeah.

So, so if you go from being lean to being obese, you're not just purely gaining fat mass. You're gaining some amount of everything. It might disproportionately be fat mass, but you're also gonna be, gaining, fat free mass. Exactly. So that's also what what we what what if we kind of acknowledge this 25% loss of fat free mass from the diet restriction studies, maybe that's expected.

Right? But maybe we want to make sure that with the drugs, we don't accept or or we don't go beyond, for example, those 25%. Maybe that's a target to begin with. Right? But that being said, why not preserve the lean mass we already have acquired?

So I think that's the ideal future, right, that we come up with interventions or strategies that, that ensures that we can preserve as much as the lean mass that we've acquired as possible and exclusively lose body fat mass. And this is of course something that the the farm industry but also academics are working on on right now to come up with ways to ensure we can preserve lean mass. They can be lifestyle interventions or they can be kind of, drug co administration type of of interventions. And when we look at the clinical data in humans in conjunction with the preclinical data that would have been done to justify those clinical studies, And we look at the weight loss, how much of that weight loss can be explained by reduction in food intake? Or in other words, is there also a change in things like basal metabolic rate that that feed into this?

So this is also a frequently debated question. So the rodent data, is less clear. Some of the rodent studies suggest that there is an effect on energy expenditure with these increasing hormones that use you see increased, thermogenesis, but the human data suggests that it's exclusively driven by a reduction in food intake. Maybe there's an effect on preservation of energy expenditure. So we see with the severe calorie restriction, if we go on a diet, we see that energy expenditure drops in order to, kind of protect body fat mess.

So it's that's what contributes to prevent us from successful weight loss is a decline in the expenditure. Maybe the drugs can alleviate that a little bit. I see. So so sort of the natural condition is that when an animal is faced with starvation or calorie restriction conditions, there's less food coming in to supply and to fuel the body. And so there's a compensatory drop in baseline metabolism so that the animal's, using up what it has less.

Exactly. We see a quite pronounced metabolic adaptation in order to protect its body weight and and fat mass. So that's that's just well described both in humans and in in animals. And then some of the drugs can maybe offset that reduction in energy expenditure, slightly. That's at least a hypothesis.

But a direct effect on energy expenditure, I think, in humans is is probably not one of the mechanisms. Okay. Okay. So, so the weight loss that many people see is largely coming from a decrease in food intake. Exactly.

Yeah. And so, so, so, so when people take these drugs subjectively, what do they report? Does, are they simply less interested in eating? Do they feel full sort of more of the time? Do they feel sick or nauseous or anything like that?

What is the subjective feeling of these drugs induce? Combination of of all these all these things you just listed. Right? So it's less interest in food, kind of, inability to finish portions. They've kind of pile up on their plate.

Some background nausea for some individuals, that's also one of the main side effects is nausea and vomiting. Right? So I've heard one one individual, an older woman say that, it kind of, she she had the sensation as as as she recall from being pregnant 20 or 30 years ago. Like, this background nausea all the time, and that's exaggerated when she was eating. So that's why you then you wanna eat less if you so that, so it's a it's a variety of these kind of, experiences that we hear from from individuals taking the drugs.

But in general, just less drive towards eating, basically. So with that in mind, so there are at least anecdotal reports that people are quitting drinking, quitting smoking. They're having help with substance abuse that they might have. And that sounds like a good thing. But, I want to think about that through the lens of another weight loss drug that we saw come and go historically, and that is Ramanuband.

Do you remember the case of Ramanuband? Can you give people just just a very short summary of what that was and what happened there? Yeah. So Ramanuband was a very good idea because it was kind of, blocking this cannabinoid receptor that we know is related to. For most people, it's something they they relate to, kind of consumption of marijuana or or similar products that contains this THC that will elicit, this receptor in the brain that we know kind of promotes hedonic food consumption.

So overeating, basically. So this kind of links with myrrhotic consumption and overeating was a good idea to come up with, like, why don't we block this receptor, this cannabinoid receptor in the brain, and then we can suppress, satay or we can increase satay, but maybe even suppress kind of this hedonic drive to eat palatable foods. And it actually this was developed, this drug, cannabinoid, I think one receptor inhibitor, and it worked quite quite well, but it also had a lot of as it turned out, quite severe adverse effects. Probably because it was targeting systems deeper in the brain than what we normally refer to as these kind of homeostatic systems. We talked about the circum matriculocytes.

I believe Ramona Ben might have been reaching deeper into the brain and then playing around with other other other brain systems. Right? I see. So so the the problem with Ramana Bant is that although it did help people lose weight, it was basically making them, there were psychiatric side effects. People were feeling depressed.

There was even suicidal ideation. So it was help people were less interested in the rewarding properties of food, but they also became less interested in the rewarding properties of basically life itself. Everything Yeah. Was less rewarding. And, the problems associated that were greater than the benefits from from the weight loss side of it, and so that was pulled from the market.

Now the fear would be that with the Ozempic's and the new weight loss drugs, we're just going to sort of replay that episode. And so the way that one way to interpret the, anecdotal reports of substance use, people quitting substance use, of alcohol and other things is that, well, we're just seeing another Ramada bond. It's tapping into the reward system, generally speaking. And so food is less rewarding than people are eating less, which is good because that's what we want here, but it's also making drugs and alcohol less rewarding. And by extension, perhaps other things, which, which could lead to bad outcomes.

Do you think that's likely? Or it sounds like maybe you think that's less likely because the drug is sort of restricted to these circumventricular organs and it doesn't get into these deeper parts of the mesolimbic reward system and and other places? I mean, we know it influences dopaminergic signaling from rodent studies. So we actually, coincidentally did a published study last year in some reports where we showed that, we're interested in the, interplay between nicotine and the GLP one receptor system. And then we teamed up with a group of researchers that had, again, this fiber for traumetys set up where they could record, dopaminergic signaling in the nucleus accumbens of the reward pathway.

So every time the dopamine, receptor is being activated in the reward pathway, we will get, like, a response in the in a recording. So if you give the animals nicotine, we see that this, dopaminergic pathway is sliding up, basically. And then we co administer it with, a GLP one receptor agonist, and we saw that the GLP one receptor in itself didn't do anything to dopamine signal. But once we gave it together with nicotine, we suppressed the nicotine induced dopamine signal quite potently, and this must be indirect. So, again, this is how is it that probably through the the brainstem circles, how is it these circuits are tapping into the dopaminergic system to to kind of fine tune it in a way that that then suppresses the dopaminergic response we get to in nicotine.

And I think at least I think this is some of the mechanistic underpinnings of of the potential effects of these drugs on substance abuse. Right? That that they are kind of playing with the dopaminergic system. But maybe we're fortunate in this case that it's the indirect effects that renders it quote unquote safer than what we saw with Ramona Ben. I think one thing we already know is that so many 1,000 and 1,000 and 1,000 of large trials have been done.

There's now the longest one where patients have been 4 year on treatment. And to my knowledge, there's there's not a very frequent reported side effect, any of these kind of anhedonia, these type of kind of more more kind of depressive type of of states, for example. So I don't know, but it it seems like Yeah. Yeah. Well, it's, it sounds like a pretty informative experiment to do in animals would be to repeat what you guys did with the GLP one plus nicotine experiment, but for a reward, a healthy reward, something that we don't want people to get sick of and to quit.

Like exposure to conspecifics, exposure to littermates, exposure to water. I don't know. Something something the animal likes that is healthy for it rather than something that it likes that it gets addicted to. Yeah. So I actually had a a journalist calling me up last week.

Said that she's talked to this kind of a very, very kind of, not the what do you call it? Not kind of a little bit of a of a tablet type of press. It said she talked to a woman that reported that she lost her sex drive with the with these two kinds of drugs. And she asked me, is there any kind of scientific foundation to support this? And again, I could speculate like we do now is that well, we know that probably the the sex is one out of several natural rewards.

Right? So I think we can envision a way in which these drugs could influence these type of natural rewards as well. But, it's at least again to my knowledge, not a very common side effect reported. So Mhmm. It may be for some individuals.

Right? But but we'll we'll have to see. Yes. So the next area I wanna ask about these drugs is long term effects and side effects. How long lasting are the primary effects on food intake?

Are there any side effects? And sort of wrapped around this whole question is, you know, how long have people actually looked? Has there been enough time to truly know what the long term effects are? So as I just mentioned, I think there was just 2 weeks ago published a study on semaglutide with 4 years on treatment where they show I think that I was a little bit surprised to see the extra show no weight rebound. Because I think even for the bariatric surgeries that works extremely well, you see, eventually some weight rebound over years.

Right? But at least on the 4 years on treatment that they saw preserve, weight loss, stable, weight loss throughout the years. It was only which wondered well, I was a little bit surprised. It was only at 10% in this study. So again, it's not the magnitude that we oftentimes report or want to write, but still it was quite interesting.

Then regarding the long term adverse events, for some of them, we will have to see. Right? But I think you can also flip it around. Right? So the reason why the the the stock for these drug companies most notably Novo Nordisk and Eli Lilly is going up these days is that they continue to come up with reports showing benefits on cardiovascular disease, benefits on kidney disease, benefits on osteoarthritis, benefits on whatnot.

They're now doing phase 3 studies with Alzheimer's disease. So I think it's more the opposite, right, that they continue to show benefits on actually, endpoints that are very important to human health. So I think one could also envision a future where we see next generations. Like, imagine this is your kind of iPhone 3. Right?

Imagine once we've developed these compounds even more, like, in 20 years, you can envision a future where everyone are taking these drugs because they are directly linked to human health spend. So and I'm not a proponent or I'm not selling, the the drugs right now, but I think if, at least, if we continue to see benefits, with no no surprise adverse effects coming up with usage. Right? I think we'll see, Yeah. Maybe it's the other direction.

Right? That they will see more and more people want to to take these type of drugs. And it probably not Ozempic or Wegovy or Monjara or what they call, we'll see next generation compounds be being developed. You recently did a study where you basically created a new version of these drugs. And can you set up that study for us?

What was the rationale for this and and how exactly did that drug work and why why did you even think to to look at this? Yeah. So there's I'll try and do it somewhat short. So we were we became interested in the glutamatergic NMDA receptor that is typically something you associate with memory research, cognition, and kind of this long term potentiation that something with synaptic neuroplasticity. The reason why we became interested in the first place was that there was these studies with Ketamine showing effects in treatment resistant depression 20 years ago, and then there's been more and more research uncovering the mechanism for this.

Why is it that kettamine seems to have long lasting benefits in depression? And then some of the data coming out in the molecular mechanisms, pointed to a role for BDNF, the brain derived neurotrophic factor, some of the mTOR signaling pathways, And a lot of these pathways we're quite interested in in appetite regulation as well. So BDNF is a very common, pop up in all the genetic studies of body weight variability. And if you give BDNF into the, ventricles of the brains of mice, they lose weight also. So the link between Ketamine, which is an NMDA receptor blocker, it's benefits on synaptic plasticity and depression, and its mechanisms involving these pathways that we know is also interested in interest interesting in satiety control was the first kind of, the first kind of, gave the first stimulate the first ideas to think about the uses of these type of channel mod modulators for obesity.

And then we could see in the literature that there were already sporadic studies, actually a few human studies, testing in MDA receptor antagonist for binge eating disorder, and we found that studies in rats and monkeys also suggest that it could have effects on on hedonic food intake, but they were like there's not many of them. And then at the same time, the human genetic studies of body weight variability clearly point to role for neuroplasticity and signal also. So these different pieces of evidence, increased our interest in NMDA receptor channel blocking weight management. So we started to do experiments with commercially available compounds including Ketamine and the approved Alzheimer's drug called Memantine. And then a drug that's not in the market called MK01, but it's a very potent channel blocker.

So we we we exposed obese animals for these drugs and looked at food intake and body weight and saw consistently that they actually lowered food intake and body weight when we gave these drugs systemically. So n NMDA receptor antagonists, drugs that block this receptor that's important for plasticity and learning and memory, they tend to help with obesity. Animals tend to eat less and lose weight. Yes. But it's not it's it's it's not like, it's not, it's not very consolidated evidence that you find in in the obesity literature.

It's kind of you have to search for it to see I see. Previous. So there's like a handful of previous studies that are spread across, decades of work, basically. Yeah. I see.

So so we had some indications that NMDA receptors blocking them might help in obesity. Obviously, these GLP-one drugs, you're very familiar with them yourself. They're out there. They're working in humans, approved, causing weight loss in some people. So what was, what, what was this new drug you did?

There's like a twist on this drug. Right? You did something kind of clever to make it work in, in an interesting way compared to the other GLP one drugs. Yes. So the NMDA receptor antagonist are small molecules.

So like remonavent, they will basically penetrate the blood brain barrier and signal throughout the brain. So we saw when we give high doses of these drugs, the animal also started to move more. They became hyper locomotive. Their body temperature increased. We saw a lot of adverse effects that's it's not it's just not a useful drug for obesity treatment.

You cannot have a weight loss drug that have these adverse effects. But we thought we want to just exclusively harvest the benefits of these drugs in these circum matriculocytes. So how do we ensure that they don't penetrate deeper into the brain? And this is where we start to make these peptide drug conjugates. So we took the small molecule and then through a chemical linker, we attached it to the peptide.

So we basically created a single molecule with the small NMDA receptor channel blocker attached to the GLP one peptide. And then through the GLP one peptide not being able to penetrate deeper into the brain, but homing into its GLP one receptor. And when the, peptide interacts with its g protein coupled receptor, it is being internalized as a complex. And then you can sneak in the small molecule into those same neurons that internalizes the GLP one receptor and suddenly you have cell specific delivery of that small molecule only in GLP one receptor expressing cells. Okay.

So you've you've essentially taken the GLP one peptide and you've stapled it to an NMDA receptor blocker. And you've done that in a way that it can't get through the blood brain barrier. So this drug can't penetrate into all of the brain, but it can get into, parts of the brain, like the hypothalamus and the brainstem that are directly touching the bloodstream that don't have a blood brain barrier there protecting them. And so it, because it's GLP-one connected to the small molecule drug, it binds to the GLP 1 receptor on the neurons that have it, like the satiety neurons, the pom c neurons we talked about before. And then it goes inside the cell, and then the small molecule drug is cut off of that.

And then it then then it blocks the NMDA receptor. Exactly. So so and I'm not a chemist, but fortunately, the first author in our paper and it's been working on the project for a long time. It's a very smart chemist. So there's from the antibody drug conjugate space in cancer treatment.

There's been developed a lot of different linker chemistries in order to kind of facilitate delivery of a of a toxic agent only to cancer cells. So you want only delivery of of kind of this, payload to specific cells. So they've been developed a linker type of chemistry that is, sensitive to the intracellular environment. So it will only be cleaved once it's inside the cell. So it can be, for example, pH sensitive or sensitive to other, intracellular aspects that will ensure the cleavage is only happening in cellularly, but it stays stable in in circulation.

I see. So so from a chemistry perspective, this thing can be engineered so that the, the sort of double molecule, the peptide plus the drug can't be broken at stable unless it goes inside of a cell, and it can only get inside of the GLP one receptor expressing cells. Exactly. Yep. So so that is the idea.

And then you have liberation of the small molecule within those cells, and then you need them to block the NMDA receptor in in that those same cells. Okay. So so sort of the end effect physiologically of this novel compound is that you're able to block NMDA receptors in GLP one expressing cells only. Exactly. So it's a very, very specific delivery of that small molecule.

And, but we believe the idea is that that's perhaps the cell type. We want them the signaling of those molecules the most anyway. So why deliver them through the whole brain when we can get them only to those, specific neurons? Okay. So my next question would be, what is the neural, so of the neurons that have the GLP one receptor that are sensitive to this drug, what is the effect on neural activity that this drug has?

Because on the one hand, we said before that GLP-one, renders neurons more sensitive to their inputs. So it should make them more excitable. But the NMDA receptor blocker is going to prevent NMDA receptors from opening and depolarizing the cell. So are are what's the net effect here? Yeah.

So temporarily so so the idea is that the NMDA receptors is in interaction with the AMPA receptor, being recruited once the glutamatergic, drive is sufficiently high. You get NMDA receptor. You remove this blocked by an embanglishment. You get signal through the NMDA receptors. So the idea is, I think in terms of plasticity, that continuous blockage of the receptor might increase the glutamate in the synaptic cliff.

And then subsequently, it might elicit some of these adaptive responses to to strengthen the neuronal connectivity. But all of these details, the short answer is we don't know what is happening for all these details at this point. But what some of the things we did was that we teamed up with a group of researchers at University of Texas that is doing a slice electrophysiology. So they take out slices of the hypothalamus and they can bathe them in this kind of specific buffer, and then they can patch onto, individual neurons. And then they have labeled the GLP one receptor positive neurons.

So these mice come with a labeling of neurons. So they know that they're recording from a GLP one neuron in this, artificial setup. And then once they put NMDA or glutamate on these neurons, you see a depolarization and inward current. And then if you put these channel blockers on that to have been developed to block the channel, you see that this blockage is comp you prevent completely this inward flux of of of ions. And if you put GLP 1 on, nothing happens.

You see again this, NMDA was a NMDA induced inward current. But with the conjugate, we see that we can mimic what we see with the small molecules. So this is one way of showing that we have retained the effect of the channel blocker in this type of ex vivo setup. In addition to those type of experiments, we also treated, we took out hypothalamic and brain stem from mice that have been treated with the drugs. And then we we use these modern omics technologies where we look at all the transcripts and proteins that are changed in these brains of these animals.

So all the mRNAs and all the proteins, and then we see that with the conjugate, we see ton of pathways related to neuroplasticity, gluten detergic signaling. So proteins are being upregulated that, is, involved in synaptic plasticity. There's an indirect measure, but still it's a quite quite clear signature that we see changes in synaptic plasticity with the conjugate. Mhmm. So we did these different types of experiments to to strengthen that the concept works as as we have hypothesized.

Right? But we're still work I mean, we're still doing this type of study setting up studies now to verify this specific neuronal modulation in vivo, through both the GLP one receptor and the NMDA receptor. Alright. So then in in essence, a lot of the experiments you did were in rodents, you're comparing, you're comparing, NMDA receptor blockers, like MK 801 to, Semaglutide, the GLP one drugs. So the normal GLP one drugs that are out there on the market already, NMDA receptor blockers, you can compare those 2, and then you can compare both of those conditions to the new dual action GLP-one plus NMDA receptor blocker drug that you just described.

Yeah. How do the, you know, on the the terms of the basic effects on weight loss and metabolism, how do these drugs compare in your hands? Yeah. So this is normally we say the the predictability or translatability of of drugs, weight loss drugs in rodents is quite good. This they translate quite well to humans, but there's one caveat and that is, once the drugs become very potent such as the semaglutide or some of the lilies, tsepatide, etcetera.

They in in rodents, they're so potent that they can basically clear the animal for excess body fat. But we can do studies where we can kind of tease apart what is the contribution from the NMDA receptor component. And that's, of course, what we're interested in to show that there is room for maximizing the weight loss benefits. So one study we did is that we pretreated animals, obese animals with semaglutide. The the we go with oil centric basically for 2 weeks.

Once they start to plateau, then we randomized to stay on on semaglutide plus additional GLP 1 on top, or we put added our conjugate on top of semaglutide. And then we saw we could push body weight, put down 8 or so percent further. Again, suggesting that that additional weight loss when you have maxed out on GLP 1, that we can get additional 8% or so on top with the NMDA receptor channel blocker. So those type of experiments we tried to, to to do in order to to to show how much we could gain from the channel blocker. I see.

So you you actually gave rodents semaglutide, the GLP one drug, and additionally, at the same time, gave them this new dual action drug, which is also a, GLP one drug plus the MDA receptor blocker. And you're saying that, you saw additional weight loss. So you sort of maxed out what you can do through GLP one by itself. And then on top of that, if you add the NMD receptor blocker in specific cells, you're getting an additional quite substantial amount of weight loss. Exactly.

So those type of studies we did and we did direct comparisons where we infused the molecule in the, directly into the brains of rodents. So in the in the ventricular system and a molar matched dose to semaglutide single infusion. And we saw even do I think a doubling of the initial weight loss compared to semaglutide directly in the brain. We saw a little bit more preserved, or slower rebound also compared to Semaglutide in in that specific study. So but but because our drug in the paper we reported doesn't have this lipidation, the fatty acid side chain is difficult to directly compare to the marketed drugs.

I see. But but in these experiments, when you when you compare semaglutide, the GLP one drug to the new dual action drug, not not giving them at the same time, but giving them separately to different cohorts of mice. The new drug is causing more weight loss. So, so, so that is, yeah. So I think that is the point I was trying to make before.

So there's a handful of drugs now that if you dose them high enough in rodents, they will basically plateau at the same point. Right? So you can clear their body fat. So that's where you have to come up with you have to either dose dose a little bit lower to see where how they differentiate, or you have to kind of do this as we did on top to see if there's additional benefits that can be be harvested. But but I guess the point of these experiments is, there is additional fat mass that can be lost through adding the dual action of this drug, the NMDA receptor component, on top of the GLP-one component.

[SPEAKER MARTIN PEREZ DELLER:] Exactly. Yeah. What about other effects, physiological effects that that are relevant to metabolic health? I know that you guys looked at things like glucose homeostasis and and insulin. You looked at other things.

What are some of the other effects that you saw with this drug? So, importantly, we saw across the board, like, markers for metabolic health were improved, like, circulating, markers for lipid metabolism, lowering of circulating cholesterols, triglycerides, and improvement in in also glucose metabolism. So those are the things you need to see nowadays with the new drug. Right? You need to show benefits on several metabolic parameters.

Then we showed at least in rodents again, we didn't see any adverse effects on blood pressure or heart rate, which I think is important again to demonstrate you don't have any cardiovascular effects. And then we saw some tendency also to this effect on energy expenditure. I think that was quite interesting. So we actually saw quite substantial protection of this metabolic adaptation. So even though the animals in this experiment has lost 30% of the body weight, the energy expenditure was as high as the control animals that were still obese.

I see. So that's interesting. So so earlier we talked about this. When animals, start eating less, there there tends to be a compensatory ink or decrease in their energy expenditure. You're saying that that's absent with this drug.

So animals are eating less, but their energy expenditure is staying where it started at. Exactly. And in this study, we had a control group that the we calorie restricted to match the weight loss of the drug, and they'd slow their metabolism was substantially slower. So they just basically decreased the energy metabolism dramatically, and we didn't see that with the treatment. They completely retained the the end expenditure throughout despite losing 30% of body weight.

Mhmm. So that could be one one one important aspect. Same goes for actually lean mass. We do see a little bit of lean mass loss, but again, compared to calorie restriction, we actually see a preservation of lean mass in the rodents again. Mhmm.

So we don't see exaggerated lean mass loss either. And because this new dual action drug has more, specificity, I I would imagine that inherently there's less chance or less likelihood of side effects because you're you're only affecting NMDA receptors and only in these neurons. Is that did you guys look at that at all? Like like any negative side effects? Is that true?

Is that like a a likely way that it would work because it is has that higher level of specificity? So we did some of the the the most obvious tests for side effects that is very that are very apparent when you use this the NMDA receptor channel doc on its own. So, we use, like, this open field arena where you would just video record the animal of the drug exposure, and then we dosed very high. So we could see that the MK to 1 treated group, they basically gets they just ran around like crazy hyper locomotive. But in the conjugate, dosed equally high, we saw absolutely no effect on hyper locomotion against showing that we don't have this, broad central delivery of the drug.

We saw that we did the same for hyperthermia like the elevated body temperature. We didn't see any any adverse effects on body temperature either. So we did this kind of tip of the iceberg experiments to show that we don't have the adverse profile of the of the NMDA receptor channel blocker. So I think it's quite fair to to to to say that we do have this specific delivery, and we don't have systemic liberation of the of the small molecule. Mhmm.

And what effects did you see in the brain? What's going on to neurons in the hypothalamus and elsewhere when you give this drug? Yeah. So in the paper, we quote, unquote only did these type of Omics experiments where we looked at the whole transcriptome, all the mRNAs, all the proteins in the hypothalamus we did in the brainstem, and we also looked in the nucleus accumbens. And then we did a whole brain three d imaging with where we imaged a a protein called c FOS, which is a indirect marker for neuronal activity.

So when the neuron is activated, c FOS is being expressed. And then if you stay in for c fos, it will indicate that that region has been activated. So bay basically, you can do an experiment where across the entire brain, you can look to see which neurons have recently been quite active. Exactly. So the brain is it's a very neat technique.

The brain is is completely made clear, made completely transparent, and then you you can basically visualize 3 d, the whole brain where neurons have been activated. So it's very fascinating method. And and what we see is that we see activation of the same regions. We did the control against the magneto tide and and the mono agonist, etcetera. We see the same regions as we know are being activated, the brain stem, the hypothalamus, but we also actually saw some activity in the nucleus accumbens with the conjugate, which were quite interesting.

Again, the molecule is unlikely to go there. So it must be some type of feed forward signal from possibly brainstem, that that that activates this region of the brain. Okay. So you see neurons become quite active in the hypothalamus and the brain stem as you would expect, because this is where the neurons live that we are affected by these drugs. But you see additional neurons elsewhere in the brain, in particular, the mesolimbic dopamine reward system that also become active.

Do you know the specific neurons that became active? Are these dopamine neurons themselves? We don't know at this point. This is just only c fos in regions that we know are quite well defined. Right?

So we have no idea how what these specific neurons are. Yeah, not at this point. So you sort of see the same areas lighting up as with semaglutide. But then you see these additional areas lighting up, and we don't really know much about what that means yet. It sounds like.

No. Yeah. And some of the the areas that we see with semaglutide, we also see and for example, an exaggerated response again, which perhaps can be explained by part of the mechanism is that somehow you potentiate the GLP one receptor signal with the channel blocker in those neurons. Again, this is speculative. Right?

But how it's working, it might be that we're kind of boosting the GLP one receptor signal in some way through the NMDA receptor channel blocking. Mhmm. And are these drugs affecting, other aspects of metabolism in any way, like lipid oxidation and and sort of how the calories are being used? I mean, they they they shouldn't be I mean, they shouldn't be too much beyond what we see with the GOP one risk because we have this exclusive delivery and the NMDA receptors is predominantly expressed in the central nervous system. There's an interesting paper published quite some years ago in Nature Medicine showing that in MDA receptors in the pancreatic beta cells is involved in insulin secretion.

And we've had many questions presenting this at conferences where people have suggested us to look more into this. So it could actually be beneficial also for even further potentiating ins insulin secretion at least based in the literature. But we haven't, again, we haven't spent much time on this as we're mostly interested in the brain, but it's something that we should look more into. So one of the one of the things you mentioned about NMDA receptor antagonists is they have a number of side effects, including hyper locomotion. But actually for something like obesity, you know, you could argue that that's an effect rather than a side effect.

How are these drugs affecting baseline locomotor levels? Did you look at anything like voluntary wheel running or or something that we might think of as akin to exercise in in rodents? Yeah. We actually did. So in this, calorimeter system where we measure the animals in expenditure over 10 or 12 12 days of of of treatment, we can also pick up on on locomotive behavior.

And here we actually don't see any differences compared to to vehicle treated animals. But we see that animals that are exposed to calorie restriction, they reduce their locomotion, which is a a way to preserve energy. In wheel running studies, we use that x we use we've established wheel running, model as, as, as a kind of model for aversion in in rodents. So we see when we give an aversive substance, the animals, they don't like to run-in the wheels, which so for us, we've tried to establish this as a model for predicting aversive, a aversion or avoidance behaviors or they avoid running the wheel. So we compared the wheel running experiments next to semaglutide to see how this affected their willingness to run.

And we saw a similar profile. The first time they see the drug, it is aversive as any other GLP one. They don't like to run-in the wheels. But on the subsequent days, they start running again. So I think the averse of effects are quite trenchant in the rodents.

I see. I see. So there's there's an averse they stop doing things they normally like doing for a little bit, but then they get they get used to it, basically, and they start doing them again. We we see this with all, these weight loss drugs that hits the brain stem that they they they have an effect on the willingness of the animals to go in the running wheels, which is quite an interesting model, I think. Interesting.

Is there anything known there about, like, in humans? Are there any have you looked at, are there any reports about people's physical activity? So they're feeling less hungry, partially by just probably not feeling interested in food, partially through nausea and malaise. So it's kind of an aversive state maybe that's being induced. Are people reporting that they are exercising more or less or the same amount or anything like that?

Good question. I I don't know. So I think in the clinical trials, there's always like this the drug is always being prescribed on top of lifestyle therapy, like recommendation to eat healthy, live healthy. But I actually don't know what is being reported back, how much the subjects are increasing or decreasing activities. That's something that would be very interesting to look look into, in the future.

Also, I think you can for some individuals, you can imagine that if they alleviate some of their issues with moving around, you know, if you lose a lot of of of of body weight, you are able to move more, like, due to your physical size. But but I don't know centrally if it's gonna be affected by your your kind of kind of predisposition or willingness to move that that I don't know. Mhmm. So where so so given the experiments that you did that you just described where you've you've made the drug more specific by basically making it a dual action drug. It's affecting only GLP-one receptor expressing cells, and it is then blocking NMDA receptors in, in the neurons that have GLP-one.

It's, you know, everything that in your paper really sort of looks good. It sort of improves everything. There's more weight loss. Everything's as good or better than than what you see with the GLP-one only drugs. Yeah.

There's there wasn't a lot of negativity to report, in terms of how I read your paper. Do you think that these types of drugs will just sort of supplant the existing GLP one drugs? Where do you see things going in the next few years? Yeah. I know that.

So here we have to have a look at the current kind of, landscape and pipeline, that is going through the clinic. Right? So already now, we can say that the GLP one mono agonist semaglutide is being, heavily challenged by the dual and triple agonists that are either on the market or coming on the market. So there is the GLP 1 GIP coagonist developed and marketed by Eli Lilly. It's marketed as Monjaro for obese for diabetes and set bound for obesity.

The clinical data shows that it has a few percent more weight loss benefits than, GLP 1 alone. So this is the first kind of dual agonist that shows additional benefits. And then there's also a triple peptide agonist in clinical development also from Eli Lilly targeting glucagon, GLP, GIP also show very promising data. At The same time, the other companies are developing, co administration versions with the, long acting version of a of a hormone called Amuline that have been developed also for weight loss. So you give a GLP one together with Amuline.

So there is, like, an endless number of combinatorial ways that are being attempted right now to potentiate weight loss to go from 15 to 25% basically. So that's that's ongoing and next to that there is also then the lean mass preservation initiatives where people start to tap into this myostatin system. So targeting skeletal muscle inhibiting muscle atrophy pathways in order to preserve muscle mass while giving an appetite suppressant. So there's many different initiatives. And then coming back to our initiative is of course, how is that gonna fit into this competitive space.

So there's that we will have to see. Right? But we think that this new repress the targeting the new plasticity could be a a might show some benefits that we don't see with the other other drugs. And here we we're dreaming about our vision is to develop therapies that will have more sustained effects. So if you kind of rewire some of the appetite or hunger pathways in the brain, you may be able to actually create a drug with more sustained effects and less rebound.

So again, it's it's, the obesity, drug market is increasingly competitive, but there's also room for many new new type of of therapies. But it's very exciting field right now. I see. So so we've got these weight loss drugs that everybody's talking about that many people are using, but there's room to improve them in the sense of making them cause more weight loss. There's room to improve them in the sense of preserving the the non fat mass with the fat loss.

Yeah. There's there's sort of all of these different you can make them more specific, so they're less likely to have, side effects. Exactly. And it remains to be determined what the long term effects will be. But it sounds like you're pretty optimistic about these drugs.

I'm pretty optimistic. Right now, I think it's it's a so far, so good. Right? But again, we'll we'll we'll have to see. But but in parallel, there's also there's been production issues.

They're very costly to make these peptides. But right now, we also see development of of small molecule GLP 1 receptor activators. So there's so many interesting things happening right now. So so so in order to get weight loss drugs to to as many individuals as possible, you also have to be able to to produce it easily and at low cost. Right?

So those are some of the issues that we don't talk about that often, but we also need to to to to talk about. Right? Because right now, you're kind of catering to, to to the part of the population that that that has a quite high income. Right? Because they they are not they're pretty costly.

But eventually, they will also go off patent and the competition will be bigger. Mhmm. So, so so insurance doesn't cover these drugs for everyone? Like, does it cover them if you're type 2 diabetic? Does it I mean, does it not cover does insurance not pay for these drugs if you're merely obese?

It's very country specific, so I can only it's tough for me to answer I guess I should know for the US, but, to my knowledge, it's very expensive to to to get in in the US. And I don't know how much insurance is covering. In in Denmark right now, it's it's also somewhere between 3 to $400 a month to to to get the drugs, which is, again, depending on your income level, it's it's it's quite a bit of money. Right? Especially if you're in the lower socioeconomic classes where obesity prevalence is highest.

Yes. What about, what about do do we know anything about so people are losing weight because they're eating less when they take these drugs for for, you know, the the roughly 85% that will see that effect. Are they eating different foods? Are they eating better? Are they merely eating less of what they ate before?

Is it having an effect on the palatability of food and what they have a taste for and, you know, their propensity to eat healthy versus junk food? So I think in the rodents, these type of studies have been done and they show convincingly there's a change in macronutrient preference. In humans, again, I think the, individual variability is quite vast. Right? Again, you anecdotally, you have reports saying that I never touched dessert anymore or I haven't drinking alcohol since I started on the drugs.

I don't like coffee anymore. I don't I can't I used to buy a whole pizza. I still buy one, but I finish half of it. And so so it seems to be there's a huge variability at least anecdotally right. I'm not aware of any scientific What are the what are the rodent results in terms of the macronutrient shift?

I I believe so I think Wayne Sealy did one of the first studies basically just showing that the change from, less fat preference to more carbohydrate preference, typically. I mean, it's a little bit of a of, the setup has limitations, right, because you give animals access to, like, a pretty boring versions of casein protein, some lot of fat, and then some, yeah, whatever carbohydrate source. And then you basically see how does it kind of prefer these type of these 3 different back pollutants in an untreated condition and then what happens to this preference once you treat them with a variety of drugs. So it's it's kind of a limited, buffet type of of intervention. But it's sync I think as far as I recall, it changes preference from from fat towards carbohydrate and keep protein at the same level.

I guess a little bit more of like a philosophical or, or societal level. If we just sort of extrapolate forward, where do you see things going in terms of development of these types of drugs and therapies and the way that sort of we, we interact with all of the things that we consume in our society, like, you know, 10, 20, 50 years from now, are we all going to be waking up and, taking a shot of the GLP-one agonist in the morning and some testosterone? Are we just going to start injecting ourselves with, you know, 5 different drugs that have been engineered with such specificity that we we all just sort of create the body that we all desire without having to do anything else about it? Yeah. It's I mean, I'm I'm happy to try and speculate.

But then again, you know, if there's some adverse effects with this drug class being reported in 2 or 3 years from now, we'll have, I mean, it can be completely scraped, right? And we'll have to start from scratch, but that's that's, imagine that that we don't see this adverse effects with the inquisitive drug class. Then I think as I I I speculated earlier, I I I have a hard time envisioning a future where we where this is not a type of drug that many people will take as they age. Specifically, I mean, we'll see the data from the phase three trial on Alzheimer's disease in 20 5 or 26. If it has benefits on preventing the progression of neurodegenerative disease, if it has benefits on cardiovascular kidney disease, I don't I mean, you you can view it as kind of, health span type of enhancing drug.

Yeah. And again, let let's it will not be semaglutide or we go it will be next or next or next iteration of these type of molecules that are being refined. And maybe again, there'll be more individualized or personalized catering to to to different needs. I think most important is that the biggest fear is that we create a large, separation between, between socioeconomic classes. Right?

So you you basically see the the rich get healthier and the poor gets no access to these type of molecules and you will see even further separation in in inequity and inequality. Yeah. I mean, yeah. I mean, you you can easily imagine that happening because, you know, if if these things are expensive and they work, then only certain people are gonna be able to afford them every month. So one question I have too, so related to just the general topic of hormone replacement therapy, you know, a lot of people do, you know, you know, you see more and more people using growth hormone or testosterone replacement therapy and things later in life.

And we know that a lot of those hormones, you know, generally go down with age. And so you're sort of just compensating for, for this age related decline that we naturally see with a lot of these hormones. What about GLP one's natural time course? Do we know anything about how that evolves over the lifespan? Good question.

No. Actually, I don't. I would be interested interesting interested in seeing, like, meal responses in very old individuals to see if they have impaired tier 1 secretion. I don't I don't think so. I haven't heard about it before.

So I actually don't think it's changing with age. I wouldn't think so, but it's a good question. But I think for the hormone replacement therapy with age, I think and this is outside my field, but I'm always worried that if there's a meaning with the decline with age that pertains to the risk for developing cancer, basically, is that maybe what as the risk for, for for cellular kind of, uncontrolled growth increases as we age. Maybe you want less, growth factors to promote that risk. I don't know.

It's it's speculation. Right? So I think that that could be one risk. But as we again become better with medicinal chemistry and targeted delivery, I mean, again, testosterone is a steroid hormone. And if we can think about ways to deliver it using peptides to tissues where we actually want it and then prevent it from going to, yeah, tissues where we don't want testosterone sickling.

I think those are more the strategies that I'm interested in. Right? So one can easily envision a muscle targeted delivery of, let's say, testosterone, where you're probably not too worried about having having that delivered, but you don't want it to the to the cardiomyces, to the heart muscle. Right? So there's these these things you need to figure out how to how to how to do.

Interesting. Well, so here's what I hope will be a fun but instructive question. Let's just hypothetically, let's just say you wake up tomorrow. You you look like you're a lean fit guy, but let's say you wake up tomorrow and you've got a BMI of 30. So now Kristofer is obese.

You're not diabetic, but you are obese. Walk us through the thought that you would have for, you know, thinking about, should you take one of these drugs? Which one should you take? How would you think about it if you were obese? I think I would I would go ahead and start with testing either.

There's 2 on the market. There is, it's it's Ozempic is marketed as we go. We it's sem semaglutide and the dual GLP one JIP coagulists, Fabimetal Lily, is marketed as set bound. So those are the 2 drugs that are available from this class right now. I guess I will yeah.

I think I would I wouldn't hesitate with trying, with starting on one of these therapies. If I have failed in all other attempts as most, individuals with obesity have for decades. Right? They've tried all the diets out there and continue to to experience failure upon failure and you have the stigmatization. Why not, for once kind of get help, with, with the pharmacotherapy if if that's now available.

And if you respond well to the drug, you don't get the I'll be worried about the the adverse response response in terms of nausea and and vomiting, and and then I would hope I would respond well. Right? So I think those are are the my kind of thinking about these considerations. But, and And with respect to those drugs that are on the market right now, is this a lifelong commitment? Do you need to stay on these drugs?

Or, you know, what what do we know about weight regain coming off the drugs? Yeah. So the few studies that have been been done on this are very clear is the moment you stop treatment, the patients will will regain weight as we know from all other interventions that lower body weight. Right? And when they regain the weight, is it the same distribution of fat and fat free mass as before?

That has yet to be determined. And, again, that would be very individual. So you can envision a scenario where you've lost whatever, kind of proportion of fat and lean mass. And then you can envision 2 individuals. 1 is going off to therapy and staying on the couch, and the other one is being very active.

So as you are in, positive energy battles, anabolic state, and if you're at the same time stimulate muscle protein synthesis, you'll have some of the excess energy go into muscle building basically. And if you have absolutely no, muscle protein synthesis going on, you can imagine that most of the excess energy will be, going into your fat depots. So I think the devil is in the detail with respect to how the weight regain will, will, will affect body composition. What, so with respect to your lab and and the research you guys are doing, what are some of the next steps for you guys in terms of these weight loss drugs? What are you working on now and and on the horizon?

So we're continuing we're excited about this peptide directed targeting of small molecules. We're excited about neuroplasticity in obesity. Very excited. So we continue to think about other ways of targeting neuroplasticity for sustained weight loss. That's kind of our long term kind of dream project to be able to better understand weight homeostasis to create a therapy that will have sustained effects with very infrequent treatments.

And at the same time, we continue also to add on modes of action. So we have, of course, started to develop this dual incretin with the small molecules. So we have kind of triple acting peptides, small molecules. And then we're starting to look at other indications also, especially neurodegenerative disease. So if we if the increase in hormones turns out to have a benefit on, preventing progression of Alzheimer's disease, maybe attaching some of these NMDA receptor modulators to the incretins will actually even benefit those type of of indications more.

So we're looking at other indications also right now. So many many different directions, but we're excited about the targeted delivery, neuroplasticity, and, and other indications for these molecules. Alright. Well, professor Christophe Clement Clemenson, thank you for your time. Fascinating stuff.

I was happy that you decided to come back on and talk about some of the newest work. And, I look forward to seeing, what you come out with next. Thank you, and thank you for the invitation. It was a pleasure.

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Transcript to 85min podcast Neuroscience of Social Behavior, Pain, Empathy, Emotion, Brain Mechanisms of MDMA | Monique Smith | #159
https://mindandmatter.substack.com/p/early-access-diet-hunting-culture 

Whether food, drugs, or ideas, what you consume influences who you become. On the Mind and Matter podcast, we learn together from the best scientists and thinkers alive today about how your mind body reacts to what you feed it. Before starting mind and matter, I spent 10 years in academia doing scientific research. I got a PhD in neuroscience where I focused on neuroendocrinology and the neurobiology of behavior. And before that, I specialized in molecular, developmental, and evolutionary genetics.

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Can can you start by just telling everyone a little bit about who you are and what you study? Well, I'm a polyphics specialist, and I, study animal bones, mostly in Europe, more specifically in France and Montenegro. And, you know, I started working about 20 years ago. I'm a specialist of Neurathals and early modern humans. And I focus my, I would say most of my research focuses on, diet subsistence, foraging.

And I do a bit of, more and more, I would say, over over the years, I'm doing more and more ethnography and ethnohistory. So the study of non Western societies and I tried to use that as kind of framework to help me interpret the past. Mhmm. Is there a particular period in time that you focus on? Yeah.

So when I say near to those and early modern humans, so I study mostly people who lived about 200 to 5000 years ago. That's basically the range, I work on, but I've worked on stuff that is, like, almost 600000 years old. Mhmm. And would this be the the paleolithic period? Yeah.

So that would encompass the lower, middle and upper polythec as well. Sometimes I work on on later stuff. So, but mostly it's it's the Palaeolithic and I would say the later part of the Palaeolithic. And can you can you just talk about, like, what is the paleolithic era? When did it start?

When did it end? And and what defines it? Are there particular archaeological discoveries or events in history that that dictate when it start? Yeah. Yeah.

So the public starts as soon as we have them any cultural objects. And so objects made by humans with the goal of assisting them in their activities. So in Africa, it starts about 3,300,000 years ago. And, we usually take the emergence of agriculture as the end of the time period. So this occurred about 12000 years ago, in the near east.

I see. So basically 3,300,000 years ago to 12000 years ago. That's the polyphic. I see. And over that period of time, just in very general terms, where were humans coming and and going?

So at the beginning of the paleolithic, where were where was our lineage of humans? And by the end, where were we across the globe? Yeah. So the palatific, it's a world of hunter gatherers. Okay?

So there's no agriculture, and it starts in Africa. And we have hints that there there are some expansion of ominous out of Africa starting probably around 2,500,000 years ago. So they start to colonize the, you know, Eastern part of, sorry, the Southern part of Europe. Well, mostly southeast sorry, Southeast Europe. And then they move into the tropics of the Asia.

And so we find them, you know, probably around 2000000 years ago, 2,500,000 years ago in southern Southeast Asia. And then the 2 continents continents are populated later. So Australia would be probably occupied around 45 to 6000 years ago. And then we have occupation of the Americas about 25 to 3000 years ago. The first species of hominids that were leaving Africa, what what subspecies would that be?

Was that Homo erectus? Was it some other species? Well, that's that's a good question. People are debating this. So some, you know, some people have argued they're possibly later, you know, the very late Pleistocene as sort of very light australopithecines.

Other people think it's only early homo that we're moving out. So that's still debated. I think on the safe side, we would say these are early homo populations. Mhmm. When we think about the evolution of the genus homo, that would include ourselves, that would include Neanderthals and other things.

What what are some of the key, phenotypic features of this of this genus that distinguish it from other mammals in particular? I'm hoping you can start out by talking about like physical adaptations, musculoskeletal adaptations, aspects of the body that relate to how we move throughout the world. What are some of the key adaptations of homo? Well, what we see in the early homo, is there, you know, we see first they're getting taller relative to Australopithecines. So Australopithecines are basically the height of modern chimpanzees.

And so with early AMMO, we see people are standing up and now are close to, you know, our height. We see in their body that, especially with homo rectus, the, postcranial that is down the neck, we see that they are having features that are similar to what we see today. So most of the changes that we see in early Ominance be occur before they move out. These Ominance moved out of Africa. Mhmm.

And so basically, it's quite similar. We see throughout the polythetic, you know, an enlargement of the brain. So that's probably a major change we see. And contrary to what has been thought, you know, a century ago and even perhaps even 50 years ago, is that what we see is that the brain comes late in the store, the human story, the enlargement of the brain as we have tools way before we have large brains. Mhmm.

What were some of the, like, musculoskeletal changes that happened that enabled homo generally and homo sapiens particular to be a hunter gatherer species to engage in the types of forging hunting behaviors that that are typical of humans. So what we see in humans that is very different from other mammals is that, we have 2 key features that are quite distinct. First, we have, the about the ability to sweat a lot. Okay? And this might seem, you know, not particularly adaptive, but there's a good reason for this is that, humans need to, well, in prolonged activities, you need to disseminate, to dissipate heat.

Okay. So if you're, for instance, if you're running, and you're running for, you know, extended periods of time, what will happen is that your body will build up heat and if you don't have a, you know, an efficient way of evacuating this heat, you will overheat. Basically think about the car that has no radiator. You know, you can do so much, but at some at some point, the heart the car will overheat and you'll you'll be forced to stop. So that's the same thing with our body.

So we need to evacuate this heat. Animals like, cheetahs for an example, it's a very good example of an animal that can sprint very well that, you know, can achieve almost a 100 kilometer per hour. But this animal cannot sustain prolonged activity for more than a few minutes. And then they they become, you know, they overheat. So that's one feature, this ability to dissipate, you know, building heat.

The other feature is that, we, you know, our locomotor muscles. So the muscles that help us to move, they are dominated by what we call slow twitch fibers, whereas most other mammals have, fast twitch muscles. So these ones, the fast twitch one are related to power. So for instance, if you need to sprint, you will use these fast twitch, fibers. And what's interesting about them is that these are, you know, they will use the stored glycogen in the muscle to fuel them.

Whereas humans will use these slow twitch fibers, which are fed by our breathing. So in other words, when we when we run, for instance, you will note if you're running the first 30 seconds, your your breath, you know, your breathing rate will not change. That's because you're still working on the stored glycogen. But when you start to breathing to breathe heavily, that's because now you're starting to use the oxygen to help transport the glycogen to the muscles. Okay.

And so that's why, that's one feature that's very distinctive of humans is that we use the slow twitch fibers way more and we have more of them. So you've got slow and fast twitch muscle fibers. They have different physiological properties. I would assume that all amp most mammals probably have some amount of both, but what you're saying, it sounds like, is that humans have proportionately more of the slow twitch fibers compared to the fast Exactly. And more relative to our close cousins too.

I mean, chimpanzees, like, for instance, if you are involved with a in a fight with a chimpanzee, you know, your your butt will be kicked. They're really, really strong, much stronger than humans. And that's because they are, among other reasons, that they have a lot of fast twitch muscles. Whereas humans, as I pointed out, you know, they have these slow twitch muscles and that allow them to run for longer, with minimal use of fuel. I see.

So if you try to fight a chimpanzee head on, you're gonna lose because they're way stronger because their muscle composition and other things are different. But if you run away, you probably have a good chance of getting away. Exactly. That's perfect. That's exactly it.

Yeah. And so if we sort of put all these things together, so we have this ability to sweat a lot, which enables us to dissipate heat. So we could move around in the environment for longer without overheating. We also have more of these slow twitch muscle fibers, which are less about power and and strong bursts of energy right now. And they probably enable the slow twitch fibers, more long term locomotor activity.

So does this point to an enhanced ability to engage in long distance running and something something that might relate to certain forms of hunting? Yeah. That that's exactly it. So those the these two features indicate that there was selection for stamina in humans. Okay.

Not power, but stamina. And there are a few contexts, you know, a few activities that that would require that that kind of stamina and an obvious locus of selection is hunting and possibly scavenging. So we can imagine that humans found a niche in which, you know, running hours after and after hours after long, you know, large prey was a locus of selection and a niche that was not occupied by other mammals. And so that's what we think we happen with, you know, or at least these are factors that probably contributed to devotion of these traits in humans. Mhmm.

And sort of related to that, you know, I've seen some interesting data around some of our metabolic and physiological adaptations, particular things that have to do with our digestive system. So if you just sort of take a broad view of human digestion and metabolism, and you ask things like, what does our gut look like? How long is our GI tract? What does our stomach pH? All of these types of things.

And you compare it to other mammals, herbivores versus carnivores versus scavengers. What sort of metabolic profile or digestive system would you say humans have in comparison to other mammals? And how does that maybe start to tie into some of these physical adaptations that tell us about what early humans may have been, adapting to in terms of diet? Well, that's not in my area of expertise, but the, you know, some notions that I'm aware of that and I've worked on. For instance, if you think about pH, you know, our pH is not that different from that of, let's say of wolves, for instance, who are, you know, noted for sometimes scavenging and so, or a hyenas.

So in that respect, we're not different. Vultures have really high pH. So these are clearly animals, adapted. Low pH or high pH? High pH.

So they can, so they can, sorry, low pH. So so they can, they can process these, you know, very, rotten meat, in a way that we cannot. So, no, sorry, low pH. Low pH, high acidity. Yeah, exactly.

So they can tolerate very acidic things. And so that helps them to process, rotten meat. And so, this could also be, you know, in some way related to our ability to use to use scavenging as an a form of, meat procurement method. So that would be, one thing. Other people think that our gut became larger for processing complex carbohydrates, And that might be related, for instance, to an increasing use of plants and plants that contain toxins.

That the invention or I would say the discovery of fire and the use of fire could be related to an attempt by humans to attempt sorry, as an attempt to, reduce toxicity of plants. And so cooking helps in this way because you you can get rid of the of sorts of some of these toxins by this way. When when were humans first using fire? Well, that's a very controversial problem. There's I would say there's a safe answer.

The the safe answer is that at least 400, maybe 500000 years ago. Mhmm. Now there's another answer which suggests there might be some evidence for use, but I would say on an occasional basis, maybe ad hoc basis. And that could go as far as some say 2000000 years ago. So steady, consistent use of fire is recent.

5 maybe no more than 500000 years old. But regular occasional use could have occurred a little bit earlier. But again, that's debated. And one reason it's because, many fires might have been very ephemeral, and they might not leave, archaeological signature that are quite robust. I see.

So so we know it's at least, at least a certain amount of years old and it might be older, but we just can't detect it or and or humans weren't using it frequently yet. Yeah, and it might have varied regionally. It's just that by 400000 years ago, we're fairly certain that it's being mastered in many regions of the world and that it's a habitual behavior. Mhmm. And is that unique to homo sapiens or did other species of homo have fire as well?

Well we sit in near adults, some see it as a different species, some as a subspecies. So that depends on your view. Moractus use if if we say 500000 years ago, that's that would be Om erectus. So, you know, we can imagine that it's, you know, was used by several species. For instance, we know of the Hobbit, the so called Hobbit in Southeast Asia.

It's unclear yet if they use fire, but that would be another species. Mhmm. So we have humans have these adaptations that enabled, stamina. We could run long distances. We could dispute heat efficiently.

We had the muscle composition that enabled all of that. It's presumably related to food procurement, whether that's active hunting or scavenging. For these early humans in Africa, in the paleolithic, do we have any evidence, any good evidence as to the types of creatures that they were hunting or scavenging, the types of meat they were eating or anything like this? Yeah. So we know what what range of species they're hunting.

So if we go back 2 1000000 years ago, it seems that they are already able to procure some large game such as gems buck or r two beast or, you know and and some smaller ones, probably daikers. These animals were probably in the range of what they could acquire. Elands are also thought to be, sometimes acquired. But there's some debate about the larger range the larger game, something they were probably scavenging scavenged more frequently than than Ethan. But so it's it's unclear.

But at least for the medium size, animals, you know, something like, maybe a James buck that seems to have been in the range of, of what the humans could, could acquire. For those who are unfamiliar with these species, James Buck would be about the size of, let's say, a caribou in North America. Like a big deer. Yeah. So a big deer.

Yeah. And do we know, like, when when these early humans were hunting, was was meat like that? Was it an occasional treat that they would get whenever they could? Was it a very, was it was it a staple of the diet? How like, what proportion of the diet came from hunting?

And do we know very much about, like, the full composition of these early human diets? That's very difficult to answer. We think that they you know, if they show up in the archeological record, it means they're you know, it's more than occasional. Mhmm. But whether this is a staple, that remains to be, you know, determined.

We have quite a few evidence, you know, that they're, you know, like we have slice marks or tool marks on bones that suggest they're using different species. We know they're extracting marrow, very early on by 2,500,000 years ago. They're already extracting marrow. In fact, that might have been one of the main incentive to these animals to get fat because marrow is full of fat. So fat is often more important in modern foragers than the actualization of meat.

So it sounds like there's, it's hard to get a lot of direct evidence for this stuff, but we have things like bones with cut marks and it's common enough that when you see it in the archaeological record, it couldn't have been rare because otherwise we just wouldn't find artifacts like that. Are there also indirect sort of measures of this type of thing? So for example, I know that when you look at cave art, a disproportionate amount of cave art seems to be centered on animals that presumably would have been hunted, and that would suggest that perhaps it was quite common. Yes. So, there's Kvart, but before we address Kvart, there is also some isotopic studies.

So when you eat certain animals or certain types of resources, you will acquire some, some isotopes, through the tissue. And this might, you know, be detected by looking at and by extracting collagen from the bones, you might be, you know, we're able to make some inferences. So we know when we look at early omens, it looks more like they're eating plants more. The acquisition or at least a procurement of game seems clear in Neanderthals. So it seems to be effort, you know, in fact, Neanderthals have been described as a hypercarnivore, which is probably, you know, a stretch, but there are definitely, you know, having meat on their regular basis.

So probably 5 I would say by, I would say 5, 500000 years ago, humans eat meat on a regular basis. Now with respect to kvart, the oldest kvart is about 50, 50, maybe 55, 6000 years ago. 6000 years old. And what we find, the earliest ones are not depictions of animals. They're often dots or hands stencils.

So the cave art with representation of animals slightly younger, maybe 45, 4000 years ago. And, you know, we see a range of animals. Often they are spectacular ones. We have bison, you know, cave lions, stuff like that. And whether this indicates that people are trying to acquire these animals or they are somewhat, scared by these animals or trying to acquire the power of these animals is of course a matter of a debate.

And, the true meaning of this Kmart remains all but nebulous to us. But, what's interesting is that, when you look at the, you know, these skills that are shown in these things, you know, early on they look like, you know, Leonardo da Vinci. They often some of them are really already beautiful and spectacular. So it sounds like the earliest hominids were eating mostly plants, maybe occasional meat. So, you know, in broad terms, probably, not that different from something like great apes like chimpanzees, mostly plants but some animal based foods.

And then as our lineage emerged, homo sapiens, Neanderthals, we have these adaptations that allow we had bigger brains happening. We had the ability to have more stamina evolving that unlocked the ability to hunt. And so meat became more important in our diet than it was for other apes, but we're still eating an omnivorous diet. Yes. What's important to emphasize on this point is sometimes overlook is that chimpanzees and bonobos, which are our closest ancestors, they both hunt.

They don't hunt very frequently. But they, they will hunt, especially red colobus monkey. Sometimes daikers, which are small antelopes. They can acquire turtles so they they can hunt and they are successful to some extent. It's highly variable regionally.

Some population will hunt more frequently than others, but it's there it until maybe 20 years ago. It was thought to be extremely marginal and now, you know, there's some evidence that in some population, it's, it's a, I would say a treat, you know, something not common, but it's definitely there. So in other words, humans are not qualitatively different in that respect from the apes and bonobos. It's more the extent and the size of the of the animals that we capture that is different. Mhmm.

No chimps will capture something as big as a caribou, you know, as far as it's not because they don't have physiological adaptations that enable them to to catch an animal that Yes. And also because they don't use tools for that, you know, or they use some very similar, you know, it's not exactly true. They do use some tools, but often it's for, acquiring, you know, the the tissue itself. So they might, you know, they might bang a tortoise on a tree to open it and stuff like that. Or, there's some suggestion made it sometimes they may be using stones, but it's unclear, you know, to what extent they use tools.

But overall, when we look at them, it's mostly catching by the hand, which, you know, limits what you can do. Humans use projectiles, they use snares, they use, traps and other methods that allow us to, overtake, you know, prey that are much larger than ourselves. And what kind of artifacts do we have for the tools humans were using for hunting when it became more common? Were they using spears and projectiles like that? Were they also using traps and other things?

Was was there a preferred method for, chess game? That's an excellent question. One that, you know, I've been working on it for a while. The oldest tools that we have, the oldest peers are about 4 100, 3, a 104, a 1000 years old. We don't have any bow and arrow that are older.

Some say that they're already present by 6000 years ago and directly based on the size of the of the spear points or the arrowheads. For snares and traps, these are very ephemeral, products. And so we don't know at all when they were used. I I assume they're quite old. We know indirectly there's some, figurines made of clay in crevice and context, so about 30000 years ago.

And these figurines, they show nets on the hair. And so these nets, you know, if they were used for, you know, as a as a piece of, you know, you know, as clothing or or at least use in for clothing, it's possible that they could have been these these skills could have been transferred to hunting. So we could assume that there are nets at least 30000 years ago, but for anything older, it's the the question is open. Mhmm. So, you know, roughly half a 1000000 years ago, I think is when our lineage diverged from Neanderthals.

And so we sort of go down 2 separate routes to some extent. Neanderthals get to present day Europe before our lineage, I believe. And eventually our lineage goes out of Africa, goes into Eurasia and, eventually, you know, moves west and colonizes what is present day Europe. And they encounter Neanderthals along the way. As homo sapiens was leaving Africa and starting to populate Eurasia and into Europe, Do we know anything about their diet and how it might have been changing over the course of that period?

Yeah. So when we look first, what's important is that there was their divergence between the adults and, modern humans, but there are also some significant gene exchange. Mhmm. That's why we see they call it introgression. So we have some evidence that there's, you know, it's not 2 population completely diverging.

There's some divergence, but also some exchange of genes in the process. Now with respect to their diet, that's a topic that I've worked on. We don't see any major differences in terms of what modern humans and neurotose eat. In fact, there's almost a complete overlap in terms of what they do. Okay.

They focus on the same kind of tissue, same kind of animals. Their transport behavior is similar. So they transport the same element usually for fat. So there's no on this on the basis of subsistence, there's no striking difference between the two population, either Neanderthals or modern humans. And like what were they getting most of their fat from animal products?

That's a good question. In Southern Europe, it's possible that they got some through nuts. Okay. You have some fat and nuts. But it's it's presumed that most of the fat came from marrow and the subcutaneous fat that is the back fat that we see on animals.

Mhmm. And what so, you know, so there is all of these introgression, at least sporadically between, homo sapiens and Neanderthals. We exchanged DNA. You can still see evidence of Neanderthal genes in you and me today. How often do we think that was happening?

Was it pretty rare? Was it can you give us, like, a sense for just how rare or how common it might have been? Well, it was probably quite rare because if not the 2 population, you know, the genome would be more similar. In fact, it would be identical if it was very common. So there's enough for divergence to occur, but there was enough gene, or gene exchange, which could have been maybe once a generation in between 2 population.

And, this was enough to prevent full diversions in in that respect. And it's unclear still what happened to the last Neanderthals. I'm, you know, some people think it's related to, in fact, a different mode of survival, sorry, a different life way that was promoted by the modern humans when they invaded and that, these, you know, cultural adaptation allowed them to overtake Neanderthals. In my opinion, I think it's related to the habitat that was occupied, the Neanderthals. I think the habitat became, in some way, there was a climatic deterioration about 45000 years ago that was probably severe enough that the population became very small.

And this could have led easily to small population, simply collapsing because there's not enough, gene flow between different groups. So in my opinion, you know, ecological aspects or environmental aspects have been neglected in that in that respect. So can you give us a sense for the time period in which there was the most overlap between homo sapiens and Neanderthal populations? Was it was it tens of 1000 of years? How far back to that stretch?

Yeah. If you go if you're in Southeast Europe and the Near East, there's evidence of Neanderthals in modern humans for at least 50 1000 years, if not more. Okay. Some say even 100000 years. So there was significant overlap in terms of the use of these two areas.

Now with respect to whether the, made, contacts and everything, that's difficult to say. But in these regions, the stone tools made by Neanderthals and modern humans are not different or not. We cannot distinguish them. So, this suggests there's some form of cultural trans cultural transmission between the two groups or at least diffusion of ideas that, you know, crosscut these boundaries or these genetic boundaries. Mhmm.

So it sounds like you you've told us so far that Neanderthals had, a very similar diet to Homo Sapiens. It sounds like we're using the same hunting tools and therefore we we would have had comparable, hunting abilities. We know that they had big brains. What about culture? To what extent did Neanderthals have culture?

Do we see them using art and ornamentation and the types of markers that homo sapiens groups used to define 1 group versus another group? 20 years ago or 30 years ago, the answer was no. Neanderthals didn't have much, you know, didn't show any evidence that they were using symbols in any forms. But in the last, yeah, 15, 20 years, there's, I would say, growing evidence that they were habitually using symbols. For instance, we, you know, with with some colleagues, we publish a number of, claws from raptors.

These claws shows cut marks on them and these claws would not have been inedible. So we think that they were probably used as some form of ornamentation. And that's interesting because claws, you know, for instance, wolves have claws, bears have claws, yet they use only raptors and not a very specific range of raptors. The big ones like vultures and eagles. And so it's hard to escape the conclusion that this has they had this had no symbolic, reason behind it.

So I saw. Yeah. So enough enough of those artifacts exist where you see the the raptor claws, the claws from birds of prey showing up over and over again, but you don't see see it from other creatures. Exactly. So it's it's a combination of evidence here.

The fact that these it's always large raptors, there are not many, maybe 1 per site. You know, now we have probably 30 sites in Europe showing the this this use of, raptor claws. And what's interesting is that, as I said, large wrap, and it excludes other form of claws from other animals. So as I say, carnivores or or, herbivores, the claws are not used for same purposes. So for this reason, it's probably linked in, at least in my opinion, to some form of symbolic use.

What about other cultural artifacts from Neanderthal sites? Do you see clothing? Do you see beads? Anything like that? Come returning to the question of symbolic use.

So what's very well known and has been known for a while is that they're using pigments mineral pigments like ochre, manganese. And, so it's open it's this is all a bit more, I would say, difficult to interpret because some people think this guy could be related to non symbolic use. That is, for instance, some people think it might be for cleaning skin, for instance, and other purposes. But I think it's, there's some evidence, for instance, in Iberia, where pigments are associated with some bone tools made by Neanderthals. And so it could have been used for decoration, you know, or body or ornamentation.

There's also some cave art now that is thought to date from the pier that was occupied by ne'er at all. So we would have ne'er at all cave art. Again, these are handstandsills or dots on cave walls, and these date about 50000 years ago in appear that would, only been occupied by Neanderthals. Although this has also been challenged recently, there are some people think there's some modern human incursion in, the upper polyphic, sorry, in the middle of polyphic in, in in France and in Iberia. But that's quite that's quite controversial.

And in terms of these cultural artifacts that are tied or potentially tied in Neanderthals, Do we know is there any strong evidence that these were Neanderthal inventions? They came up with these things independently, or is it possible that they acquired them from coming into contact with Homo sapiens or vice versa that we acquired maybe some things from them? Yeah. For the raptor claws, as far as I know, this is something this is a feature we only see in their atolls. Pigments are found, you know, from basically from France to South Africa.

So this seems to be, you know, a widely spread trait, for kvart. The kvart, we see very early kvart in Southeast Asia, probably around 45 to 50000 years ago. So this would be linked probably to modern humans. But, again, this, this is, you know, unclear. So right now a few lines of of evidence that is only limited to Neanderthals or modern humans.

But we for instance, modern humans early on by 50, 6000 years ago, they're using and even before that, they're using shells, you know, shells that they're found on the beach. These are sometimes have natural perforations and they're used possibly as necklaces. These are not found in Neanderthals as far as I know. So there's some differences like that. But that's to be expected because we have some regional variation.

I think the point here is that what whether it's, shell or claws is not important. What is important is the fact that both are some form of symbolic and they're present in both population. And when approximately when did Neanderthals disappear? When were they gone for sure? Well, that's that would have happened about 30 to 4000 years ago.

Mhmm. That's about the dates we have even yeah. So 40, 35000 years ago, that's where, the last Neanderthals, those that are genetically, sorry, anatomically identified as as, Neanderthals. These are the last ones we find. Are there any Neanderthal burial sites?

Were there indications that they buried their dead on purpose? Of course, that's an important line that I forgot to mention. So there, in fact, Neanderthals are some of the earliest Neanderthals that we found in 190 8 and, are from burials. From instance, La Ferracie or La Chapin aux Caix. These are our burials.

There has been some debate about whether they are true burials, but for people like me who work on on fauna, this does not, seem very convincing because when you look at the fauna, the fauna is shattered. You know, we never find refits between, you know, we only find sometimes a wrist, a complete wrist or a complete foreleg, but that's very rare. And so when we see these complete, fully articulated, neonatal, individuals for us that it's clear it's related to intentional burial. Some people have argued that this has no symbolic purpose. That's possible.

But I think that's in some ways some kind of double standards because if it was a modern human being buried in that position, nobody would question that it has symbolic meaning attached to it. Paul Moore (3zero forty four): So, I mean, I think we've already hinted at this to some extent, but how has our picture of Neanderthals and how sophisticated they were changed over the past few decades? And how does that relate to, I don't know, any potential biases we might have as humans wanting to think that our lineage is too special? Yeah. The Neanderthals have always been well, we still say, you know, my brother looked like the Neanderthal or so we still have this we decided that the Neanderthal is somewhat, you know, retarded or, you know, you know, backward and so on.

So I would say the last 50 years has been to push the boundaries about their cognitive abilities. Like, you know, in the eighties, there was a much debate about whether they could speak. Now we say they're they're able to, you know, express, you know, some form of symbolism. So we have moved a lot. We have moved a lot.

A lot of the the arguments that have been put forward to show that they could not survive, have not fared well over the years. And so, that's why people like me would, would emphasize rather environmental, factors to explain their or extinction rather than some cultural ones. Mhmm. And it sounds based on what you told me before, like it wasn't like modern humans in Neanderthals met and then Neanderthals very quickly disappeared. It sounds like it was a pretty gradual process, and you have smaller and smaller pockets of Neanderthals persisting near homo sapiens for tens of 1000 of years, and they just sort of gradually fade away.

Is that more or less accurate? Yeah, I would say that's variable regionally, for instance, in an area is clearly the both populations who seem to have coexisted for long periods of time. But in other regions, for instance, if you go to Western Europe, at least at the geological scale, this was fairly quick. So or Russia, for instance. So, it it depends where you are.

And that's why it makes it all bit difficult to make, general, to to look for a general factor to explain the disappearance of Neanderthals because they are variable. You know, who live in Iberia had a probably a life way that was quite different from those who live in the near east, for instance. Yeah. And I I think that makes sense because even among modern human populations that I've discussed with others on the podcast, where it depends on the region. Sometimes 2 groups come together.

They mix a lot. Sometimes 1 group wipes the other one out very, very quickly. Sometimes they sort of live in close proximity but effectively in separate niches and they don't really interact that much. And it probably just really depends on where you look on the globe. Yeah, I think the real challenge is that if we had only the archaeology, we would not see 2 species or 2 semi species.

When we look at the physical or skeletal evidence, we seem to see, you know, different population. And that's why it's hard to reconcile the 2, you know, based on the cultural fact, the cultural aspect, they don't look that dissimilar. But the skeletal specialists tell us that they're you know, you can you can easily not easily, but you can segregate the 2 population based on their features. And so the challenge has been trying to reconcile these two lines of evidence that conflict, you know, on on 2 important aspects. Mhmm.

By the time you get to the late paleolithic, if you just look at the bones of homo sapiens and you compare them to modern humans today, are we more or less phenotypically identical to humans from the late paleolithic or are there distinctions between us now? I'm not a specialist on this question, but I would say based on my knowledge that distinctions are not different. That being said, we know from a genetic perspective that there are some important distinctions, for instance, you know, tolerance to lactose. You know, this is a recent trait. It was evolved at least twice in Europe and Africa if I remember correctly.

And this occurred in less than 6 or 7000 years ago. So, you know, there's we know our genetically speaking that some of these features are very recent. They don't show up in our skeleton, but they're there. And so what, are there any major so when when humans left Africa, homo sapiens, you know, some of them went east, some of them went west. They went to all different parts of the globe.

Were there any How much divergence was there in terms of physical adaptations related to things like diet and hunting strategies? Did it vary heavily region to region or are there a lot of similarities? Well, I would say it has to because if you're in Southeast Asia, you know, the range of species you can hunt is very different. The plants are different too. What we know, for instance, in Southeast Asia, there's evidence for fishing that is quite early by 45000 years ago.

We have also evidence they're using some tree skrills, which probably required some form of projectiles, maybe blowpipes, stuff like that. So some of this occurs very early in that region. Whereas if you look in in France, for instance, at the same time, they're basically just hunting large game. So there's quite a bit of variation, you know, when you compare different regions and that's that's to be expected. Mhmm.

And so in the work that you've done related to ethnography and looking at hunter gatherer tribes from more recent times. Is there anything that studying recent hunter gatherers tells us about the hunting strategies and things of ancient humans in terms of when we think about the adaptations you spoke about earlier, our high stamina, our ability to sweat, were we running down game, like running miles and miles and being persistence hunting? What do we really think that hunting actually looked like that was unlocked by some of those adaptations? Well, that's a good point. First, what we learned is that many, many archaeologists and many ethnographers tend to think that recent ethnographer, sorry, recent hunter gatherers, are more or less, or I would say, tend to perceive them as being relatively static.

That is not having changed much in the last century or 2 centuries. Whereas, and of course that's here, I'm exaggerating a bit, but when we turn to ethnohistory, so that is, to the records left by people before the emergence of ethnography as a field which occurred in the 1850s to a 100, you know, year in 1900. What we see are sometimes quite different pictures, because people tend to forget the impact of colonization. It has a huge impact on native population. 1st, it led to decline in predensities is that was, you know, if you read, some geez wits or missionaries or travelers, they will all tell you that in the 19th century in Africa, there's a big decline in the number of large game that is being encountered.

If you're in Europe, sorry, in North America, you will see similar picture where people say since the Europeans came, we see fewer and fewer animals. Other introductions were really important. The horse in North America completely to change sorry, completely change the way of acquiring bison. Mhmm. It also changed the way, prong or the antelope were were, acquired.

In other regions, the impact was probably less important. For instance, in the north, you know, horses are not as useful in the Arctic. So, in this case, there was the the impact could have been smaller, but then there are other aspects that were, very detrimental or at least have the significant impact. For instance, the introduction of firearms, you know, especially the repeat repeating rifle. The early firearms, contrary to what people think, early firearms, they they were really bad.

You know, they would explode. The accuracy was low. They were noisy. And so native were not really fond of early gods. In fact, when we read about, you know, let's say 18th century, accounts, the native still use bow and prefer the bow and arrow because, you know, it's more accurate than it is less noisy.

Because with the bow and arrow, you can shoot 5 deer one after the other. But, you know, with the with a rifle, you can only kill 1 because after that, the animal fleet. Okay. So the noise created by the, you know, by the impact will will scare the herd away. So that's so these things in combination means that the native habitat, the ecology has changed significantly since the the arrival of Europeans in North America and Africa.

Yeah. It sounds like what you're saying is, you know, we can't just, you know, hunter gatherer populations have changed for many reasons in the past few centuries for, for all, you know, all the reasons that you mentioned. And therefore, we can't just look at recent hunter gatherers and assume that they're a good proxy for ancient hunter gatherers. Yeah. And here, as I said, I've exaggerated that, you know, archaeologists, ethnographers, they're, they're not naive.

They know things have changed, but I think the amount of changes underestimated. Okay. With with these, with the expansion of Westerners into Africa, Asia, and North America, and South America. And, and also because these are the best models we have. The, we have so much data that at some point, we, you know, we forget that there are a lot of blind spots in our study.

And therefore, like the some were extremely influential like the study of the sun or the sun, the study of the Hadza, or the Achi in South America. So these population became proxies. And in some ways, by maybe be because they were the only good models we have. They became, you know, you know, the proxies for the politic. But when you go back in time using that no historical record, sometimes you see things that, you know, are now lost and the entrance pursuit of large game is a good example.

Until the eighties, this was not mentioned at all. And then David Carrier came up with this model of, you know, he noted that there were some important differences in physiology between mammals and humans. And he suggested that this might be related to endurance hunting. And, when we started to, work on this, my colleague Bruce Winter Alder and I, this method was described as being marginal, anecdotal. It was described as costly.

And in fact, when we, when we start to dig in that historical literature, we started to find examples of endurance pursuit all over the world. Not, you know, just in the arid open environment that was, but we found it in the tundra. We found it in the bore of forest, in the mountains of Hawaii. We found it, you know, in the tropical, settings of Southeast Asia and South America. So it became a common method.

And when I say common, I don't mean that was practiced daily, but it was something that was habitually practice in certain contexts. For instance, when there's a lot of snow or when the weather is very hot. And so that's an example of a technique that became obsolete when the rifles was introduced. I see. Yeah.

It makes sense to me that endurance hunting in particular would have been relatively common in our species because of the adaptations you spoke about before. Yeah. Their ability to sweat and the changes to our muscle fibers. Because in the absence of those adaptations, hunting is still possible, right? Humans could have quietly crept through the woods and used camouflage to engage in hunting.

But the endurance hunting aspect seems to be what those adaptations really unlocked. Yes. And it it so it it's probably related to the context of hunting. But what's important also to notice about the endurance pursuits is that they have a higher success rate than other methods, than many other methods. Because you exhaust the animal, the animals does does not have many options when it's getting very tired and, overheated.

Whereas an animal, you're trapped, you know, creeping on. Well, the animal, you know, often you cannot, you know, keep in mind that these these games have evolved and co evolved with humans for a long time. Yeah. So their sense of smell is highly developed. They their sense of hearing to is well developed, so it makes it very hard to creep and come close to, to an animal.

Like for instance, a good example is moose. You know, when you read about moose, people will say it's extremely difficult to get close or even to view, you know, to see, I'm moose. Most often, the animal will have vanish way before you see it. And so just to rebound on this, many people describe entrance, hunting, will say that you run after an animal you don't see. You try to predict where the animal is going and sometimes you'll, you know, at some point you will succeed in catching up with the animal.

The animal will be scared away and bounce and, you know, leave again and then you catch up again and so on. And it's this repeating cycle of sprint and rest that leads to the procurement or at least to success. Okay. So, and it's again, it's the buildup of heat that allow us to to, overtake these games and other methods either snaring, spearing, ambush. All these methods are assessed with a lot of failures.

Yeah. That makes sense. I'm not sure if this is your area of expertise, but as you leave the paleolithic and you get to the period of time when agriculture is developing, when people first started developing agriculture and becoming sedentary, did this lead to any phenotypic changes based on how their diet was changing? Because I've heard before things like, you know, at the dawn of agriculture, skeletons start to become less robust. There are changes in bone density and teeth that have to do with eating different foods.

Can you speak a little bit about what we might know there? Yeah. So, what we what we see, at least in terms of the skeleton. Yeah, there's some of them more cavities associated with, you know, you know, a greater, intake of plants. The skeleton is more or less robust probably because they're, running less.

They're, you know, ranging less also. In terms of the brain, we don't see as far as I know, there's no difference in in, but there's probably also some genetic evidence, that there's selection for greater tolerance to certain buxom. As I said before, lactose intolerance, you know, that's something a feature we see in many humans. This, you know, with agriculture often you have domestication of animals with the domestication of animals. You have milking.

When you're milking, well, some people don't tolerate milk well. And so there was probably selection, for, or, you know, people who can tolerate lactose lactose better. And so all these things are indicating there are still significant changes occurring at the genetic level. At the skeletal level there, the changes are more modest at the geological scale, of course. Mhmm.

What, like when you, when you look at humans, modern humans, our lineage in comparison to the many forms of now extinct species of homo, what are some of the salient differences that you think explain why our species persisted and these other ones declined all over the world? Does it have a lot to do with our symbolic cognition and our big brains and our ability to have and generate culture? Does it have a lot to do with our ability to adapt to physical environments and our locomotor capabilities and things like that, Or is it not so clear cut? Well, one aspect that is very clear to me is the importance of socialization. When you look at other species, you don't see, for instance, sharing much other than between offspring and mothers.

But in humans, you see humans giving food to a non kin, which is very unusual in mammals. And I think so that's probably one of the key features of our lineage is this, you know, selection for increased socialization, increased cooperation. This is something again that is not seen in, in man you know, is rare in other mammals. You will see it, you know, for animals that are gregarious to some extent, but not to the extent we see it in humans. Mhmm.

And do you think that relates at all to how our diet and our procurement of food evolve over time. So for example, I could imagine, I mean, if you want to go hunt big game, you can do that in a solitary way, I suppose. But I imagine that a lot of a lot of those sounds probably require coordination between individuals. If you want to scavenge a big kill from Apex Predators, I would think that probably necessitates a group that really coordinates between each other and uses language and is able to move and use tools very quickly. Do we know anything about the relationship between, the ability to cooperate in order to get food, either from hunting or scavenging, as being maybe a part of the basis for our, our cooperative abilities more generally?

Yes. I think we can definitely say that procurement of food, the, the, the aspect of cooperating is very important, but not just with animals, for instance, with plants, it's very important to transmit to transmit import, sorry, to transmit information about plant phenology. For instance, if you are, moving around the landscape, you know, you need to know where plants are first, but also in what state, you know, do do the, flowers are the, you know, where are the patches? How can you detect where, for instance, if you're looking for tubers, you want to know how deep they are, which man are likely to be edible and so on. So this is in a very important aspect and that would respect to animals.

Well, you know, if someone sees tracks of animals because when you read the the ethnographic record, the ethnocircle, the literature, often people will say what's very critical is that I was informed there were tracks over there. And so a man will tell that his wife told him to look for steambach in that region or for gemsbok or for caribou. So that's when you're you have individual hunting, but a form of hunting that has been very important before, let's say, 1900 was communal hunting. And we just published a paper. I actually, it's still under, not under review, but it's still being, it's it's in press right now.

And in this paper, we stress the importance of communal hunting as another form of hunting that was impacted by Western, Westerners impact, you know, sort about Westerners in Armenian to Eurasia and so on. Sorry about Africa and South America and so on. And so in this paper, we stress that this is a locus for selection probably because, you know, with with, with criminal hunting, you increase also the the odds of success because you, by using a lot of beaters and by driving them toward a special locust, you can have spears away there. And you know, these huds tend to have high returns, especially if you're hunting gregarious species like bison or caribou. Some of them, you know, will result in large quantities of meat being acquired.

But then this creates a collective action problem. How do you distribute this meat? Who gets a part? Is it only the person who I've hunted? Is it the person that we're beating?

Those who did not collaborate or could not collaborate. Do they get a share? So this creates, you know, very important, problems where socialization becomes a key. And so I think that might have been a key, I think in terms of devotion of socialization in humans. I mean, these kind of settings.

Mhmm. And, you know, given how much diets varied regionally and across time, even before the dawn of agriculture, right? People living in different parts of the world would have been eating vastly different things just based on the local flora and fauna that was in their habitat. Given that diversity, does it make a lot of sense to you when people today talk about things like the paleolithic diet? For for archaeologist, this is a nonsense.

This is pure nonsense. There is no palatific diet. They're palo diets, plural. And because this is not possible, when you look at the diversity, I mean, it would be in terms of selection, it would be crazy to have a palo diet because in some regions, you know, plants are not available, during, you know, 2 thirds of the year. In other regions, large game is not abundant.

In other regions, What you have are marsupials rather than placental mammals. So you have to adapt and to the environment and that create that that calls for flexibility. That's what we see in humans, variability, flexibility. So the parallel diet is nonsense to archaeologists. And when you so so one of the key physical adaptations we talked about was aspects of the body that enable physical stamina, and that unlocked the ability to do things like endurance hunting, as we were talking about.

This also presumably created a selection pressure for mental stamina. We had to focus on a problem for extended periods of time. So do you think those two things evolved hand in hand, the ability for physical stamina on the one hand and our attentional capacities, our ability to sustain attention on the other? That's an excellent question. I think, you know, I found, an excerpt about, about stem mental stamina.

Maybe just a month ago, it was really interesting because the guy was saying we have in our group, I think he was a a aishinaabe or so someone from the boreal forest in Canada, around the group the bad some bay. And it was saying, basically we have, you know, in a paraphrase basically said we have something about mental toughness that is being transmitted between, you know, in our group and we tell each other and we, you know, tell the kids how it's important to, you know, keep on running and running and running and not give up because the animal will give up before you and so on. So there's part of it. That's probably cultural, whether it's also genetic, that's, you know, that's, a topic that would be a little bit more difficult to evaluate, But clearly, there's there's something about, about cultural and cultural transmission that is important. And one thing we have to keep in mind too, is that running, it has other important evolutionary implications.

Keep in mind that, you know, in a politic past, what we have are groups that are, you know, competing for resources. So warfare and in the context of warfare running is key. So we see, you know, even if our sample of running pursuits just show basically the presence of males, females are poorly represented in our sample, maybe 4 or 5%. We have a lot of evidence that women are running in, you know, and training for running. And we have, you know, examples where dads are telling their daughters, you know, you have to know how to run because it might save your life, you know, and so, this this aspect is also critical to keep in mind when we address this problem.

And as, you know, does the is the archaeological record rich enough that we can see as humans were spreading across the globe, you know, we're hunting animals of different types. How, how sensitive were humans as they were migrating to the maintenance of animal populations they were interested in hunting, are there any instances pre colonialization before modern technology, before guns and those things, would people move into a region and just sort of hunt everything until it was gone? Did that happen sometimes? Were they able to figure out how to hunt enough to feed themselves but not so much they deplete local populations or did ancient humans drive a lot of animals to extinction through hunting? That's an interesting debate.

What we see, we have to think a little bit about how the native see these things. First natives are incredibly knowledgeable about animals. It's just astonishing the amount of information they know. One aspect that is harder for them to evaluate is the metapopulation level. For instance, if you hunt caribou and you live in a region, let's say close to the Hudson Bay, it's really hard for you to know how the population is doing at the scale of a continent.

And so your decision will be, of course, based on your local knowledge. And so when you ask about, when you ask natives or at least when you read about natives, what they say, often they say, if you kill an animal, the animal is not really dead. Its soul, if you behave in a respectful way and if you do the proper ritual, the animal will actually go and or the soul of the animal will go and will create a new animal. And in fact, the animal will come back. And they say that about fish, for instance.

You say if you treat fish with respect, you know, the fish will come back. I even found an example where the guy says I made a mark on the bone just to make sure. And then later on, I found an, another animal of that species, and I found the same mark. So the animal came back. And so when you have this kind of thinking, then you don't have the idea that the species can become extinct.

Because if you are spiritually and ritually taking care of the animal, the animal will come back. And so when we and some, studies have been done on some ethnographic studies that have been conducted and the natives are not trying to, minimize their intake of females or, you know, of juveniles. They just kill what they need. So and I would say that makes sense, because if they have been doing it for millennia. Why would you change your method?

You know, why would you start to focus on certain game? And for those who do ecology, in fact, if you kill a lot of animals, you reduce pressure on those who survive and those who survive will often do better. And so they come back. So extinction is a very difficult concept until you have some metapopulation data. In fact, until, you know, the early 20th century, we didn't have a really good idea of extinction.

You know, it was a topic. It was really hard to address because we have poor data. And so to make a story short, extinction is not something that people worried about when they hunt because their method had a small impact on the on the game population. And also because they believe that if you are treating, animals with respect, they come back. Mhmm.

Where do you think, like, a lot of the a lot of those rituals and spiritual beliefs, do you think at all about the purpose, the sort of ecological purpose of those things for human hunter gatherers? Are the spiritual practices and beliefs that the different tribes have, are they epiphenomenon or do they serve some kind of behavioral regulation purpose that's important for survival? Well, that's a good question too. We talk all, you know, there's a lot of talk about sympathetic magic. You can imagine if you are, you know, living in a boreal environment where, you know, it's cold during 6 months, there are no plant.

So, you know, game procurement is critical. One way to reduce stress is to use rituals, you know, and, you know, to reduce, ambiguity about, you know, procurement. So these rituals often have this purpose of trying to help, you know, and to secure success in the future. So there's some, I would say maybe evolutionary aspect in that respect. So it's cultural, but it has some evolutionary implications too.

So I don't, you know, I I would not dwell too much on that, but it's interesting to keep in mind that these things are there because there's some stress in the in the first place. Mhmm. What's, so, so over the course of your career, in your own understanding of paleolithic humans and the evolution of our lineage, What's something that has, what's an example of something where your viewpoint has changed or, or the field has really come to a different conclusion in terms of where it's at today compared to where we were 10, 20, 30 years ago? Are there any major sort of 180s or or something like that that we've done in terms of how we think about the, the evolution of, early modern humans? I would say that happens a lot more than you would expect.

For instance, you know, the idea that the middlepolitik was only occupied by Netanyahu was a, you know, a given for everybody. Now it's being, you know, thought as something to rethink about. That's a good example. Endurance hunting is an example. I didn't know about this method or had well, I shouldn't have said I didn't know, but I thought really it was marginal.

And so that's an example where I completely changed my mind about its importance. I remember the Hobbit, discovery of the Hobbit in Southeast Asia. Some kind of, species that looked like an austropithecine, but dating to a 100 to maybe 50000 years ago, that came to a shock to everybody. Nobody thought that there was nothing that there was a species that would be that would look like an Australopithecine, but being so young in age. So that's another example.

Another one, and this is a more of a conceptual one 40, let's say 30 years ago, the idea of speaking about kinship, how people relate to each other was unthinkable when you think about the polythec. There was nothing we could use to talk about kinship. But now with DNA, there's a study that has been published a few years ago where they say Neanderthals were petrilineal, which means basically males stick together and women migrate to other groups. This is something that we never thought we could do. I never thought this would be possible to talk about this in my lifetime.

And this is a major, you know, for me, a major, kind of change. So some are technological discoveries. Some, you know, are important, I would say, conceptual findings. Another example is the importance of fat. Before I started doing, prolific research.

I never thought that fat was that important, you know, like any Westerner, You mean western dietary fat? Yeah. We think about meat. You know, when we think about animals, we talk about meat. We always talk about meat.

Whereas when you talk to, you know, a native, it's about fat. They, they wonder about how fat the animal is. They don't really care about the muscle, you know. Another example, a few years ago, I published with my colleague, John Speth, about rotten meat. You know, rotten meat is something that Western think is, you know, not eatable.

Well, we found tons of evidence that it's being eaten and sometimes preferred by natives in the rotten state because it makes digestion easier and some prefer to taste. And so that's another example where rotten meat was considered a no no. And then, you know, by doing some non historical research, you discover that now this is a control construct. Actually, rotten meat is palatable. And if, you know, if you're used to eating rotten meat, well, over the years, you will, you know, be able to metabolize it in a in a reliable way and you'll be fine.

That would actually that reminds me of what we spoke about earlier, where we talked about the fact that humans like certain other animals, wolves, hyenas, vultures, that scavenge a lot of meat, eat a lot of rancid or partially rancid meat. They have very, low, very acidic stomach pH. Is it possible that, you know, this is something that goes way back. Humans were scavenging meat to some extent for a long time. And it's actually it's actually a modern aberration that we think of, meat sitting out in the middle of the day.

Yeah. Yeah. What's striking and when I say rotten meat, I don't mean, like, high meat. I mean, like, meat full of maggots, like, really, really transformed. Okay?

Really, you know, rotten, not just hot. And some groups, we have examples, an excellent example during the Franklin expedition, you know, when they were trying to find the Northwest Passage, there's an Inuit guy who come to a boat to the boat of the Franklin expedition, and he comes with a seal full of maggots stinking like crazy. And the guy said, you know, he comes, you know, so he's holding that seal. And the guy said there's no way you're going to put that on the boat. And the the the Inuit is pissed because for him, it's like he found a brie, you know, or, you know, a green cheese, you know, a a a camo bell.

He was excited. He's he's being told to get rid of it. And for him, it makes no sense. You know? So that's that's an exact another example of of where, you know, encountering other people's view makes you think your own, you know, make you rethink your own views.

Wow. So rotten. Yeah. I mean, I guess I mean, if I stop the thing, I mean, obviously, it's it's not what I'm used to. It doesn't sound appetizing to me, but when you start to think about hunter gatherers and living out in the wild as an ancient human, If there's maggots, the maggots have protein.

Maybe they've pre digested some of the food material, and it's easier if it's eaten raw, if you can't cook it or things like that. So, oh, that's interesting. Yeah. So, you know, doing ethno history, it's you're you're colliding with others view all the time and some are trivial, but the others are quite spectacular, you know? Are there any other what are, I mean, are there any other aspects as like an ethnographer and and a paleoanthropologist, like everything that you've studied, are there any what are some of the things today that we take for granted that we think are normal that, like, you think most hunter gatherers would probably find very bizarre?

I mean, besides the obvious, obviously, they wouldn't know what an iPad is. But in terms of something that's maybe more of an everyday thing, do do we also also do weird things that would be seem very weird to them? Well, simple things like, you know, we have 3 meals a day. There's no that's culturally constructed, you know. Some groups eat twice, some some eat a little bit all the day, you know, all through the day.

Some, will have a big meal in the morning and a lighter one. So it's highly variable. So the idea that we have a lunch at 6 together as a family, that would probably be strange to many people. Well, maybe the obsession about hygiene. Okay.

When you read about natives, what the what you see is that they say it's stinky, dirty, and everything. And we have example, for instance, a beautiful quote we found where a woman has a child on her and she's cutting meat. The baby poo on her. She used the knife to scrape off the excrements and she continue cutting the meat, you know. That's the level of hygiene.

If you're used to that and you live like that, it's not the you don't think about that. But the idea here that, you know, you must have perfectly sterile toilets and stuff like that. That would be so foreign to native people who have not met Westerners before. Does your study of humans and human evolution in particular, you know, things like diet and our ability to adapt and be flexible and the things they eat. Do, does that influence how you think about what you eat today in our in our food environment?

Yes. Completely. Like the, you know, about the high meat, for instance, I'm less concerned that I should be, I guess. So that's an example. A lot of things you just realize, okay, that's that's this is a cultural construct.

I'm not saying it's it necessarily changes the way I do things on a daily basis, but it clearly opens the mind about how you view things. And, and it makes you understand also why people behave in a certain way. Like I said about the, when I was talking about the collective action problems, you better understand why people, why it's so hard, for instance, to prevent people from hunting, species that are, you know, that are, close to extinction. It's very hard because you require some kind of knowledge about the mid population that nobody has, you know, you require scientists to collect information for you and tell you this is how it's going, you know, for that species. But, you know, on the regular empirical basis, you know, observation basis by people, There's no way to know other than saying it seems that there were more of that animal before than than now, but that's it.

You know. What, in your research today, right now, what are some of the questions that you're thinking about and working on today? Well, right now I'm working on the for some working on the monograph on hunting. I try to, whether we want it or not, when we think about the Palatik, you know, very quickly we come to the idea of spears and individual hunters. But, you know, the ethnohistory and the ethnography made me realize there's way more to hunting than just a single method.

And now I realize that hunting is probably, in fact, a range of different methods that are used in different contexts. You know? In our society, a hunter is a guy with a gun probably waiting in a shelter or something for an animal to show up. Okay. That's that's painting our way of looking at hunting.

Whereas, you know, for native, it's probably a range of methods that when you are in situation A, you use method 1 and in situation B, you use method B, method 2 and so on. So that's what I I, you know, I'm concerned with right now is trying to and lower in other words, to enrich or at least rethink our models of hunting. Are there any final thoughts you wanna leave people with with respect to human evolution, how you think about it, or maybe a good takeaway that you think people should have when when they think about our own species and and where it came from? Well, I would say, first, we underestimate how things have changed in the recent past. Okay.

When you look at foragers today, there are tiny portion of the variability that existed, let's say, in 1500. There's so much more to learn from these, you know, these, travelers, these these jeez woods, these missionaries that were traveling through, so called wowed, you know, countries. So there's a much, much to learn. So, you know, the past was probably way more worried than people think. And, you know, a lot of models are simplistic.

They assume, you know, one population moving out, replacing another. I think life is way more complicated than that. And, as a result, you know, what we need is better, richer models that are used that are based on ethnographic observation at at no historical observation. Alright. Eugene Moran, thank you for your time.

That was fascinating. A lot of cool stuff. I think you you do really interesting research and, I had a lot of fun looking at some of it the last couple of days. And thank you.