Episode Transcript

Audio Podcast Transcript

Trevor:  Kirk We're back.

Kirk: Hey Trevor, how's it going?

Trevor: Good, so I'm gonna start on a digression. Radiolab, when our podcast grows up, I want it to turn into Radiolabs. Radiolabe, I think is still my favorite podcast out there. They do lots of science-y stories, it's surprising that's, but it was started by Jad Abumrad. It does lots of really cool audio stuff. But they do a lot of science episodes and one of my favorites ties in nicely to this. So the title of their episode is "the Dirty Drug and the Ice Cream Tub" which is just a great title and it is about the discovery of rapamycin which is was discovered by a scientist who spent some time in Canada. Found on Easter Island or as the local inhabitants Rapa Nui, so that's why the rapamycin and rapamycin is one of these things you know it's got some legitimate uses as a drug but more and more people are talking about it being just you know the cure-all for everything including just aging. So and which all of which may or may not be true but it was just going oh and we're going to touch on that a little bit in this paper but fact that our guest started doing some anti-aging research and then did some cannabinoid research and they found the two go together and we talked a little bit about rapamycin. I had to mention a Radiolab episode so right after this go and listen to the "Dirty Drug and the Ice Cream Tub" and you can hear about how a podcast should really be done and the origins of rapamycin and now I'm going to come back to our guest. So today we've got Dr. Andras Bilkei-Gorzo and he says his name much better than I do. He is a researcher at a German university, but he's originally from Hungary. And our producer, Rene, said, hey, there's this thing about cannabis and anti-aging mice. That sounds interesting. And we got him.

Kirk: Yeah, yeah, I know. You're talking about mTOR, right? When you went on about rapamycin. Yeah, well, and mTOR is all has to do with the endocannabinoid system and how the endocannabinoids system actually has an effect and touches on aging. So this is a really interesting study. It's one of your Heady episodes, the study out of Bonn University. They did it in conjunction with the Hebrew University at Israel, which is where Raphael Mechoulam came from.

Trevor: Mechoulam

Kirk: Mechoulam Yes, that's where he came from. So there's a definite link to the root of cannabinoid research. I enjoyed reading the summary and the paper was really dense for me. It's a classic paper for pharmacists and those science guys. But I found it very interesting. The restoration of the CB1 signaling on old people, you can actually maybe make us younger by using cannabis, but I may be jumping ahead here.

Trevor: No, no, that's... And also listen, you damn youngers out there, depending on how young that is. We talked about a previous episode, how elderly keeps moving in my mind, but there is even some in mice, in mice not people, but when they gave doses to the young mice, their brains started looking a little bit like old people and they gave them the old mice and they started looking like young mice. So I thought that was interesting that, you know maybe us slightly older people have more reason to use cannabis than the young bucks out there.

Kirk: Yeah, maybe for the non-sciency type, mTOR, the mechanism of it, it targets the rapamycin.

Trevor: It is where rapamycin binds onto.

Kirk: Right, so it's the central hub of cell growth metabolism, right? So this is where our cells age, is in this area, and the endocannabinoid system affects it.

Trevor: Yeah, and Andres explains it better than we are, but we've known for a long time that if you starve things, like little worms and stuff, if you starve them, don't starve them till they die, but don't give them quite enough food, they actually live longer, like these tiny little worms and dishes, they've made them live two or three and four times as long as they normally do by giving them slightly less calories and they've done that with all sorts of different beings and there's people who argue that you know if us humans ate less again not starving but ate less we might live longer and kind of the idea being if your body thinks there's not enough food because it isn't it's slows down, i.e. slows down, doesn't age as fast. And if you, one of the things rapamycin might do is kind of trick your body, even if there's enough food around to think it's starving and thus slow down the aging process. And again, Andras will get into this better, but one of fascinating things about the low dose THC is it might do two things. It might tell like your fat cells to slow down, but keep your brain cells working at full speed because normally if the mTOR goes off that rapamycin signal goes off in your brain cells it tells them to slow down too and that makes them be dumber like not produce enough protein to do their thing. So if that was That's that that's this bi-directional parts. But anyway, we're getting ahead of the guest

Kirk: Well, let's let's listen to him.

Andras Bilkei-Gorzo PhD Hi, this is Andras Bilkei-Gorzo. Indeed, I'm from Germany, from the University of Bonn. But to tell the truth, I am Hungarian, working since 25 years almost here in the University of Bonne. And I had two major fields. One is the endocannabinoid system and the other is aging. So the biology of aging. And during my studies... It just happened that these seemingly separate fields, I learned that they are interconnected with a lot of, I would say, branches.

Trevor: And that that's fascinating and that's uh actually how our producer stumbled upon your study and for another German connection he actually grew up in Hamburg so you know we've got a few German connections on this um so and we'll post links to this but we're going to talk about two different studies that uh Andras's team has done but we are going to start with a 2017 one. "Chronic low dose uh THC restores cognitive functions in in old mice." Now the first and you know I'm a pharmacist so I'm just always amazed by this and we've talked to other researchers who look at mice and one of them called uh mice just livers on legs. Low dose in a mouse, three milligrams per kilogram. So you know if you had a hundred kilogram person that'd be 300 milligrams that'd be a huge dose in a person but in a mouse, that's a low dose.

Andras Bilkei-Gorzo PhD Yeah, it would be an extreme dose for the human beings. If you calculate it, it's much of the usual dose that one would use for medical purposes, I would say. If you compare the human brain and the mouse brain, and even if you consider that they contain more or less the same amount of CB1 Cannabinoid receptors. So receptors that bind cannabis in the brain, more or in the same distribution, but compared to the mouse body to mouse brain and the human body to the human brains. So the point is that rodents generally are much less sensitive, less sensitive to psychoactive substances. To any psychoactive substance. So this 3 mg per kilogram in a mouse do not induce any, but absolutely any physiological effect.

Trevor: That that's interesting and that's why you know we have to the studying mice are are interesting and but and like you said you can study a young mouse is two months old and an old mouse is 18 months old so that makes it much more convenient but we have to remember mice aren't people. Uh okay so um in this first one we had uh young two months, mature 12 months and old 18 months old mice and you gave them placebos or low dose THC and then you check to see how their mental facilities were doing with something called Morse Water Maze Test. So maybe just tell everybody what that is.

Andras Bilkei-Gorzo PhD For human beings, it's relatively easy to test whether they learn something or not. We can just ask. They have to sort of test, fill out the form or make any task. It's easy. For animals who cannot communicate so well, it is not as easy. So usually we say that learning is something that the animal change their behavior in an adaptive way so that they have a better outcome after doing this behavioral change. So it's very easy to say that this Morris Water Maze Test, they put the animal to a pool filled with water and mice not only can swim, they can even float on the water. So unlike human, they just they just really floating in the water, but they really hate it. So they do everything to get out from this, from this wet environment like water maze. So usually in this test, we put an escape platform under the water, but from the angle the mouse went, cannot see the platform. So at first, it just swims random up and down, try to escape and only by chance find the platform and it's happy. It takes out, dry the animal and after five minutes, I have to admit, I put it back. And then again, the most swim everywhere, find the platform and to be repeated after the repetitions. Then you will just learn the position of the otherwise invisible platform. It's invisible for them again.

Trevor: Okay.

Andras Bilkei-Gorzo PhD And we just measure the time the animal has spent from start to find the platform. And obviously the animal learn it will be shorter and shorter and shorter and after a while we put the animal to the water, swims directly to the platform and it's over. So sometimes it's like four seconds, they finish the task and then they learn the position of the platform. So in this way, when we measure the time the animal need to find the platform individually, and compare these times between the groups. We can just learn that which learn better. Better means that they learn quicker where is the platform.

Trevor: Okay, and not surprisingly to all of us getting a little bit older, without THC you found that the young mice find the platform faster than the old mice, right?

Andras Bilkei-Gorzo PhD Yeah, it was somehow expected. I have to admit, I checked in the literature and it was 100 times checked in this particular line that this particular age learns slower. Otherwise, good for us and good for the animal. It depends on the behavioral test or learning test we use. So sometimes we see this age-related decline very early, like in the social recognition test or later. So that they can maintain their learning ability up to the longer age. But there are some modalities, I would say, learning forms that they just lose relatively quickly.

Trevor: Okay, and so now this leads into you putting little pumps on the mice for putting in either a placebo or a low dose THC.

Andras Bilkei-Gorzo PhD Yeah, exactly. So the very background from the whole study, we had like two findings before, I have to tell probably in the...

Trevor: Sure, yeah, yeah.

Andras Bilkei-Gorzo PhD These are really boring descriptive tests, but we found that also the cannabinoid system activity in our body, because probably not everybody knows, but our very body can produce cannabinoids, the so-called endocannabinoids. It binds to the cannabinoid receptor, which has very important functions, for example, maintaining our psychological abilities, which is a very important function. And surprisingly, despite of this important function, the activity of this cannabinoid system declines in aging. So the older the animal or the older human being, it's less active. That was one pillar that in aging, the cannabinoid system activity goes down. The other pillar was that we tested knockout animals. That they are genetically modified animals where one gene is missing. In our case, that was the cannabinoid receptor 1, the very receptor that is responsible for the THC effects in the brain. And when this receptor was missing from the animals, they showed an accelerated brain aging. So they were very good, absolutely good in young age. You cannot distinguish white type and knockout animals, but when they get older, they became worse and worse in different learning tests. And they interpreted that they had a accelerated brain aging. So here came the idea that if the cannabinoid system activity declines in aging. And we do know that low cannabinoid system activity, or in this case, low cannabinoid system activity that accelerates brain aging. What happens if we increase the receptor activity, the cannabinoid system activity in young and old animals because obviously, if we give the very same treatment to young animals, we overdrive a normally functioning system. Very simply to all the animals, then we restore practically the activity of the system to the original level.

Trevor: So that was all sort of things you sort of knew before we started this test, right? This was kind of, okay.

Andras Bilkei-Gorzo PhD These were the two starting points.

Trevor: Okay, so... It's you did this test and a few other cognitive tests to to these mice and you found the low dose THC like you were saying basically made the older mice be able to do some these cognitive tasks similarly to the to the younger mice and when the placebo went in that's not what happened.

Andras Bilkei-Gorzo PhD They never became super animal or very wise animal, never ever. But they could return their learning ability or memories to the level that was typical to the young ones.

Trevor: And then you sort of got into the how or the why and now we'll try to get you to explain some slightly more complicated things simply for us but everybody's heard of DNA, it's in the middle of all of our cells and DNA is usually bound up with something called histones and that makes a tightly packed little structure called chromatin. And something about the histones getting, uh, acetylated opens it up a little bit to, to let, let things in there to sort of do, to get the information of the DNA. We call it an epigenetic effect. Do you want to talk a little about that and what we think the, the THC was doing to and open up that epigenetic bundle a little bit.

Andras Bilkei-Gorzo PhD Exactly. So there's a lot of speculation. What happened with those cells during aging? Because the genes are more or less the same. So if there is no major mutation in an animal and a human being, the genetic composition is absolutely the same in a baby, in a middle-aged person, and in the very old one. The genes are the same, so that is why the regulations so how would these jeans express. How they act differs. And what that we found that although in each cell there is all the information that's necessary to make such a human body in a human cell. The cell that is in your skin makes only skin. The cell is in your brain makes only neuron and so on and so on. So also all the information is there but they use only a very very small percentage of this huge amount of information. And indeed, this, the so-called histones that govern that which genes allowed to express and which genes not. And it's very well functioning in young individuals. And we do know that in younger ages, the strict control is disrupted. Very simple explanation for the cancer. The cancer is a normal human cell that forgets that it should be like a blood cell producing cell or a skin cell or whatsoever, but turns back to the embryonic stage. And that here also, in most of the cases, there is histone deficit in the background. And it's not so bad, but also in the brain, where usually the neurons do not go cancerous under normal circumstances. There is also a change in this histone regulation. So again, this original strict control will be, I would say, loosened. So genes that they shouldn't be expressed will be expressed, and genes that should be expressed are not expressed as well. In the mouse brain the second is very typically associated with increasing age. So more and more genes will be blocked. Usually they should be expressed, but they are just blocked. And what we found that when we do this load of long-term treatment, practically this blockade will be erased. And the gene expression in THC-treated old animals is very, very similar than in the control young animals. And maybe a bad message for younger people. What we found that the same treatment in young animals, the THC treated young animals showed a very similar expression profile like old controls.

Trevor: Yeah, I read that. That was very interesting that you almost had the opposite effect when you gave the THC to the younger animals. Did I get that right?

Andras Bilkei-Gorzo PhD So practically we can so briefly summarize that the THC at least in this expression level, need the young brain old and the old brain young.

Trevor: That's really interesting. Now you touched on it a little bit with sort of some of the research leading up to this but let's talk about the CB1 receptor. So you talked about if you had knockout mice. Mice were sort of genetically picked to not have CB1 receptors and then they aged quickly but you you used and I'm tell me if I've got the terminology right. Some mice in one of the that had a disrupted CB1 receptor and initially their learning and memory was better, and then it declined rapidly. Do I have that right?

Andras Bilkei-Gorzo PhD Exactly, absolutely. Absolutely. As a young age, they were just brilliant, better than the Y-types. I always felt that they are like cars without brakes. Really, say if you go to a race, without brake on the short term, it will be faster. In the long term it's not that good.

Trevor: Alright, that is a very nice analogy. Okay, and but the interesting part from this, well, other interesting part for this is when you added low dose THC to these mice with the disrupted CB1 receptor, they didn't get the reversal of the cognitive processes like the mice with regular CB1 receptors, right?

Andras Bilkei-Gorzo PhD Nothing happened.

Trevor: Okay, so that just sort of reinforces the thought that CB1 receptor is key to this eventual cascade that affects the histones and affects the epigenetics. That's sort of where that was going.

Andras Bilkei-Gorzo PhD Yeah, absolutely. In science, it's always how you can lose the memories, because there's always like a chain of evils, a logical chain. And, you know, in the childhood, small babies, small kids, how to work something, they just damage it.  Like break it or stuff like that. So the researchers are like, the small kids. Just let's break it and let's see what will happen. So that was the logical chain... Let's see whether CB1 receptor is important for this effect. Let's break it, let's delay it, and let's see what happens. Really, we can do it with the effect of THC, so congratulations.

Trevor: Nope, nope. And then one of the last lines from your discussion from this first paper, I thought was really interesting. You said other research has shown that blocking histone deacetylation in mice has had shown to be anti-aging, but then when we move to blocking histone deacetylation in humans with disastrous effects. What happened when during the testing of just blocking histone deacetylation in humans.

Andras Bilkei-Gorzo PhD The biggest problem with playing around with histone modifications, if you take any compound that modifies that, it will modify in all in your body, in all the cells. And we shouldn't forget that loosening this expression profile, loosening the expression, the control expression, it can lead to cancer. It's all in this big danger. So here the point is that when we created animals with THC or create somebody consumed THC and it changes also the histone acetylation, let's imagine, but it will do it only exclusively on cells that express CB1 neurons and not in the whole body.

Trevor: So that's why, so more specific and with far less side effects, like you said, than if we change histone acetylation everywhere and that can lead to cancers.

Andras Bilkei-Gorzo PhD Absolutely thats true..

Trevor: So that was my quick run through of the first paper. So now we've the more recent one. The 2024 one. The bi-directional effect of long-term THC treatment on mTOR activity and the metabolome. Now I have literally never heard of the Metabolome before. How about let's start with what's that and what are we looking at?

Andras Bilkei-Gorzo PhD Test the activity of a cell, tissue, or any being, you can do it on different level. And one level is how the whole biochemical act, how the biochemical activities, the bio chemical networks functioning. Then one possibility is like the Metabolome analysis that one measure the level of each possible small molecule that can technically measure in the cell or in the body. And can deduce how the energetic of the cell or the tissue or organ works. Whether it's activated or not activated. Whether its prone to diabetes or it can cover high energy demand or actively synthesize its lipids like hell or shouldn't do that. The Metabolome analyzer is a very good tool. To see what happens actually on the cells, in the organism, in biochemical activity level.

Trevor: Okay. And the other part I've heard of and maybe other people have because, uh, rapamycin is just a fascinating compound originally found from some fungus on Easter Island and may or may not be the key to anti-aging everything. Uh, so there's lots of interesting stuff in the world about rapamycin and what it may or might not be good for, but tell me a little bit about the mechanistic target of rapamycin, sort of what it does kind of in general.

Andras Bilkei-Gorzo PhD It's an extremely useful molecule in each cell because just in aging, there are times also in our lives when the scarcity and there are good periods in life, hopefully for everybody, but there's plenty of goods, we have plenty of money, plenty of time whatsoever. So there are time when we have to save energy. There're times we can't build. Can travel.  We can use it, it's good. By the sense, it is absolutely the same for any animal. Just imagine that if there is a scarcity, it shouldn't move a lot, should seek for shelter, and so on, and if there's a lot of food, then come on, let's go out, let's eat a lot and let's multiply. This is the typical. And this true for each cell. So there are times when they had to switch on energy reserve function and times when they can just drive, duplicate themselves, synthesize a lot of molecules. And this mTOR is the sensor, it's the sensor if there is enough energy or not enough energy. If there is not enough energy, then it switches to energy reserve and starts anti-aging. If there's a lot of energy, then it switches off. It starts, OK, come on, let's synthesize everything. And that is why the rapamycin, it makes a bloody trick. There is plenty of energy in the cells or in the environment, but it turns to the mTOR, it blocks the mTOR  activity and says, there is scarcity. Please reserve, reserve everything. And it's good. It's generally anti-aging. And so if I wouldn't have a look on the negative side effects of rapamycin, it would be good to slow down aging, but it has a really negative effect on the brain because for the brain, for the memories, for the formation of memories, for learning, we need against the synthesis of new molecules, new proteins, we need new synapses, connections between the neurons and if we block it because of scarcity, then it will impair the learning and memory abilities. And here the background of this article was that how could it possible that treatment that has anti-aging effect and at the same time it improves learning and memory. Because until that point we thought that they mutually exclusive. When they exclude each other.

Trevor: You're right. And that was one of the many fascinating things about this. So like you just said, it looks like if you decrease mTOR activity in most of the body, we'll say fat cells, that's good. That's anti-aging. That's fantastic. But if you do the same thing in the brain, it forms less connections, makes less proteins. Bad, you know, makes you dumb. Sure. You know, could, and this is sort of where the paper is getting at, how could something maybe do both? Maybe it does different effects on mTOR in the brain as in the body? Is that kind of where that the paper was going?

Andras Bilkei-Gorzo PhD To tell the truth, we had no idea how is it possible to solve this mystery.

Trevor: Okay.

Andras Bilkei-Gorzo PhD Because again, it's just, it just excluding, excluding each other. You cannot have both, but we had it. And that is why we wanted to go on that what on the earth happens in the body, in the Metabolome and mTOR THC treated animals

Trevor: Okay, so what did you do to our poor little mice friends this time? Were you making them swim and recognize each other or were you checking out what was going on in their brain and cells sort of after the fact? What did you to them for this test?

Andras Bilkei-Gorzo PhD So usually learning is always nice, but there's always a big skepticism behind that. Because if you say that you take any medicine or compound that binds a receptor, and then it changes this and that and that, and there's a very, very long chain of events until you get to behavioral change. And usually behind behavioral change can be thousands of factors. That is why, in this case, we went even to a lower level, and we checked how the connections between the individual neurons change in treated animals. Indeed, we could find like a time-dependent change, a time dependent increase in the concentration of proteins that indicate or show us how many connections between the neurons exist. So we could really see that in THC treated animals, time period long, the concentration of this protein went up. Meaning that there's a lot of new formations, a lot new connections happened in the brain, which is good. That is to support the learning and memory abilities.

Trevor: Okay, so that's the increase in synaptic density.

Andras Bilkei-Gorzo PhD I didn't want to tell this bloody well.

Trevor: No, no, no. If people read the paper, I know you explained that very, very well. The increase in connections, but another way of saying it is the increase of synaptics density. No, but I think you explained it better. I just, in case people read that paper, that's that term that was used in the paper. So, tell me more about the bidirectional, what sort of happened in different time frames of the mice being on low-dose THC.

Andras Bilkei-Gorzo PhD No, that is really interesting that when we give THC, we affect the whole body. But seemingly there was a different time scale in the reactivity of the body and different organs. And what we do think that as rapamycin cheated and there is a scarcity. And that is why it switches on the protective systems. In this case, THC cheated also, and talk to the neurons. Neurons are full with CB1 receptors, cannabinoid receptors. Actually, in the brain, the cannabinoid one receptor is the so-called G-protein-coupled receptor is in the far the highest concentration. This is the dominant receptor type in the brain not in the body, in the other organs it's moderate low expression, if any. So first the brain reacted and in the hope there is a lot of food, they can do whatever they want, it just started to synthesize new molecules, form new connections, so it boosted the learning and memory abilities. But after a while the whole body had to realize that it was a lie. Not as much energy. So it's absolutely normal. The animal never eat more. So the feeding body weight just was the same. So that is why after a while, when the body realized, this body realized so it's not very conscious, but the molecular system that has very good sensors for that, they realized that they run out from energy. That is why then it switched off this mTOR signaling and started this preserving anti-aging activity in the body.

Trevor: And. From the paper, 14 days seems to be this magic time period between the body, or the brain anyway, thinking that I've got lots of resources, lots of food, and then after 14 days I was lied to, I better go into scarcity mode. Is that about right?

Andras Bilkei-Gorzo PhD Yeah, so we had several time points that we measured. We do know that the day, so it's continuous treatment. After three days, we do not know that it's before because we don't have day one, two. But we do know after three days the mTOR is very happy and active and thinks that there is a lot of energy. We do know that day 14 the whole brain extremely happy. And uses this allegedly a lot of energy to synthesize a lot of stuff. And we do know that at day 28, despite of the continuous THC treatment, everything goes back to normal. So at least in that time, at day 28, up to four weeks, the brain realized that, oops, it's not as it was told. If you focus on to the brain.

Trevor: Right, but you said a different thing is happening in the body like for example in the adipose tissue because there's no CB1 receptors there.

Andras Bilkei-Gorzo PhD Absolutely. Absolutely. It's an adipose tissue, see the cannabinoid system activity also has a good effect on the adipose tissue. Okay, not so good. Okay, so it increases the adipose tissue, so usually it increases fat deposits. But here we did say that due to the downregulation the mTOR activity, the adipose tissue started to burn up. The fat reserves, it's very typical if somebody has hunger or continuously don't get as much energy as needed.

Trevor: Different and a bit of a side thing but you mentioned in the paper and I was a little confused. So low dose THC and we've talked about this for the two papers seems to increase things like memory and cognitive function especially in older mice but the high dose one seems to impair memory and might be and this mTOR and high dose THC might be involved in why high dose THC causes that amnesiac-like effects. Can you kind of go over how that all works?

Andras Bilkei-Gorzo PhD It's not easy to compare these studies because high dose was 50 milligram per kilogram. In one shot. So, it was one acute treatment with really high dose. So if you just think about that 10 milligram per kilogram, if I treat animal with 10 milligram, per kilogram usually it starts to show signs of analgesia and hypo mobility. So they move less. By 20 milligram per kilograms it's not only obviously hypo, but the body temperature also drops down. So 50 milligram is really a good dose. So what I do think that by this high dose, one shot, 50 milligrams per kilogram. You can activate totally different network as with a very very low dose. But simply you can envision that there are cells and receptors, they have different affinities. And if you apply a low dose, you can activate only receptors and cell types that have the highest affinity for that particular substance. If you increase the dose, you will activate more and more receptors. More and more brain areas and regions. So it's absolutely true. If somebody takes a huge amount of THC suddenly, it's very bad for the learning and memory and it induces amnesia. That's absolutely true. The effect was indirect but its fine. That's true.

Trevor: Nope. Nope. Nope. Good. Now, towards the end of the paper, you were sort of, the team was sort of thinking about how long we had to give low-dose THC to have these good metabolic effects. And, you know, was 28 days a magic number, was 14 days a magic number. What would happen if someone was on the low dose THC longer or maybe even chronically? What were you, what were you and the team thinking about duration of treatment of low dose THC in mice, at least?

Andras Bilkei-Gorzo PhD I guess you know something, so it's an ongoing study that I'm just working on. So it is an ongoing study that we treat animals from the age of 12 months, each fourth month, 20 days long with THC. And there's a big colony of animals, male and female, and we continuously test them. It's like health checkup every second, third month. And again, it's ongoing. And we will see how it affects the whole body aging and the life duration of the animals. But I have to tell you that it's high time to start the human studies because whatever I find in mice, the first question will be what does it mean for human life?

Trevor: yup  I want to know.

Andras Bilkei-Gorzo PhD 18 months old, animals are old. No, you believe me because I'm the expert old, but 18 months on human being, it's a toddler. It's not easy to compare. Even if you say that y'all... Mouse can live like three years long. Human beings, let's be generous, 120, 140 times more, but it's not quite true because like female mice in the age of 12 months, they can't get babies anymore.

Trevor: Like menopause.

Andras Bilkei-Gorzo PhD Yeah, it's not easy to calculate one to one or simply give a factor that how much older they are, how much they age, how quickly they age. So that is why I do think that when we make this kind of speculation about dose where we see that these animals receive almost 100 times more THC than a human would get. They get older much faster. Then we humans do that. So I do think that we learn a lot from the animal studies. We have the same cannabinoid receptors react in a very similar way to cannabis as mice. That is why I do think that we can interpret the result that it must act in a similar way in human. What about the dose, the duration, and the critical age when one should start? Come on, here we are missing a lot of information. I would say no idea.

Trevor: I think those were getting close to the end, but those lead to, you know, where I was going was, you know, what, what do we think humans can learn about this? But how about before I get to that, if, if we could give you an enormous bag of money and you could design a human experiment, what would, what would you, who would you like to study and sort of what if we had a bunch of volunteers and a bunch of money to run this. What would you like to know? What kind of study would you like to run in humans if you had a magic wand and we could let you do whatever you want?.

Andras Bilkei-Gorzo PhD  Yeah, it would be great to have like a 60 plus person. And there to do like a health checkup, also for cognitive health check up every year. Like three, four years long. And the treatment shouldn't be to have continuous because we see in this human example that when we started to treat the animals, at the metabolic changes, being that day 14. And the day 28, it was just over. So what I do think that in human beings, it's also would be like what the low dose repeated treatment, but like periods of treatment, like one month's treatment, five months without. One month treatment, five months without.

Trevor: So like a dose every six months or twice a year.

Andras Bilkei-Gorzo PhD Like that and by the dose we also speculated because we are blending since years the human study, never found the support for that somehow. So we plan to add like three milligrams per day. And three milligrams is really something that depends on the country, but probably you can even drive.

Trevor: No, no, that would, I agree that most people, most places that would be considered a low dose. Um, so no, th- that, that, would be a fascinating study. And then, you know, and I'm sure the answer is, well, we don't know because all the studies have been done in mice, but for your average older person, we'll say your 60 plus person who may or may not be doing using cannabis medically for other things any sort of takeaways for them about what their cannabis use, they're using already may or may not be doing for their brains? Do we know anything yet or is it all still, we need more study.

Andras Bilkei-Gorzo PhD You know, the usage of cannabis in older age, it's an interesting question because it's used in Alzheimer patients, but only to alleviate some symptoms like aggression or insomnia like that with a very low N number. But for these studies, they did some safety studies. So we do know that under 10 milligram per day per person, the cannabis seems to be safe. That is what we do know. But nothing else.

Trevor: So this has been really interesting. I really appreciate you making the time for us and walking through the studies and the tantalizing, you know, everybody's getting older, so everybody's got an interest in, you know keeping their brain working and staying as young as possible. Did I miss anything? Was there anything else that you think our audiences should know about anti-aging and low dose THC?

Andras Bilkei-Gorzo PhD No, I think the major take home message I want to transmit is that THC acts very differently in young and old individuals. It's one point. The second that in young individuals, other than fun, I don't think that there's medically too much positive effects. No, it was nice. I think it's rather negative, but in older age, in older words, that same treatment seems to be positive. So, really, I would encourage older persons, again, with low dose, it's 3 mg, maybe disappointing, but it doesn't have psychoactivity effect. But it is something that could save good memory for a longer term.

Trevor: So, so there, there was really two studies there, you know, the first one they did mean things like made mice swim through tanks and try to find the invisible platform to get get dry. And not surprisingly, old, you know, if you make them do that two or three or four times and time them how long it takes them to find the the invisible little platform, the younger mice did better than the older mice. But if you gave them a low dose THC, the older mice now found the platform as on repetition as fast as younger mice. So that was cool. And that was sort of along the lines of your endocannabinoid system gets older and then you perform. And then your CB1 receptors seem to go away. And having a little bit of low dose THC seems to make them not quote unquote go away and then the second one was a really interesting part. That was the bi-directional. Make your brain think it's got lots of food and make your body think it has not got lots of foods, your brain keeps being smart and your body keeps anti-aging. That's my real brief summary.

Kirk: Yeah, no, that's good. I am. I always try to bring this stuff so that I can apply it in clinical practice. And I guess one of the things I found interesting, and I guess it's, and it might be, this might be really elementary and maybe too basic, but the reduction of the mTOR activity through a low-caloric diet, intensive physical activity or pharmaceutical treatment therefore has general anti-aging effects. That's a quote I pulled. So here's a question. So... Maybe in the Western culture, less obesity, you would live longer, and more activity, opposed to dying with a heart attack during a marathon run. Okay, it happens, but more activity keeps you younger. And of course, because pharmacists need to make money, if you got pharmaceutical treatments such as cannabis, you might live longer also, or at age in a body that helps. I mean, one thing about getting older, and this is a quote of my father-in-law, and I love this quote, aging is not for the young. Right? It's just not. I mean, because if the young age quickly, they would be really pissed because it's very gradual and, you know, your knees tell you you're getting older. You bust enough ribs on Northgate Trail, your shoulders will start telling you that you're aging. But one thing I've known for a long time as a nurse, as a public health nurse, as a wellness nurse, is that when I'm doing up my laces of my boots, if my belly's in the way, I know it's time to start lowering my intake, right? So like having a body that's easier to function with less, you know, a more balanced diet and more activity, you will age more gracefully. And that's very much an opinionated thing. But it seems to work for me, right. No, no,

Trevor: No, and that's all true. And that's where the rapamycin comes in, is the sort of tricking your body into your, we'll call it below the neck thinking you're starving and above the neck thinking there's lots of calories because your brain and I just try not to go too far afield. I listen to lots of podcasts and other ones have talked about how in times of stress either you know you are you don't have enough money you just got let go of your job or you know literally you're not eating enough your brain doesn't make real good decisions and I'm probably stretching it a little bit here but if your brain doesn't think that there's lots going on lots of food going on it doesn't seem to do good things for you so this is just another way of thinking of sort of making your brain think There's lots of good and plentiful nutrients around and they found it literally can make more synapses more more connections so that was really cool and the other and I kind of the reason we had a good conversation after i stopped recording is probably because I stopped reporting but Andres went on afterwards about he has actually tried to get this study done in people. And he said, yeah, all it would have taken was, and I think it was like 500,000 euros, which called ballpark a million bucks, which, you know, sounds like a lot of money and is because you were, neither you or I have that in our back pocket, but in drug trial, that's not a huge amount of money for a drug trial. And yeah, I just kept thinking because what he was, again, this is all in the maybe, but you know if you gave someone like a three milligram dose of THC, maybe for a few days a month or maybe a week every quarter, like four times a year, what would happen? And, you know, it'd be really easy to administer. And then he was just thinking it could be done. You wouldn't even have to see them because there's been lots of, especially during the pandemic and even before, it's really easy to administer cognitive tests to people over Zoom. So, you could do the standardized cognitive tests. You've got enough people you know maybe you'd only have to do it for a year less people maybe you'd have to it for five years but you know and you have the placebo group you have I used you know low dose like three milligrams THC a week, a week of a month or a week a quarter and see how their brains do and that'd be so cool

Kirk: Well, you know, a couple of things to comment on that, going back to our episodes that we did, Episode 115 with Peter Sue banking on cannabis. We also did an episode with Episode 109 with Ryan Kocot, cannabis business attorney. We also one with David Traylor with the Golden Eagle Partners, Episode 110. These are all financer, so maybe we should turn him onto those guys so he can find money to do this because quite frankly, his results go completely against the classic stereotypical stoner, you know that someone someone on cannabis is you know brain dead and all they want to do is eat munchies and and you know sit there and watch Netflix all night. But but what I find interesting is is that the endocannabinoid system keeps us younger with a low dosing, and they're finding that with lots of psychedelics right now, you know, low dosage mushrooms is helping people with depression. So I can't help but wonder why we can't get funding to do this study. But also, to consider our episode, Episode 91, on dementia and long-term care with Dr. Blake Pearson. He... He also, you know, helping people in sundowning from dementia with cannabis. You know, we've said this a couple times, it just seems we go through these windows, you know, early in our podcast, in, you know, from Episode 107 to 114 seem to be a lot of bankers. The last several episodes seem to be really focusing on the elderly. And I love the fact that you know, low-dosing cannabis may actually keep me younger and keeping my brain active like, for example, doing sunoku or doing crossword puzzles, because they often say that as you get older and if you do retire, when you retire from your job, one of the most important things to do is to find a hobby, find something of interest, keep your brain occupied, right? So...

Trevor: Well, I've got something to occupy your brain. We should crowdfund our own study. All we need is a few hundred thousand dollars, and whichever company we partner up with, they can have a certifiable anti-aging pill that people only have to take three days a month. Who knows? We'll figure out the exact timing, but yeah. Start sending us wads of money. Kirk and I will run the study. Hey, we'll have it on the podcast every step of the way. And whichever company we partner with will have a magic, you know, Reefer Medness, certified anti-aging pill. They should make billions. Everyone should be happy.

Kirk: Yeah, yeah, I'm on that train, Marrakesh Express, off we go. Your know this was another good one, this was a really good study obviously I really believe, the study was 2022 eh?

Trevor: Well, there was two of them, sorry I have them here, the original one he wanted to talk about was 2017, that was the making the mice swim one, and then the bi-directional one is 2024.

Kirk: Okay, all right. So that's why we found them. It was new. It's cool. It just another study that suggests that maybe the whole stigma of cannabis, it is medicine, man. It is medicine and it works and it needs to be studied. Canada needs to get into more medicinal cannabis studies. Maybe somebody somewhere will listen to this and go, let's call them up get this study going, because they've been looking for the fountain of youth forever and wouldn't it be wonderful if the cannabis plant was it.

Trevor: Yeah, and just because you don't want to be altruistic, if just you're a greedy bastard who wants to make a lot of money by selling the Fountain of Youth pill, call us up. We'll set you up with Andres. We'll record the proceedings. Everybody will be happy.

Kirk: Or just grow it in your backyard.

Trevor: Well there's that too.

Kirk: If you were allowed to in Manitoba.

Trevor: Well, no, sorry, before we do the wrap-up, it came up, not surprisingly, at Country Fest, people, oh yeah, you do that cannabis podcast, yeah, and you're talking about the price and too much taxes and not a profit margin, and someone came and said, well, you know, well why would anybody, you know just buy that, you, know, they can just grow it in their backyard, and I came up with what I thought was brilliant, so I'll test it out on you, why not just grow in in your backyard, you absolutely can. How many people grow a tomato in their backyard versus buy it? Everyone buys it because it's easier. So it's not to say you can't grow it, you can. Growing tomatoes, easy. A lot of people still don't. So, you know, we should definitely have a place to buy it.

Kirk: Well, certainly. I mean, certainly and and not to get too political, but we should also have a place where we can consume it, you know, but that's again, go back to episode, what was it 149 when we were talking about talking with the Manitoba government that those are issues. When was that episode? Yeah, episode 146. Boy, we've done a lot of episodes there, Trevor.

Trevor: We've done one or two. And this was another good one. I am Trevor Shewfelt, I am the pharmacist.

Kirk: I'm Kirk Nyquist, I'm the registered nurse and we are Reefer Medness The podcast found at Reefermed.ca. We have a very robust webpage. We have huge cannabis library. You can search it not through the Dewey Decimal system, but actually through drop down menus and you can, we have opinions.

Trevor: No one knows what Dewey Decimal is anymore.

Kirk: Well, well, people over 55 plus might, maybe 65, maybe 65 plus.

Trevor: And if they took low-dose cannabis, they'll remember absolutely the Dewey decimal system.

Kirk: Longer. Yes, very true. Very true. Okay, man, we'll we'll talk to you again, I'm sure.

Trevor: All right. Talk to you later.

Kirk: Cheers.