Health Effects & Risks of Kratom, Opioids & Other Natural Occurring Medicines | Dr. Chris McCurdy

28:36Really? Okay, we'll definitely double click on that in a few minutes. Yeah. And so that's an interesting group of people. But I'm not sure that that's the largest group that are out there. It's really these mood elevations. You touched on a little bit too with the exercise. The people are using this as a pre -workout stimulant to give you more endurance. Very similar to that traditional use, right? These people in the outdoor hot environment being able to work better, harder, faster. And people are using it as a post -workout pain treatment, right? To help kind of soothe them through that all that lactic acid build up and that pain feeling.

29:21So there's a variety of groups, or reported groups of users. But the biggest one is really that mood elevation, that sort of kind of energy boosts just overall general good feeling, not a high feeling. And we specifically ask for those questions. Are you using this to get high? And yet there's a population of people that are purely out there to say, this is my thing. This is what I use it for. I get high. I know people that on Friday nights, they're like, this is my Friday night jam. And this is what I do. And it makes me feel, you know, euphoric and relaxed. And that's it. And so I think there's just various user populations.

30:10And we can't even get to a granular point in that to say, you know, are these populations that are trying to get high? Are they using those really concentrated products more than likely? That would be the assumption. And are the people that are using it more on a daily basis? Are they doing it with more of the powder leaf material and those types of products? And that's generally what we've seen. And interestingly enough, I mean, we looked at the time of day. One of our people using these products, right? They wake up and within the first half hour they have it. Would you say they have it or they need it?

30:51It could be they need it. It does. It absolutely causes a physical dependence. You said it absolutely causes a physical dependence. Do you mean it absolutely causes a physical dependence at every dose and every desired effect? I would say not. So if you take it one time, you're not going to be physically dependent on it. But if you're utilizing it over a course of time, and I can't tell you what that time frame is, because we don't have any chronic studies in humans. And, and, and sadly, we don't even have chronic studies in animals. Although animals aren't going to be able to tell us, I need, I need this, right?

31:28So the physical dependence feeling that most people will report is very similar to that. And, and I, I, I get caught making this comparison many times because people that are using leaf material, excuse me, if they get up in the morning and they want to go get their leaf material, they're not drinking coffee, they're drinking cratum or cratum. And they, they have a headache or they feel miserable if they don't get that into them. Very similar to what we would get with a caffeine withdrawal or physical dependence on caffeine. Now, I can't speak to how much intense that gets as you start to ramp up into those various products because we don't have good reports around those.

32:19But I can tell you that anecdotally people have said they get more restless leg syndrome, they get more severe type physical dependence signs, which restless leg is much more related to opioid withdrawal type issue than it is to a coffee withdrawal issue. So there, there's not only is there a spectrum of physical dependence symptoms, you know, you, you, you have this spectrum of products and which ones are causing which we don't, we don't have a handle on yet. I'm gathering at this point that there are basically three paths of cratum usage in the United States. One group of people is using cratum products to achieve an energetic lift, not dissimilar from the lift they're seeking with caffeine or an energy drink.

33:12Sounds like they're using cratum products pretty regularly to achieve that. And if they don't use their cratum product, they feel a little bit more lethargic, maybe a little bit of minor headache, not as energized and clear as they would otherwise. Sounds a lot like caffeine to me. With one caveat, I should add, when somebody consumes a lot of caffeine, at some point the effect starts to drop off because they gain a tolerance. The effect of caffeine doesn't shift from a stimulant to a more opioid -like effect the more you take. It tends to just make you less sensitive to caffeine over time. It's more of an inverted U -shape function as opposed to a two different curves.

33:55But you will become, you know, you get jittery with caffeine and you get, it actually causes anxiety when you get into higher amounts of it. Yeah, I mean, point while taking, it's just a matter of where you are in that U -shape curve. You got to get over that sort of jittery anxiety point before it really starts to, it doesn't bother you. I mean, when I was a young assistant professor, they would see me come in the restaurant with our guests and they would immediately put a pot of coffee on because they knew I was going to sit there until 9, 10 o 'clock at night and drink coffee the whole time.

34:33And I'd go to bed, no problem. Yeah, I was sitting there today. Recently on a podcast I was a guest on, I shared that I drink and I do not suggest people do this. But I legitimately drink somewhere between 600 and probably 900 milligrams of caffeine per day. People say, well, that's impossible, but I'll drink five zero sugar, cold brew, yerbomatta, each one of those 120 milligrams plus a strong coffee, probably another half cup. I limit it to the early part of the day or up to about 2 p .m. But no problem. But most people who get their commercial vendor coffee, let's say, a venti coffee, take that away from them for two days and they will be complaining of headache and maybe even nausea because there's so much caffeine in those.

35:18Okay, so we got this first case caffeine -like usage. Right, right. Let's just bend that. Second path of creatinine usage seems to be people who use fairly high doses or concentrates to achieve an opioid -like effect. A mild sedative effect, euphoric effect. This sounds a lot like opioid use or higher dosage alcohol use, for instance. And then we've got this third category that you mentioned that are using creatinine to get off opiates or to stay away from opiates. And for whom you told us, creatinine is a real benefit for them because otherwise they would be strongly addicted to opiates. And I should just mention that this third category of people are the ones that I heard from when I mentioned on X, formerly known as Twitter, I said something kind of negative about creatinine.

36:14I just put out a, a, a, a, then tweet now post, which alluded to the darker sides of creatinine. Right. And I got attacked actually by this community that said, hey, were it not for creatinine, we'd see a lot more opioid dependence, we'd see a lot more fatalities. And actually I learned about you in large part through the dialogue that emerged from that response. And so hopefully what listeners of this podcast are starting to hear is that this molecule is complicated, super interesting, and that the usage patterns are complicated and varied and very interesting. So we can't just say, creatinine bad, creatinine good, we really have to explore how it's delivered and what people are using it for.

36:58And again, we can't just say creatinine because it's, that's just like just saying alcohol. Right. So there's, there's a variety of different forms of product that are, that are out there and that are being utilized. And, and it could be that those, those are being utilized in, in very different ways. As I mentioned, we don't have good strong data to suggest one way or the other, but you can assume an anecdotally say that it would make sense. Right. So I think two things that will really kind of probably blow this open a little bit more. One is, is that, uh, creatinine itself contains multiple compounds, multiple chemical compounds.

37:41So it's not just one thing. It's an alkaloid. It has at least 20 to 40 alkaloids in it. Can you explain to people what an alkaloid is and some other examples of alkaloids they might be familiar with? Sure. So alkaloid is a organic molecule that has at least a nitrogen in its structure. So it has to be nitrogen, carbon, hydrogen, it can or cannot have oxygen. But those are essentially the, the template for what we would define as an alkaloid. And then there's various classes of alkaloids. Many things that people are familiar with dopamine, serotonin, these are alkaloids. But we could go further and we've just talked about caffeine, caffeine is an alkaloid, cocaine is an alkaloid, morphine is an alkaloid.

38:29So all of these molecules contain a nitrogen that, that is core to part of their activity. What we believe is essential for them to interact with the proteins in the body. Can I ask a question about nitrogen and protein interactions? Given this as a science slash health podcast, without getting too far down in the weeds, a number of people will hear, okay, it's got a nitrogen. That probably have vague or clear memories of chemistry class. But the fact that you have this, this N, this nitrogen, and you have cells that have proteins, it for the non -chemist. Could you explain how the nitrogen allows that molecule to do something?

39:11Does it bind with more affinity? Does it change the gene expression? What is it about having a nitrogen that really changes the properties of a molecule? Yeah, so there's, there's a couple of important pieces here. Nitrogen is an element that can act as a base. So it can, in a technical term, can accept a proton. So it can also develop a charge. Charges are important because if you think about magnets, right, we have a positive charge, magnet, face, and a negative charge, magnet, face. And those two things will attract each other. You can set them on a table and they'll find each other, right, depending on how strong or close they are to each other.

39:56That's a very similar thing that happens between a nitrogen that can gain a positive charge in our body, and say a carboxylic acid or a negative charge that would be present on a protein. And so that nitrogen being charged, I always call it when I teach my pharmacy students, is almost like a tractor beam, that molecules floating around and it's trying to find that negative charge to interact with. And when it finds the right one in the right space and the right fit, boom, it's into that protein and it causes whatever it's going to cause. Whether it activates that protein or whether it blocks that protein from doing its function, it is a key element of life.

40:42All our amino acids, amino is nitrogen. All of our amino acids are building blocks of life, have that nitrogen, and they have the acid part to it. So they have a positive and a negative charge by nature. And that's what makes up all of our proteins. And so the proteins can have positive charges from the nitrogens and they can have negative charges from the acids. And what we generally see with plant materials is they have alkaloids within those plants. And those alkaloids have helped define really archchemical neurotransmitter systems. Nicotine, perfect example. It's an alkaloid. We have an entire acetacolinergic nervous system, which is the exclusive nervous system and insects.

41:30But nicotine binds to nicotinic acetacolinergic receptors. That whole system was defined by nicotine. Right, and people just to take a step back, what Dr. McCurdy is explaining is that there are receptors throughout the brain and body that are responsible for everything from muscle movement and contraction to your ability to focus, to your memory, neuroplasticity that are so called nicotinic acetacolineric receptors. They didn't evolve because we thought that people would take nicotine. It just so happens that this plant, that tobacco plant that contains nicotine, was used as an experimental probe to understand where these nicotinic receptors are in the body.

42:16So this reflects the fact that humans have been nibbling on plants and seeing what happens for a long time. There's an explikative version of this, which is efferound and find out kind of experimentation. But this is really what old world primates, including humans, have been doing for a long time. And then just seeing whether or not your buddy that ate the plant died, got energized, mated, fought, slept. And I mean, this is kind of still what we're doing. It's just that we do this now with lab coats on. In many ways. And you're 100 % right. There's the old joke. There's two types of mushroom hunters, good ones and dead ones.

42:59Good job because it's going to keep a lot of people safe. And that's the point. And in fact, I've done a lot of work with ethno -bottonist and ethno -pharmacologist and somewhat M1 myself, being in that work we've been doing and actually going into the native places to learn more about it, which is what ethno -bottonist or ethno -pharmacologist would be doing. And we have a lot to learn from the things that have existed on this earth for a long time. Many of those are animals. Animals were probably the first pharmacists and the first physicians, because they learned which plants to utilize when they were ill or sick, and they used which plants to avoid the stay alive.

43:46So they learned these things long before humans were capable of looking at and understanding what the animals were doing and then mimicking the animals, right. And then this is sort of how modern medicine started to develop was all by observational, all by anecdotal, hey, that looks interesting, right. This is happening. And you still do this now in your laboratory. You study animals and we advance to human clinical trials. Animals have a certain advantage in this regard, because they don't subject themselves to the placebo effect, as far as we know. And in addition to that, most animals, including insects, but many non -human mammals, have a much more powerful sense of smell than we do.

44:36And many of the compounds in plants, if they have, like some people will, be familiar with the discussions about testosterone and estrogen, as steroid hormones, having, and then the aromatase properties, aroma. They literally have an aroma that chemists and have know, or you could smell if something has a steroid -like chemical structure by virtue of the way it smells, but animals are very good at seeking out plants that have estrogen or testosterone in them, just by virtue of their ability to smell those compounds. Very, very sensitive. And you take it a little step further, it's also the taste part that's involved.

45:14I had my original mentor, he's gone now, one of my original mentors, he actually would come into the lab, was so old school that he would dip his finger into whatever I made and taste it and say, yep, you got your product. I knew that was coming. Because I knew one of these older, he was a neuroanatomist, and I can't believe that these guys did it. These guys did it. He's dead now by way of age, but he was a member of the National Academy, and we had a shipment of, please do not do this, of non -human primate and human brain tissue being shipped in for his brain bank. Friends of mine will know who this is.

45:51And he opened up the jar that was shipped in, it was in liquid, and he took off his glove, which itself is crazy. He dipped two fingers in, and he goes, 30 % sucrose. But this could have pre -ons in it now, it was fixed, also being a paraphromellum. Exactly. No regard whatsoever, rescrew it, put it on the shelf, and then people got to work. And it was obviously a demonstrate, this was kind of bravado in laboratories to self -experimentation, terrible habits. But it was not uncommon. I mean, this is the way chemistry was done. One of my great men is, and I'll spare him sharing his name, but his master's thesis was making analogs of methylphenidate, which is ridolin.

46:37And so, he, ridolin is a methyl ester. So it's a carboxylic acid that has one carbon attached to where the acid part is. So this makes it what we call an ester. And if you extend the carbon chain of an ester, you can, one, increase how it is absorbed in the body, and two, you can potentially increase how long it lasts in the body. And so his whole project was making from the methyl. Now we take two carbons, which is ethyl. We take three carbons, which is propyl. We branch those carbons to make isopropyl or whatnot. And he would try each one of the compounds that he made himself to see if pharmacokinetically and pharmacodynamically, it's improved on methylphenidate.

47:26Well, guess what's still on the market today, methylphenidate? So that ought to tell you the result of his work. But when he told me those stories, it just blew my mind because I'm so averse to even smelling the chemicals we work with. Good. You blow out your olfactory up, if you'll. I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens. As somebody who's been involved in research science for almost three decades and in health and fitness for equally as long, I'm constantly looking for the best tools to improve my mental health, physical health, and performance.

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50:55That's roca .com and enter the code Huberman to save 20 % off your first order. Again, that's roca .com and enter the code Huberman at checkout. What's clear to me now is that what we're talking about, scientists and everyday apes that we call humans, smelling stuff and tasting stuff and experimenting on one end of the spectrum. And that on the other end of the spectrum, somebody going into a convenience store, we're looking online and buying a little bottle and slugging it down and getting some effect. And I actually think in between those is some important experiential stuff that's missing that perhaps explains a bit of where we are with cratum at this point in time, which is historically, or what you call the traditional use, people would harvest the plant, they have knowledge of the coloration of the plant, the texture, the feel, a lot of unconscious knowledge too.

51:57Maybe it's passed down through generations, maybe they just learn it in a couple of years. And next thing you know, they're brewing it, they're drinking it, as they're brewing it, they're smelling it. There are many more avenues of information coming in about the concentration. You're not just going from product purchase ingestion effect. And I think that perhaps this explains a lot of how we end up with the highly processed food industry, where much of what we're talking about today is paralleled. Sugar is, we have an innate desire for sugar, who doesn't like sugar. We have an innate desire for protein and amino acids, but the highly processed food industry has figured out how to put all this into a package where there's two servings worth, ingesting far more calories, far more preservatives, etc.

52:48In trying to get some effect, but what happens is your threshold changes. And the next thing you know, you're going to the highly concentrated version. In other words, we don't go through this process of stepping through and getting familiar with a molecule. And I think that could explain why people, you know, you're prescribed an opioid. Next thing you know, you need that opioid. Good people have been very willing, it's clear, to do bad things to other people in effort to try and avoid the withdrawal symptoms of opioids. And often the person they're harming the most is themselves. I think what you hit on is a really deep philosophical conversation on a whole nother level, because I just had this conversation with a colleague.

53:36We've lost totally in our culture where it is that medicines have come from. If you look at prescription medications, FDA approved medications, in the neighborhood of 75 % of those that are available today, were either discovered because of a natural product or modified natural products that made it into our drug stores and our hospitals. Aspirin. Aspirin is one perfect example. Salicylic acid. Salicylic acid. It comes from salicyne, which is in the bark of the willotry. And people used to chew on the bark of willotry and that salicyne is the active form. You know, you get salicylic acid, makes it more stable.

54:22And there's a long story there, but it's important because we've lost that sort of connection to nature, that connection we just talked about with the animal world, right? Watching the animals do things and learning from the animals. Metformin, Burberine, a tree bark that lowers blood glucose and works for all the world as well as metformin. Well, look at the biggest selling weight loss drugs right now, the GOP1s. You know, that story, they actually came from the saliva of the Helomonster. So this is a lizard that eats only a few times a year. But in its saliva, it has GOP1 peptides. And this was learned to help control glucose and help do all these things.

55:20And that was modified. And now we have wigovian whatever, those epic out there as blockbuster drugs that are really changing, you know, the shape of our society for hopefully for the whole world. And that's a good benefit and getting people away from some of these sugary things you mentioned earlier too. But yeah, there's just this history, rich history of how drugs have gotten to where they are. And most of us, including myself, you know, we've run in and we pick up a prescription or we pick up something over the counter and don't even think twice about it. We know that it's going to give us this effect and boom.

56:02And so you're 100 % right. And like I say, it's a very long, deep philosophical discussion to get this whole thing circular. But we've lost that whole understanding of where things are coming from. And that's one of the things that I've always loved. And my training originally as a pharmacist, I've always felt like for every disease that presents itself in this planet, there's got to be a solution. There's got to be this balance in nature. And natural products has always attracted me because of that. I'm just struck by the number of examples that are just like popping to mind, about how we've gone from plants and food and compounds it out in nature to through experimentation and observation to medicine.

56:57And then how those same medicines are extracted and concentrated and in some cases diabolically hidden in other things like food. Because I don't think sugar is poison in the same way that heroin is poison. But sugar clearly can be destructive in a way that makes it poisonous. And the way it's used in package and marketed, et cetera, and kid cereals and things like that, I think is absolutely clear. And so the arguments about whether or not sugar is addictive in the same way that heroin or cocaine is addictive are, they're kind of empty arguments until we really define what we're talking about.

57:34And it is that the dose makes the poison. It's also whether or not people are aware of what they're doing. I think this lack of awareness that we're using medicines when we consume products and that we're using medicines at high concentrations that are not typically found in nature is a big part of this. I also heard you say that you believe that for every human ailment and disease there's probably a treatment and or cure out there in nature. That's an exciting thing to hear from a medicinal chemist who runs a laboratory, which by the way, folks, looking over Chris McCurdies, a CV, they publish at an absolutely staggering.

58:18And rate and all high quality papers, I mean, there's never been a single retracted paper. They're just beautifully done studies that just the amount of work coming out of your lab in terms of trying to parse what these molecules are doing is just like mind blowing. So I just want to point that out. It's clearly clear that you're very passionate about this. I have heard the concept of slow food, you know, this idea that instead of just consuming pre -packaged food and you know, we're going to slow down, we're going to cook our food, we're going to get in touch with the food and that will give us a better understanding and health relationship with the food.

58:53I almost feel like we need a slow medicine movement. Yeah, I like that. As somebody who has been using supplements since I was in my teens and I know it's a less well regulated industry. I've long been interested in herbs like I use and I'm open about the fact that I've used Tonga Ali as a like for vitality for a long time, things like Phidogia. I continue to use these and my blood work says it's fine and I enjoy them and it works well for me. But if those were put into a pharmacologic agent, very high concentration, I can bet that it's an entirely different molecule and experience and might cause shutdown of the food.

59:37And I think that's the kind of certain hormone pathways and things like that. There seems to be something kind of unregulated and yet more nuanced and stayed about the use of medicinals in their more natural form. And this is kind of the the the eating of it is like, yeah, you can't get an exact milligram dosage and concentration, but you're also not playing at very high concentrations. Right, right. I look at it like a natural products. They have evolved in Mother Nature's kitchen for you know, millennials. I mean, they've been there for thousands of years. It only took humans coming along to figure out how to manipulate all that right and mess it up.

1:00:30So Mother Nature's kind of got it right in many cases. A couple of examples just just to bring this back to more of a discussion around alkaloids. Opium, opium poppy, long been used and yes, it's problematic, addictive and all these things. But it's nowhere as bad as once morphine, which by the way was the very first alkaloid ever isolated characterized identified morphine. When that happened, the poppy became sort of not that important anymore because we found the magic piece. The same thing happened with the second alkaloid ever isolated cocaine. Cocaine comes from coca leaf, which has been used for thousands of years in South America and indigenous tribes and cultures there.

1:01:26It's still used today. It's one of the only places on the face of the earth that it's legal. When cocaine was isolated and discovered, the rest of the leaf was criminalized and thrown out like the baby's bathwater. Yet there seems to be great medical potential with coca leaf. And this is something that my lab is getting right and embark on next as kind of like our new challenge. We still have a lot of work to do with cradum and understanding that. But you get to a point where a lot of the initial excitement starts to wear off and yeah, we know we need to do these other things. But we want to come back to some of that initial excitement project type work again.

1:02:13And that's why we're embarking on that. World Health Organization is actually doing a critical review of coca leaf again to consider removing it as a globally banned substance and returning it back into potentially the food supply, which is a very nutritious plant. It's utilized by tribes in the high mountains, the high elevations in South America where they don't have much dairy in their diet. There's tons of calcium in this in the coca leaf. There's tons of vitamins. It's so nutrient rich and just a remarkable plant in and of itself. But again, we've forgotten about this because we found this smoking bullet cocaine.

1:03:04And we don't want people to mess with that plant because there's a chance they're going to get that out of it. And this has been a somewhat of a cautionary tale bringing this back to cradum because what we're seeing now is these cradum derived products where they're actually taking compounds that are rich in the naturally occurring leaf. And they're manipulating these into very potent opioids. They're chemically changing these molecules. And these are now products that are out in the market that are available, easily purchasable. And unfortunately in the same places you can buy the more benign leaf if you will.

1:03:50And it's not benign and please don't think that I'm saying cradum is benign at all because the leaf material can be dangerous. And we know that people have problems with even just the leaf material over time. And so we don't understand where those things come from. We don't have a good scientific history of how that evolves. But what we do know is that if we go down the same pathway that we have for things like identification of morphine identification of cocaine to a product that we started from nature again, cradum. And now we're whittling down and figuring out actually it's a metabolite in our bodies.

1:04:36It's a metabolite. Controversially that may or may not exist in the plant. We've never found with all the work that we've done with expert biosynthetic, biosynthetic plant folks. We've never found enzymes that will produce this compound, seven hydroxymitriganin. And that's a metabolite of mitriganin, which mitriganin is the major alkaloid within the plant cradum. And as I mentioned, there's more than 20 alkaloids within this plant. And I really want to come back to this discussion about the differences in some of these alkaloids because they're very, very different. I look at this plant as almost a pharmaceutical shotgun.

1:05:24It's got different alkaloids that are targeting different systems in our body. And this is what makes cradum different. You refer to it in the past as it's opioid, but it's different opioid. It's a different because it's interacting with multiple other systems in our brains. And so we need to come back and revisit that. But before we do that, what we know is that this seven hydroxymitriganin, this metabolite, that our bodies produce naturally from the major alkaloid, is being chemically produced now and sold in commerce. And these are now cradum derived products or isolates or synthetically derived products.

1:06:11We know that that molecule is pure opioid in its activity. It only interacts with opioid receptors. You said these are cradum derived or cradum isolates. If they're going to experiment with or use cradum products, they need to pay attention to serving size. And also pay attention to whether or not the product is contains cradum derived products within it or cradum isolates. Because those more closely mimic powerful opioids. A pure drug. A pure drug. And I actually am of the belief that many people taking cradum products are not aware that they're not taking the leaf type product. Even if they're drinking it, because we just call it one thing.

1:06:56I agree. And that's where we've published commentaries on this because we've felt it's just really important to get this message out. And it's important to get this message out to the medical community because the medical community that are dealing with patients, humans, first hand, they show up in an emergency department. They don't know to ask, did you take leaf? Did you take extract? Did you take a concentrate? What product is it that you actually take? Because most people, if they know, if someone was with them and they got intoxicated by a product, they're probably just going to generically say it's cradum.

1:07:40They're not going to specify what it was. And so this is a big thing that we're trying to, as many of the researchers in the community are really trying to get out, is this differentiation of not all cradum is the same. Well, fortunately, we have the ear on this podcast from some of the folks like Jay Batacharya, NIH, and others who are thinking seriously about revising laws around packaging. I don't have any direct relationship to them, but we have their ear. So I think one thing that I can't imagine anyone would oppose would be the careful wording of warnings about this contains cradum derived products or cradum isolates.

1:08:31In the same way that you like cannabis is legal in many places now or at least decriminalized as I learned from a guest on this podcast, who's expert in cannabis science. People who smoke cannabis are pretty good at regulating the dose based on number and duration of inhales. But people that take edibles are often the ones that end up in psychotic episodes or anxiety attacks due to overconsumption because you can eat something very fast before it hits you. There's like this, there's this delay. I want to parse each of the things that you raised, but I think there's likely to be a couple of basic questions that are on people's minds that maybe we can tick off really quick as we head into that.

1:09:15And I know it might be hard to answer these with a yes -no, so feel free to say maybe or it depends. Kids 18 or younger, avoid, don't avoid or it depends when it comes to cradum. And here we're talking about leaf cradum or cradum products and we're talking about kids in the US so we're not end to end in Europe. We're talking about outside of Malaysia where they have a more innate historical understanding of the plant. I will preface it by saying I am not familiar with anybody young using this in Southeast Asia in a traditional sense. Well, that's good to know. So it's mostly used by people that are labors that are out doing this more adult, if you will.

1:09:57Most of the regulations that have been drafted and put into place in some states are either limiting age of 18 and older or 21 and older. Do you agree with that? I agree with that from the standpoint that the brain is still developing until we're 2425. We know from studies with cannabis that can slow brain development and people can have lower IQs if they start at a younger age versus people that never smoked and develop their brain fully. So we have no idea what the impact is of cradum on developing brain. A lot of people will hate me for saying this but my feeling is the drinking age should be 2425.

1:10:46Just like when your insurance rates go down for your car, it's 25. It's because you have a prefernal cortex. And I think when you hijack that system with any substance that can be psychoactive, you run into problems. And so the best recommendations are in my opinion, getting all the way up to that 2425. But I would be okay with people saying 18 or 21 because that seems to be more acceptable in society as to where we've set barriers in historical precedent. So yeah, I don't, I have great fear as a parent that my own child would go into one of these gas stations not knowing what they're getting because one of their buddies told him, hey, this is cool, try it.

1:11:38And consume it and something something happens. And as you're well aware, there's a big difference between someone who's naive to any substance and takes it for the first time versus someone who's gained some experience with those substances. And so young people are again, because there's not that executive control of the prefernal cortex are much more likely to take those risks. But not because they're being dumb. They just don't, they don't understand. Well, they're not getting the information. And correct. Thanks to you, they're getting the information now. The second cohort that I'll ask about would be, you know, people, let's just say, you know, 18 to 25 and older, who are seeking a caffeine stimulant like effect, assuming they can get a hold of the more plant -like product.

1:12:35So the, you know, where it's not a cratum derived product or isolate are most people able to use a cratum product in the same way that they use caffeine. So on a daily basis, but were they to not be able to get it? They would have a couple days of mild discomfort, but they'd be okay. They could drink caffeine instead and get over the hump, so to speak. Yeah, so it's a, that's a definite maybe question. It depends on the person. It depends on the person. As you know, that we're all so different and we all respond differently to different are the same thing. But I think that let's just say the most frequent thing I hear from people that are using cratum and particularly cratum leaf products on a regular basis, they always say less is more.

1:13:27They always say that the lower amounts they take, they seem to derive more benefit from it. And I've struggled with that from the standpoint of just understanding pharmacology and understanding tolerance and understanding, you know, after you've been taking something for so long, you naturally think you've got to take more to benefit from it. And I think it comes again back to the group of users that we talked about. What is their goal at the end of the day? But if they're just taking it as this sort of mood lifting, elevating energy derived thing, then the recommendation that, and I would say this for anything is stay low and stay slow and, you know, never increase things.

1:14:19What I've been told, because again, there's not something that I use up is, is that people benefit from this on a consistent basis, just like most people benefit from a couple of coffee or two a day. And yeah, if you go a couple of days without it, you're going to have a headache where people start to develop problems is if they are using this for pain treatment or something else like that. And they initially start out, and this is great, everything's good. It does seem that a tolerance develops to the pain relieving properties of this. We don't know what that time scale looks like, so we have no idea.

1:15:06And it'll differ for everyone. We've not done these studies in animals to tell you that, you know, a mouse or a rat is going to take this much time. And therefore we can, you know, scale this to what it would be on a human. We've not even done those types of studies to understand. But I can tell you anecdotally from talking to people, that's what happens. They'll develop these tolerance, and they'll suddenly have to take more to get that relief. And as we take more of anything, we get closer and closer to a problem. Because it's not the benefit that we're getting that generally gives us the problem.

1:15:44It's something off target or off, off of that original frame that we're focused on that gives us into the problems. You know, opioids for just a clear example. Opioids are fantastic pain relievers. But humans develop tolerance to the pain relief properties of opioids quickly. Unfortunately, we don't develop tolerance to the constipating effects and the respiratory depressive effects of these as well. And those are the two things that limit clinical utilization of opioids. If you're getting constipated, then we have to stop using opioids from a clinical standpoint to treat your pain. Because it's, you can get too stopped up and this could be worse.

1:16:34Same thing with respirations. Of course, the main reason that individuals die from opioid overdoses because they stop breathing. And that respiratory depression is nothing to do with the analgesia. Has nothing to do with the pain relief. It's just this off, off side target. Yeah, it's these receptors in the brainstem. I think it raises the question whether or not creatum can cause respiratory suppression. It's a good, it's a good segue to a paper that should be coming out in the next week or two. Oh, great. Well, since it's already accepted, yes or no? It's complicated. Is it so? So I will say this in creatum as a whole, we've not studied in respiratory depression.

1:17:21So the products that are in the marketplace, we don't know. I don't know an answer to this. It's long been said that there's much less respiratory depression from creatum than there is from clinically or illicit opioids. I think that's pretty well accepted in an anecdotal way. Scientifically, we can't say definitively what that is. The paper that we have that's coming out. It should be in the journal of pharmacology and experimental therapeutics. It's already on bioarchive right now, but bioarchive is not a peer reviewed site. We just wanted to get this information out as soon as possible because we think it is vitally important for public safety.

1:18:05The seven hydroxymitrigine in products that are now being sold as I mentioned as semi -synthetics or isolates are actually causing respiratory depression equivalent to opioids. Wow. Okay, so these are the specific alkaloid metabolites. So to back up again, both the alkypid creatum contains somewhere between 20 and 40 alkaloids. One of them is most abundant. The metabolite of that is what's active in the body. Chemists have figured out how to manufacture that metabolite. People are taking products of the pure metabolite mixed in with some other things, and that can cause respiratory depression on par with opioids.

1:18:55In a rat. So I will caveat that. But it's one of these things that we talk about all the time. If it walks like a duck, if it quacks like a duck, if it looks like a duck, it's a duck. Yeah, I think when it comes to translating animal studies to humans, it's hard often to take a dosage by kilogram of body weight and translate because of metabolism is different, et cetera. However, I think when it comes to neural circuitry, which is what we're talking about when we talk about respiration, these two nuclei in the brain, pre -botsing or in paraphacial nucleus, which have abundant receptors for these things that control breathing.

1:19:32That machinery is so highly conserved from mice to rats to non -human primates, as I always say, rat cat monkey bat and human, that it would be remarkable and extraordinary for the system to work much differently. No, and I think in humans, it's going to have exactly the same effect. But I can't say that definitively, and it's not an ethical thing to really do, right? But we know that that effect, even in the animals, is completely reversible with Narcan or Naloxam. So it's also highly opioid receptor involved. I'd like to take a quick break and acknowledge one of our sponsors, Function. Last year, I became a function member after searching for the most comprehensive approach to lab testing.

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1:22:11But if I were, I would say, okay, based on everything I've learned thus far, the plant -based cradum products that were still close to the plant price seem like it's a maybe scenario. Kids and people up to 18, maybe 21 or even 25. It's a hard no. Stay away from it. People older than that are going to have a varied response. Could be like a cup of strong coffee or an energy drink or two. I mean, some of these energy drinks now, I mean, they pack a serious punch and you look at the total caffeine count. And it's not that high. But then you look at the serving number and you look at the other things that are in there that serve to amplify the neuromodulator.

1:22:54In fact, like increased dopamine napene, I mean, they've got hooprazine alpha GPC. They've got things to enhance the serotonin pathway. They've got things to take away the jitters like altheanine plus the caffeine plus some additional stimulants. And pretty soon you go, yeah, the caffeine count isn't that high. But what you've got is a neuromodulator cocktail in there. So, you'd say, okay, for adults, use with caution, figure out minimal effective dose, and be aware that it could be habit forming in a serious way. Something like that. But then I would probably also create a third category, which is, and I'm going to get the pronunciation wrong, but the seven hydroxymetabolite of mitra genin.

1:23:34Mitra genin. Mitra genin. Are mitra genin, some people say. Mitra genin, seven hydroxymetra genin. Tradgenin, tragedy, okay, should be, if I were FDA commissioner, I'd say, this just sounds all bad. Just flat out make it illegal. Yeah. So, you're not making cratomy illegal. You're making the opioid -like derivative illegal, or extremely hard to get, or maybe you need some additional barriers there. Why isn't that way? I mean, why did we sit down here today, me, ready to ask you, should cratomy illegal, when we're really talking about two different use categories, younger and adult people, and we're talking about basically two completely different compounds.

1:24:20Yeah. Well, even very different products, period, right? So, it's extremely complicated, because under the FDA's dietary ingredient rules, a metabolite of a dietary ingredient can also be considered a dietary ingredient. I see. So, this is kind of the loophole, if you will, that's allowing this to be in the marketplace. But there's several group of advocacy, nonprofit organizations out there. There's American Cradle Association, there's a global Cradle Coalition, there's a holistic alternative recovery group. What's the whole, are these people who are looking at this as a good alternative to opioid abuse?

1:25:09So, in many of the cases, yes, all of the cases, yes. So, I should say that. The American Cradle Association and Global Cradle Coalition are much more advocating for science -based information, and knowledge around cratum and cratum products, and putting actual guidelines in place that will give some regulation to the industry, that they claim the FDA is not doing right now. The FDA is just letting it exist in the marketplace in whatever form, shape, size it wants to. Some of these groups are really trying to put guardrails around what a product should be, what should be on the label, what a serving size should be, what limits of alkaloid content should be.

1:26:04There's this other group, the heart group, which is really a proponent for this seven hydroxy product, and saying that it's out there to reduce harm, it's out there to help people benefit from a product that is not an opioid, right? But it is purely an opioid, but it's not a prescription opioid, and they're saying it's reducing harm. I don't know that anybody has evidence to demonstrate that yet. There's no solid evidence. There's some, again, anecdotal evidence. They released a statement recently suggesting that there's no mention of these in the FDA's databases of adverse events, the fears database.

1:26:45But then again, it makes you wonder if these products have only been in the marketplace for a couple of years, is there even a coding to put it into the fears database so that can even be recognized? If somebody were to take a cratum product, either an isolate or the plant product, and then drink alcohol, are they at greater risk for dying from respiratory failure? In the same way that if somebody takes an opioid and drinks, they can die. Actually, sadly, I know a lot of cases of this, of people who even took prescription opioid a day before, an afternoon or night of drinking, and were pretty good drinkers, if I'm going to say it wasn't, it wasn't someone real close to me, but what I understand were good drinkers and then end up dying and they're typically in their sleep after the night of drinking.

1:27:39This is not uncommon. This is independent of all the fentanyl issues. Correct. Does cratum have the same potential risk? So, cratum as a whole, it's hard to say. Nobody's done any studies combining this. In fact, interestingly enough, the studies that have been done with alcohol are looking at reduction of alcohol intake. So, it has been reported anecdotally again that cratum actually reduces alcohol consumption. Interesting. And this has been anecdotally mentioned by many people that use it. I just don't have the interest in drinking anymore or I can have a couple drinks and I'm not trying to get drunk.

1:28:22Now, there's a lot to unpack there because there could be all kinds of different things happening, pharmacokinetically, drug interaction wise, if you will, just like you're mentioning. There are groups that are funded now. We're not one of them from the National Institute of Alcohol, Alcoholism, Alcohol Abuse. And I triple a to study specifically cratum as a harm reduction agent in alcohol use disorders. So, such an interesting molecule, right? I'm talking about a molecule that can be potentially used to help wean people off opioids, maybe even limit alcohol consumption for people with alcohol use disorder, what used to be called alcoholism.

1:29:03And at the same time, can serve as a stimulant and maybe even an aphrodisiac. Are there any data, excuse me, about the binding sites in the brain and some of the pathways that would make this molecule an aphrodisiac? Not specifically. So, you know, I earlier said it's kind of natures by agra, but it's not interacting with the phosphodiesterase pathways. It's not causing these ideologies. That we are aware of. Which is what biagro basically does. Limits the enzyme that would lead to vasoconstriction. Correct. Correct. So, you have, we don't really have clear evidence of that. And what it may be is that it's this increased sort of stimulant, stamina activity.

1:29:54But let's back up to one of the very first goals when we were funded by the National Institute on Drug Abuse to study this. The main question that was asked was, can you isolate as many of these 20 to 40 alkaloids as possible. Purify them and tell us what each one does individually. Okay. So, the easy one to get was metrogunin. And if you look at the majority of the literature around creatum, and there's almost a thousand papers in PubMed now, I look this morning just on creatum. We account for almost 10 % of that for my lab. Yes, that's quite the thing. And the vast majority of the studies that are in the literature now have been done with the major alkaloid metrogunin.

1:30:45And I always remind my lab and my team and my collaborators, metrogunin does not eat bull creatum. Cratum is a complex natural product with all these other alkaloids in it. And so, let's, I wanted to come back to this, so let's just unpack those alkaloids very quickly, just to tell you what's going on. So, metrogunin in the major alkaloid actually has affinity for opioid receptors, but very weak affinity and doesn't do much from an analgesia or pain -killing perspective, which you would think the major one, that's what it's there for, that's what's going on. It also interacts with a couple of other important neurotransmitter systems.

1:31:26And there are other alkaloids within the plant that are majorly exposed when you ingest the whole plant product into our bodies that are heavily interacting with serotonergic system. So, our sort of satiety center, our mood elevating center, if you will, most of our antidepressants are targeting increased levels of serotonin and increased levels of noripinephrine in our bodies. And so, we know that we're engaging in activating the serotonin system, which by the way is also involved in pain processing. And then, some of these alkaloids are heavily hitting the adrenergic receptors, which is our stimulant sort of activity centers, our fight or flight sort of system, if you will.

1:32:16And it makes it into this very complex alphabet soup, what I like to call a complex symphony orchestra, that's playing multiple instruments in our brain at the same time. And some people say that this is the best pain relief they've ever had. And I come back to it as a science, and now saying, okay, we've looked at all these different mechanisms that are involved. We've never treated pain from those three prongs at once, in a single drug or in a cocktail of drugs in the human. Can you list those off the screen? Yeah, so those three are opioid, which obviously we used to treat pain. Serotonin, which we sometimes use now for chronic pain, drugs like amatryptoline, which is a serotonin, reuptake inhibitor, old -school tricyclic anideopressin, used the lot for neuropathic pain before things like gabapentin, neuroton came along, or pre -gabaline.

1:33:22And then the adrenergic system, the adrenergic system, which is actually one that we target in some of the side effects of opioid withdrawal, with drugs like clonidine, which are alpha -2 receptor agonist that help shut down neurotransmission in our brain. This is really fascinating because all three of these neurotransmitter systems are intimately involved in pain processing. And we've always looked at, and I'll say this from a medicinal chemist standpoint, medicinal chemist goal are to make the best compounds, the most selective compounds for one target. So pharmacologists can figure out what that target is doing.

1:34:04And here's another example from nature that's saying, look, if we hit all of these targets at once, you don't have to step on the gas quite as hard on each one, and you get some kind of relief. And that's why I'm saying what I hear from a lot of people is less is more. So a lot of people that are reporting pain relief or mood elevation, they're not reporting psychoactivity. They're getting the benefit without the psychoactivity. But if you have the goal when you take these products that you want to get high or you should feel like you're on a drug, then that's I think where people are starting to push in saying, well, I obviously can't be benefiting from this if I'm not feeling like I'm on a drug, right?

1:34:51So I want to say, first of all, thank you for that description of this tripartite effect of the creatin plant and how pain relief in its ideal form, not too much sedative effect, pain gone, but still the noradger, nirgic effect where people aren't sedated to the point where they can't do anything, is ideal. And that what you said also really highlights and you said it better than I ever could, that what we do in science and medicine, reduction of science and medicine is we're trying to isolate receptors in pathways and do stress response curves, and we're trying to come up with essentially pills of isolated compounds that hit one, maybe two of these different pathways.

1:35:37In fact, it's interesting that whenever a drug impacts multiple pathways, we call them off target effects, right? That just that language alone, it tells you everything you need to know, which is that you're trying to target specific receptors and pathways, but the way that the brain works isn't like that, right? Earlier we were talking about breathing, I mean the cardio respiratory system are intimately involved and it's no surprise, therefore that you have some of the same receptors and systems involved. You mentioned increasing serotonin for the treatment of depression, SSRIs, these days a lot of people are down on SSRIs because of the negative side effects, reduced libido, appetite or increased appetite.

1:36:18I will say in fairness to SSRIs, SSRIs have helped a great people, especially with people with true clinical OCD, these are not people that are obsessive of nature, these are people who are really stricken by their OCDs, so there are places where SSRIs are valuable, but I think that the interesting thing to me is always that a really good scientific study isolates variables, so that you can assign any observed effect to that compound, to that dose or that behavior, at that frequency, in that population, but that's just the nature of reduction of science, plants on the other hand, as you pointed out before, the fact that they hit multiple pathways and that when the dosages are appropriate, it seems like they can be very beneficial in certain areas, I'm not suggesting people use cratum, but the cratum leaf, it sounds like could be very beneficial for people in certain contexts, not just people trying to get over opioid addiction, but maybe pain relief, etc.

1:37:22But you have to kind of wonder, this is kind of a philosophical slash spiritual question, I mean it's kind of amazing that these plants contain a compound or set of compounds that can activate the pathways that we're seeking them to activate in a desired way, plants by the way can also kill you folks or make you crazy if you take too many of them legitimately crazy or dead, but you kind of have to wonder, like you can ask the why, quite a lot of people, but you'll never get there, I wasn't consulted the design phase and neither were you, but it is kind of beyond statistical probability to assume that a plant would contain the solution to pain by dosing each of the impact on these different pathways, it's just the right way.

1:38:09And yet, it sounds like such a plant exists and that plant is cratum. This has been the fascinating part in, I have to just say one of the biggest changes in my entire research program is when we move to the University of Florida and the University of Florida is unique in that we have our College of Medicine and we have all the health sciences on one campus, including veterinary medicine, which we've been doing for a long time. We also work with, and we're doing clinical trials with cratum and companion dogs, which is a whole nother discussion. Yeah, it's because you're in pain relief too. It's right.

1:38:47And we have very poor pain control in animals, particularly in dogs. We can come back to that if you want. But most universities in the United States, state universities have either the medical college or they have the agricultural college. University of Florida has both 800 pound gorillas, if you will, in the same system. So University of Florida is extremely well known around the state of Florida and around the country for their unit called IFAIS, which is the Institute for Food and Agricultural Sciences, which has a service facility in every single county in the state of Florida to work with agricultural industry.

1:39:36And we've worked with plant scientists on cratum to understand what is this plant doing and why is it producing what is producing? Why are these chemicals there? So to get to the answer to your question, we think we've figured out why the plants are producing this. It's definitely not for our benefit. So plants produce chemical defense all the time. Right? The alkaloids are, by the way, bitter compounds by nature. So most of the time they're anti -feden to make sure that the passing by deer, giraffe, whatever is not going to eat all the leaves off of that tree. They're going to have a couple and realize this is nasty.

1:40:22I don't want to do this. I'm going to move on to the next plant. However, interestingly enough, metrogonospiciosis, the cratum tree does not grow in a place where it's going to be attacked by herbivorous animals. These grow in very swampy conditions. And in those swampy conditions, it's very humid. It's on the equator. It's incredibly hot. And what grows in humid environments? Fungus. These compounds that the tree is producing, which yes, they seem to interact with our neurotransmitter systems for whatever reason, are highly effective antifungal agents for the plant to ensure its ability to survive and stay in that environment and thrive in that environment.

1:41:19Is it a good antifungal, potentially in humans as well? So that's a great question, right? We decided we would look at this from human pathogenic fungus. So what fungus disease causing fungi in humans? So far, we haven't seen anything. But as far as agriculturally important fungus, it seems to be able to be very potent on some of these. And so we're actually looking heavily into this area. So there's parts of the chemical structures that are conserved on all of the alkaloids that we see this tree producing. And that chemical structure, actually, the way that it tipped us off was we equated that back to a naturally occurring antifungal that's already used in the agricultural industry.

1:42:12It has the exact same chemical pattern, what we call moiety or a function in the molecule. And those are called strobe allarins. The molecules that are used and they're used in USDA agricultural industry as anti -natural antifungals. So we always kind of made the joke that if this gets put into the controlled substance act, we'll just go to the agricultural chemical pathway and see if we can develop new antifungals for the ag industry, particularly in a state like Florida, that's very hot and humid that could benefit from good antifungals. So there's a reason that plants are producing the molecules they're producing.

1:42:58But through trial and error, as we've talked about before, through watching and historical just trying things, the efferone and find out, you know, they figure out there's some benefit to humans from these plants, right? Plants are protecting themselves and trying to evolve just like any other species years ago. I had a friend who's very serious about Chinese medicine practitioner. And I said, what sorts of goodies does Chinese medicine offer for somebody who's interested in supplements and medicine and formal medicine also? And they gave me, don't do this at home, kids, they gave me an alkaloid that's from gecko skin that's been shed and it's a stimulant.

1:43:50And it's very bitter. I know because I opened the capsule and it tasted it before I took it. And it was a pretty decent stimulant. I prefer caffeine, but it was a nice arc stimulant and it was clearly a stimulant. And you think, okay, well, how did they arrive at this? Well, somebody observed that geckos are able to survive in an area where there are a lot of birds that feed on reptiles and other small critters. And that's the way that the geckos have learned to be less tasty, be bitter. Yeah. Because if you're sweet or you're a great protein snack, which most every moving organism is, well, then you're better off being bitter than being sweet.

1:44:32Species won't be around long. Exactly. So there's a lot of this out there. A couple of days ago, I asked my ex audience, does anyone have any questions about cratum? A lot of praise for you and your efforts to really be discerning and nuanced about the messaging around cratum and for your work. So someone asked something that I have no idea what it means, but this person is a researcher. I know them. They're well known neuroscientists. And they asked, is there really a difference between white vein, red vein and brown vein? What are we talking about here? I'll answer the question very quickly.

1:45:10Most of this is marketing. But what we realized is that there's on the tree itself, the trees leaves have veins. And those veins are red in some cases or green in other cases or white. You can think about this like rainbow shard at the supermarket, right? You know that we've got beautiful colors or rhubarb or whatever you want to come to oranges versus. Yeah, sure. Sure. So what we have seen, and I'm going to caveat this answer to because a lot of marketing goes into this white vein, red vein, brown vein, green vein, yellow vein. And there are actually five colors of products that come into the United States.

1:46:01And it has to do with how those have been cured or dried after they've been harvested. So green leaves, fresh, not dried very much, dried in a cool environment indoors. They're going to retain the greenish color. And they're ground in polvarizing that powder comes in green. That's it. That's your green vein, many in many cases. And vice versa, as you go through the colors, it really depends on how the color of the leaf material was. We grow these trees at the University of Florida. And it's interesting because if they they can get sunburned and they can there are undercover canopy crop. So the trees naturally exist sort of underneath a higher canopy of trees.

1:46:56So they're shade grown. If they get direct exposure into the sun, they'll actually burn and the leaves will start to turn brownish red. We've done that with specific wavelength light studies and greenhouses and whatnot too. But they'll also get damaged when it gets cold. And they'll get brownish color or they'll turn redish color again. And that's some sort of response, chemical response. But it is a chemical response. And this is where I put the caveat in. Because when we've isolated it, when we've not isolated, but we've analyzed the different strains and colors of powders for their alkaloid content, they're all very similar.

1:47:42So the alkaloid is not changing. So we always said it's kind of a marketing deal. And it's more of a potential placebo thing like, oh, this is more relaxing. This is more pain. This is very reminiscent of the indica sativa question that I got around cannabis. And yet when you talk to users of indica versus sativa and different strains and different amounts of terpenes and types of terpenes and cannabis. People will swear by the vastly different effects of these things. But it became clear to me anyway that some of that, not all of it, some of it is related to the fact that you have different, you call them chains of custody as you go from the plant to the product.

1:48:27So people will associate a particular effect with a given product. That product might be labeled green vein or red vein. So the effects may indeed differ, but it's hard to trace back to the actual differences in green vein versus red vein. That's what I'm gathering. In terms of their alkaloid will make up. So when we analyze things and let me just let me take a step back here. So plants produce many classes of chemicals. Right. Alkaloids are the ones that traditionally people think of with pharmacological activity that are interesting that are going to have psychoactive activity. So most people focus on alkaloids as being the biologically relevant plant materials.

1:49:10You mentioned cannabis. Cannabis has no alkaloids. So those are terpenes, which is another chemical class of molecules. They do not contain nitrogens. And they we know no interact with specific proteins in our body as well. Like cannabinoid receptors. So plants are producing many classes of compounds. They produce steroids. What we call phytosteroids. They produce tannins, which anybody who's like me likes wine. You know, you talk about tannins and all the different types of tannins that can be present at wine or teas. Yeah. And to that point, there's antioxidant type compounds in there. You know, all kinds of classes of chemicals.

1:50:02No one to my knowledge has studied anything other than alkaloids in the crayon plant. Likewise, with cannabis, a lot of it hasn't been explored besides THC and CBD. And many of it is because it's in such low quantity. And coming back to the point when we talk about most of those studies that have been in the literature have been done with the major alkaloid, because that's the thing that people can get a hold of. It's easy to isolate, purify. And if it's the major alkaloid by default, it should be causing the activity. It makes for good science, right? It's hard to risk somebody's PhD career on.

1:50:39On a gene or molecule that's in low abundance, you want to err towards probability of success. Okay, so there's your answer on white vein, red vein brown vein. Sounds like it's more product dependent and source dependent. In terms of the, for the user, the potential user, and maybe you shouldn't trust them. Yeah, I mean, just just finalize that with the fact that we don't know if there's other changes in chemical composition outside the alkaloid. So there could be something there. Is there a potential use for creatamines an anti -depressant? I think that's probably one of the areas that needs to be investigated much more thoroughly.

1:51:20We got a specific marching order. We were looking at many things, including regulation of blood glucose. So we can talk about a lot of potential things that are going on. But the mood elevation and the sort of overall well -being, feeling that many people report. It's all anecdotal, right? But at certain point anecdotal is a signal because it tells you once enough people are saying this, it must be something. So we need to pursue that. And we need to do it in very good control clinical trials with humans so that we can understand if there's true benefit. Next question for you is, and this was a very common question, how to get off creatam.

1:52:18This person says, my brother was on it and is having a dreadful time with it. He takes it now just to feel normal. He feels like he's a slave to creatam. We don't know what product he's taking or how much. But I will tell you, even though that's just one question, this came up numerous times. And it's a great question, unfortunately, without answer right now. But I do want to stress a very important piece of this research and what we're trying to understand. I've talked a lot more about the chemical nature and the pharmacology and differences in pharmacokinetics and potential benefits with this plant.

1:53:00But it's clear that there's potential harm as well. And we've seen that in many, many stories. These are examples of that. I have a pretty routine lunch with addiction physicians in Gainesville, Florida. And pre -COVID, many of them said, hey, this will be interesting to you. One of our patients came in an opioid treatment and said they started using creatamins. They're doing much better and they're benefiting. And then we didn't see each other for a couple of years because of COVID. We resumed our lunches and they said, you won't believe what we're seeing now. People are coming in seeking treatment to get off.

1:53:46We've unpacked a lot of discussions over lunch table in trying to figure these things out. Most medical practitioners go to the fact that this is opioid -like and they're using buprenorphin or suboxone, which is one of our gold standard treatments or even methadone to get individuals off of creatam. And they say it's working. But my problem with that is we've said already, this is not a typical opioid. Cratum is not a typical opioid. It's atypical for sure. It's having these other pharmacologies. And so yes, we may have success in converting people from taking creatamins by putting them on an opioid, which many of them might have been trying to get off of in the first place with this.

1:54:44But the pharmacology of creatamins is so complex and different that you're only pressing one of those levers in the system that we just talked about is at least try partied in its activities. So you're ignoring the serotonergic piece. You're ignoring the adrenergic piece by only giving an opioid like methadone or buprenorphin. Is that the right way? I don't know. I don't know the answer to that question. We know that in certain cases when we've tested animals and we've pushed them into toxic levels of certain alkaloids, not creatam itself. But we know that in many cases opioid antagonists won't reverse some of those effects.

1:55:35Because of these non -opioid pathway effects. So it sounds like for this person's brother or sister or somebody that wants to get off creatam, suppressing the same pathways that are used to get people off opioids like buprenorphin, naboxone, etc. Could be useful, but there could be still other aspects of dependency related to creatam that those won't resolve. That's what I'm here. That's that is and in the concern is by moving someone from a creatam product to a pure opioid product. Like are you actually potentially making things worse? Because it's going to be hard for them now to get off of those products.

1:56:20It's a circular question, right? It's very difficult to answer. And this is one of the things we're really trying to get to the bottom of what is what is a better what is a more appropriate treatment. But for right now, it seems that what is working as opioid use disorder treatments. Buprenorphin. Buprenorphin. I will say there were a number of people in the response and obviously this isn't a formal study who said best way to get off it not to start, right? Just don't touch it. There were a lot of don't touch this stuff. That's based on observation. It seems, you know, I'm, it's conjecture here.

1:56:57But based on observation that they know people have had a terrible time getting off it. Like the best way to to avoid dependencies to not start. There were a couple questions about that specifically and the effect on the serotonin system is there. You know, you could imagine if you're trying to come off creatam. Because of an opioid like dependence. Taking Buprenorphin. Maybe doing other things to support the serotonin system at the same time. Like it doesn't have to be just one treatment. But obviously this has to be overseen by somebody that can prescribe these drugs. Yeah. No, and I think the key there is is is not ignoring and trying to do it on your own, but getting medical professional help and getting someone that can give you not only a, you know, medication assistance in treatment, but giving you support of treatment.

1:57:54In other words, counseling and social aspects of that as well. I'm going to just tell you one comment that somebody asked I relay to you because I think it's informative for everybody. And then I'll I have one more question from from the online audience. Please tell your guests I quit prescribed topical boot trans patches for lower back pain. Cold turkey by switching to create them as an alternative treatment. They want you to know that. So this is somebody for whom it was effective and apparently they wanted you in particular to know that. I appreciate the comment and it's not an uncommon theme that I've heard and I've gotten emails from from people that have had that story.

1:58:36They've been able to switch cold turkey and just just to touch on what you said earlier too. You know, we had a first case report that we published in the literature was in 2008 with a human case with my long time collaborator Ed Boyer who's a emergency department physician. And Ed called me and he said, you're not going to believe what I have in the ED. He said, I've got someone. The ED is the emergency department came in with a full blown seizure. And this is all in this paper. It's unpacked. It was what we think happened is that he took a Modaphanil, which is a drug for actually narcolepsy.

1:59:23He was feeling tired. His his wife had these drugs. And so he took this on top of his well established use of of creative. And this a lot of people use Modaphanil as a stimulant cognitive. Very very common. Now you have to remember this this took place in 2007. Okay. So the only product that was in the market at that point in time was leaf. So leaf, create them and Modaphanil. Yeah. So it caused him to have a seizure. In the emergency department, they had no idea what to do. Luckily, Ed knew me and that we were working on this and we were working on another thing called Salvia Divinorm, which is a whole nother study about hallucinogenic mint plant.

2:00:11But we started talking and when this guy came conscious and and was fine. By the way, he quit a habit of delotted, which is a prescription opioid cold turkey switch to create them no issues. Creative leaf. And then after he had the seizure and came to in the hospital, he quit cold turkey, create them. The only thing that he had was a running nose and he said he had no desire to go back and take it anymore. Now, at the moment in time that that happened, this was an equals one case ever. And my friend Ed said, this sounds like the Holy Grail. If you can get off of it, off the law, you never off the lot of off of cratum.

2:01:04And now you don't even have a craving to go back to it, right? Now, that's a huge caveat in this story. The guy had a seizure. So significant event occurred that he decided at that point in time he was never going to touch cratum again. Speaks to the precariousness of polypharmacology done at home. Yes. And I once took Modaphanil, half a dose. I'm very susceptible to medication and it kept me up for almost two days. Wow. And I took it in the morning time. Some people I know can take it just fine and use as a stimulant when traveling, especially to give talks after whatnot and for narcolepsy, etc.

2:01:51I'm wondering if we can have a bit more fun talking about plants and some of the things that come from plants and their interesting uses. You mentioned the coca plant earlier. I don't think anyone except a cocaine user would say cocaine is a good thing. I mean, it seems to destroy a lot of lives. And I'm sure there are people who can use it at low doses or low frequency and not end up in the gutter in one way or another. But it does seem to be a fairly destructive compound on the whole. And yet, as you mentioned, the coca leaf has these interesting compounds when it's used as a leaf product. There's a similarly sounding leaf which is the coco leaf chocolate and then there's cacao.

2:02:38And I'm not trying to get down into the romper room version of plant medicines here. But recently I started eating roasted raucaca cow beans for their polyphenol content. I actually like the bitterness. They have a lot of fiber. You have to not over consume them. You have to make sure they're clean source so you don't consume heavy metals, etc. But there's a lot of interesting healthy stuff coming from plants. So let's talk for a moment if you wait about the coco leaf and coco and chocolate. I like 100 % chocolate. 100 % Venezuelan chocolate. Delicious. People want to be like, it sounds like baking chocolate.

2:03:12But it's smooth. It's got a bitterness but a little bit of sweetness. It tickles my brain just right. It's healthy. It doesn't have sugar. I don't over do it. And wow, it's a, it's a, it's a real thing. Yeah. And it's delicious and I look forward to it. And I don't feel like I'm addicted to it because I haven't had any for a little while. And I'm fine, but I'm looking forward to it. Tell me about the benefits of cocoa and some of the alkyloi and other things that are in cocoa. This is not to send people out to ingest a bunch of sugar, sweet and chocolate. We're talking about 100 % cocoa or cacao beans.

2:03:48Right. There's real medicinal power in this. Yeah, yeah, there absolutely is. And it's fascinating too because there's, there's a few things that are in there. And this is not something that I'm an expert on by any means. But playing around in these areas, you start to learn and you start to take notice. One of the main components in chocolate or cacao is a compound called Theobromine. So Theobromine is an alkaloid. It is what we specifically call a xanthine alkaloid, which is identically a cousin, almost maybe like a sibling of caffeine. Okay. So caffeine is a molecule, again, a xanthine alkaloid.

2:04:45And it has three nitrogens that contain methyl groups on them. So a carbon with three hydrogens on them attached to the nitrogens. And caffeine is an easy one to remember in this class because it is fully methylated. So I call it high -test full caffeinated, substituted xanthine alkaloid. And then Theobromine has no bromine on it. It has nothing to do with bromine. I have no idea where the name came from. But it's missing one of those carbons that makes it different from caffeine. But it causes stimulation. It actually improves respiration when it's been studied very similar to things like theophilin.

2:05:30That have been used long time for asthmatics before we got to the inhalers and things evolved in terms of our understanding of that treatment. But there's also compounds within cacao that very much mimic our dopaminergic type system and turn us on to feeling like, you know what? That was really good. I want that again. It's not like a dopamine release that you get from a hardcore drug like cocaine or something like that. I've done a close. But I agree. It's a subtle kind of push toward, yeah. I'd like more of that. But I feel pretty good. And the anticipation of it is positive. And you certainly can work and do other things.

2:06:22It's not a... It certainly does not destroy... As far as I know, it does not destroy lives. It's rewarding. Unfortunately, the industry to harvest is what destroys the lives. So there's a lot of very poorly sourced and many of the individuals that work those fields and places are really abused. And it's a problem in the chocolate industry as a whole. There's some really great companies out there that are really promoting good, sustainably sourced, ethically sourced cacao beans. And that's just a side note for something they look for when you're looking for a good solid chocolate sourced. So ethically sourced.

2:07:09And you mentioned cacao beans. So the raw cacao beans that I'm now eating every morning. Usually not immediately in the morning. Usually a half hour before my first meal of the day, which for me falls a little bit late morning or closer to lunch. But I'll have five or ten of those things. Boy do I look forward to it as I mentioned. And those raw cacao beans are essentially the same as the 100 % chocolate in terms of polyphenol content. Pretty much. I mean, again, I'm not an expert and I haven't done the analysis of those. But I'm pretty sure that most of those would be retained in the processing into chocolate as a food.

2:07:51You know, one thing that strikes me is probably one of the first things I ever learned of a natural product was the shells for the beans. So growing up as a kid in Pittsburgh, there was a lot of rose bushes around and people would use cacao shells as a fertilizer for the rose bushes. And so you walk by and as a kid, I would get this waft of chocolatey smell along with that smell of the roses. You know, and I think what a Valentine's Day. It's like these things were meant to be together. So it's just a weird side note, just a memory that you brought back. I love that. And I really think there's something pseudo spiritual or spiritual about these combinations of molecules that exist in plants.

2:08:45And sure, the plants are fending for themselves and the fungi are fending for themselves and the birds and the geckos and the humans. But the same biological motifs are used over and over again throughout nature. And of course some species like insect species rely more on one neuromodulator. We're more a cocktail of serotonin dopamine epinephrine and acetocolene. But there just seem to be something to it. Maybe AI will pull out some of the some of the thematics of that going forward. So cacao, great. So I'm not alone in my love of rock acalbeens and 100 % chocolate, but look for a sustainably sourced.

2:09:29Ethically sourced. Ethically sourced. Ethically sourced. No, that's an important distinction. So there's a myth that Coca -Cola at one point had cocaine in it, not just the coca leaf, but actual cocaine. But then you hear various versions of this myth slash legend. What's the deal with Coca -Cola, the coca leaf and cocaine? Yeah, so it's a great old story. John Pemberton was a pharmacist in Atlanta, home of Coca -Cola these days. And developed a formula that contained the coca leaf extract from the coca leaf and extract from the cola nut. So Coca -Cola. And put this together, sold it as a tonic.

2:10:16It's an interesting, just a quick segue on soft drinks in general. So soft drinks came about because they weren't hard drinks. So it was an alternative to liquor. So they weren't hard alcohol. They were soft drinks or soft beverages. They also generally had effervescence to them or carbonation. And most of those were available out of pharmacist soda fund. So 7 -up had lithium in it in the past. And it was, you know, for mind wellness. Pepsi had pepsinogen, which is a digestive peptide in it. Most of the soft drinks, Dr. Pepper, was developed by Dr. Pepper in Waco, Texas. And was a special formula that he had come up with for well -being as well.

2:11:02So all these soft drinks have a really cool history. But John Pemberton's story of Coca -Cola was, it actually goes way back further than Coca -Cola in terms of putting Coca -leaf into beverages. But we'll just stick with Coca -Cola. So Coca -Cola definitely had cocaine in its original setting. And then as time went on and we realized that cocaine was problematic and addictive, there was pressure for him to take that out of the process. And so what they realized was the Coca -leaf, in many people that chew Coca -leaf, talk about the different varieties that are available within South America and different flavor profiles that are there.

2:11:52Well, the specific one that they use for Coca -Cola has a definitive flavor profile to it. And when they took that out, it lost the flavor that people were used to. And so they decided to keep this in there. And Coca -Cola is still the major importer of Coca -leaves into the United States to this day. They do it through a company called the Stepan Company in New Jersey. The leaf comes from Peru, comes from a state -run company in Peru that oversees the production of the Coca -leaf, comes into this company in New Jersey. They then process the leaf into two parts. So they take all of the cocaine and all of the cocaine metabolize essentially the alkaloids.

2:12:46Right? We talked about these alkaloids. They take the alkaloids out. And that gets sent to a pharmaceutical company. And those are processed into cocaine, which is used as a pharmaceutical still to this day. A lot of people probably don't know this, but cocaine is the best local anesthetic that's ever been discovered. It was the template for all the local anesthetics that we use now like Lodicane or Bapybacane. It was the template. And it is still the best one that we have. And it's used almost exclusively for nasal and eye surgery each now, where you have to stay awake and you have to be functioning.

2:13:24And we can't intubate you and we can't do these things. So this is the ideal drug. It's also obviously put into lots of drug testing kits and supplies and whatnot for the forensics industries. But what's the fate of what's left? Well, that Coca -leaf extract, the deoclinated extract, decoconized extract, if you will, is the secret sauce, if you will, for Coca -Cola still. So that is a grass substance, a GRAS generally recognized as safe food substance. And that is the flavoring agent that gives Coca -Cola its unique flavor. And there was a period of time I believe is in the 80s where Coca -Cola really wanted to distance itself from the cocaine industry.

2:14:18Cocaine became hugely the drug of choice, sort of drug of abuse. Lenn Bias, one MBA basketball player, died from overdose. It just became a very nationally aware drug of abuse. And there was a problem associated with cocaine. And so Coca -Cola said, we're going to cut our ties with the Coca -plant completely. They came out with this product called New Coke. And it didn't last long, because the flavor profile couldn't be replicated to the old Coke. And so, indeed, they re -upped their sort of contract and have been bringing it in ever since. And to this day, Coca -Cola classic and Coke zero are the two products, interestingly enough.

2:15:08Diet Coke does not taste very much like Coca -Cola original. A lot of people complained about that for a long time. They got smart and made this product called Coke Zero that has the flavoring agent from the Coca -Cola plant in it. And Lenn Bias, everyone started saying, gosh, this tastes a lot more like Coca -Cola does. Well, yeah, it's got the flavoring ingredient in it. And so, everybody in the United States, almost, has had a Coke at one point in time. So you've all had Coca -leaf already in your dietary chain. And I think it'll be interesting to see where things develop as we start to do more research as the World Health Organization, and reconsiderors removing Coca -leaf from an international ban and looking at it as a potential product to work into food products and develop further.

2:16:05And so, you know, it supposedly has no abuse potential as the leaf. But again, it's that story of isolating that one alkaloid out and sort of destroying the rest of it forever. However, Coca -Cola was smart enough to keep sort of a monopoly, if you will, on keeping that plant alive in their product. And so, it's there. And the next time you have a Coca -Cola or a Coke Zero, just realize that it's got natural product in it. That's incredible. And I'll keep that in mind. And the next time I have a Coke Zero, is there any evidence that what's still retained from the Coca -plant in Coca -Cola is psychoactive and not just there for flavor?

2:16:54That's a great question. And that's been debated quite a bit. So the one thing that we know is that probably it is not having any psychoactivity. And the other thing that we know, back to my pharmacy days, we used to sell Coke syrup. So when Coke is sold for fountain beverages, it's the syrup that's then blended with the carbonated water to make Coca -Cola. And that's why a lot of people say Coca -Cola out of a fountain is so much better than out of a canner bottle because it is sort of formulated on the spot product, if you will. Yeah, on tap. And Coke's syrup, we used to sell it out of the pharmacy for nausea and vomiting, particularly in pregnant women, is one of the safest things you could use.

2:17:49And it really calms and settles the GI tract. And this is interesting because one of the big benefits that people report drinking Coca -T is that it soothes their GI tract and it calms their GI tract and it helps them be able to be alert. Of course, the Coca -T's got all the alkylids in it. But that same GI tract benefit is still there. And that's probably what's still remaining within that extract that's now devoid of the alkylids. You are not paid for by Coca -Cola? No. In fact, we went to Coca -Cola to see if we could work with them on developing some type of medications or something from the Coca -Leaf.

2:18:42And I have a former colleague that is in their natural products division at Coca -Cola and they said they won't even let us touch the Coca -X tract. And they've also got all that cocaine that they've pulled out of the Coca -Leaf in this plant in New Jersey. I can only imagine what the security is on this place. I don't know. But you can fact check me on Wikipedia, which is not a great place to fact check. Got my agreement there. But the Pong Company is listed there in New Jersey and their connection to Coca -Cola in this whole story is actually out there in front of everybody to see. It just takes knowing where to look and find it.

2:19:27Love it. Last question about soda. Is there still lithium in 7 -Up? No. Lithium has gone from 7 -Up. But that was the whole idea, right? Up, mood, lift your mood up, lithium. And we know lithium carbonate is still used to this day as a treatment for psychosis. I'm curious a bit about you. You know, like I know a few chemists. There are a couple of good jokes about chemists. But it's clear that you love chemistry. And you love the chemistry of plants. And you're also interested in public health. And you're interested in, I'm gathering. I'm not a psychologist, but kind of the psychology behind all of this as well.

2:20:15When you were a kid, were you always, were you playing with a chemistry set? Yeah, you would think, right? No. Interestingly enough, my father was a pharmacist. And I just never really paid attention. But I was always under tow. And so I saw what he did. And I, you know, I'd see him behind the counter at a store somewhere. And just never really thought much about it. But I knew that he knew a lot about medicines. And he knew a lot about health care. And what he was doing was really trying to benefit people and help people. And I always thought that there'd be no one. My mother, interestingly, she was a stay -at -home mom raised us kids.

2:21:07But was very much into education. And was a teacher prior to myself being born. I'm the oldest. I have a sister, younger sister, Lisa, who's a nurse, by the way, a nurse practitioner. So medicine has stayed within the family and science has stayed within the family. But my mother once we were old enough to be on her own, if you will. She went back and became a Comprehensive Science teacher at the high school level. And so I just watching her work through getting her recertification, education process, and how passionate she was about educating others. Obviously stuck with me as well. And so those are the things that drove me.

2:21:55I have no idea where the sort of, I really think innate passion came for the chemistry side of things. But when I was in high school, I did an independent chemistry project coming back to caffeine. I was just curious, like, what's the best caffeinated beverage for me to be drinking? So I can stay up for as late as I can and have fun. Well, at the time, it was Jolk Cola, which doesn't exist anymore, right? But Jolk Cola Mountain Dew was second. I drank a lot of guy Mountain Dew in graduate school. I can't say I recommend it. I mean, that was our, I was a band geek in high school. What instrument?

2:22:35I played trumpet and I played piano and a bunch of buddies and I would get together on Friday nights. And we would drink a case of Mountain Dew. You know, it was like, everyone else is out drinking beer. We were doing musical things and drinking Mountain Dew. So it was kind of crazy. But I just wanted to know what was there, right? And I wanted to see and I got vibrant tablets and I extracted the caffeine out of the vibrant tablets to quantify how much caffeine was in those. And still, I didn't really think anything of it. Now, I decided very late in my high school career that I needed to do something with my life.

2:23:16I was bored in high school. I did not do well. I was not a great student. I think if I was lucky, I graduated with a 3 .0 from high school. And my father said, you need to decide on something. And so I said, well, pharmacy looks like it's been pretty good to you and our family. We've had a good, a good life. I went to pharmacy school. And in pharmacy school, taking biochemistry and my first medicinal chemistry course, I got taught by a brand new assistant professor. Someone very relatable, you know, close to an age. Just thought the world of this guy. And he said, hey, I'm looking for anybody who's interested in working in a lab to come work in a lab.

2:24:05And I was like, my chemistry, he's cool. I'd like to get known. So I went to the lab, started working in the lab. And he told me, he said, you know, you have some gift here or some talent. You should really explore it. I'm like, yeah, I'm going to be a pharmacist. What are you talking about? I said, now I'm going to set you up with my PhD advisor, which happened to be the guy who tasted this stuff. I talked about it. Down at the University of Georgia for the summer. And so I went down and did a summer intensive research program in medicinal chemistry at the College of Pharmacy at the University of Georgia.

2:24:40And left there, went back to a hundred other in the University where I did my pharmacy degree, finished out all my clinical rotations. I was getting ready to graduate and take my boards and become a pharmacist. And the phone rang. This was back before cell phones. So I'm dating myself, obviously, but phone rang at home. And I happened to be home because I was doing a local rotation near home, so I could save money. And it was the department chair of medicinal chemistry from the University of Georgia and says, we don't have your application for graduate school. What's going on? And I said, I'm not going to graduate school.

2:25:20I'm about to finish pharmacy school. And 15 minutes later, he was a great salesman. He had me going to graduate school. And so that really changed the course of my life. And I ended up going to Georgia, sitting for my pharmacy boards in Georgia, becoming a licensed pharmacist in Georgia, practice pharmacy while I was in graduate school, which today is almost a no -no. But I worked five days a week in the lab and every Saturday and Sunday in the pharmacy, which made me the party guy because I was making money and all the other grad students were making their stipend that we all know what graduate school stipends were like.

2:26:06But I would be the ones that treated us every so often to nice dinners and things like that since I had a little extra to share with my friends. But got done with a PhD and was working as a pharmacist during that time. And I realized that I had a passion for education. And I had a passion for the chemistry and the pharmacology and talking to customers or patients when they would come in, I worked in a grocery store pharmacy. And they would come in and I would tell them, oh, you're on this new drug that's brand new to the market. It interacts with this protein. It does all these great things and you're so lucky to be trying this.

2:26:52I'll be anxious to hear how it works for you. And they would just look at me and say, do I tell you what food or not. And that was the, I realized I was standing in the wrong place to impact the public. And it came to me that if I'm going to do something with my PhD, of course I fell in love with the research along the way, but I realized that impacting pharmacists to then impact their patients was going to be a much more effective way for me to use my talents and skills in the classroom and education was. And then obviously doing the research and that following that passion, I was lucky. I mean, my PhD was around synthesis of analogs of a natural product called lowballine, which came from Indian tobacco Native American Indian tobacco, not cigarette tobacco.

2:27:50That was used actually as a respiratory stimulant. So this is hop A. No, this was a low Bella and flota was the plant. So low, low ballene was the compound that we worked on and made analogs of. We were looking at it interestingly enough coming back to the core, nervous system. We were looking at it as a potential treatment for Alzheimer's disease because at that time, a paper came out in science, noting that smokers did not tend to develop dementia and Alzheimer's disease. And so it also left the caveat of do they actually live long enough to develop dementia and we don't know. However, since that time in the 90s, the whole core allergic hypothesis of Alzheimer's disease evolved and those are the major treatments we have for dementia through the FDA approved process now.

2:28:43So glad you mentioned I've gotten myself into real trouble covering nicotine with where I put the caveats after the statement about nicotine being potentially neuroprotective in Parkinson's and Alzheimer's. Yeah. People take that, cut that, run with it, come back later and say I'm addicted to nicotine pouches. I always follow that statement with it raises blood pressure. It's highly habit forming slash addictive and as a bunch of other issues that might make most people want to avoid it, but nonetheless nicotine, which stimulates the colonergic pathways you point out does seem to be protective against a loss of cognitive function, at least somewhat and loss of neurons dopamine and colonergic neurons.

2:29:29That's right. And that's where I don't get paid by big nicotine. Yeah. And that's what drove a lot of research back in those days to really see, could we find something the idea was the hypothesis really was, could we find a nicotine that one wasn't addictive to didn't interact with the cardiovascular system. And three, ideally that we could put in a vitamin every day that people could take to subordinate off neurodegeneration. And? No. Don't. Otherwise, I don't think I'd be sitting here talking to you. No, no, you'd be on a yacht someplace. Actually, I take that back. You'd probably be on a yacht someplace that has a small chemistry lab and you'd be probably probably running mass spec.

2:30:12Marine natural products. So, yeah, but I think, you know, that led to me going to a postdoc at the University of Minnesota, I'm working for opioid chemists that really defined chemically the opioid receptors through analogs of naturally occurring opioids like morphine. And then it kind of launched me into my own career of saying, hey, I've worked now on natural products. Even I didn't work directly with those natural products. I've always felt what I said earlier about this sort of balance in nature. And I wanted to pursue natural products. And so when I got to the University of Mississippi, which happens to be natural products mecca for pharmaceutical natural products research, there's the National Center for Natural Products research there.

2:31:02There's the National Institute on Drug Abuse's federal marijuana farm is there. It was the only legal federal marijuana farm for decades. And it was like landing in the perfect place to do what I wanted to do. And so that's where I started working on Saviah Divinorum and Saviah Divinorum generate a compound called Savinorum A, which is to this day thought to be one of the most potent hallucinogens. Non -nitrogen containing di -turpene, we talked about terpenes very similar, not very similar structurally to cannabinoids, but in composition, just carbon hydrogen oxygen. It interacted with capa opioid receptors and capa opioid receptors.

2:31:48There's a huge difference between mu opioid receptors, capa opioid receptors and delta opioid receptors. Those are the three sort of traditionally accepted opioid family receptors. Mu is actually the Greek letter and was defined by Morpheus, the God of Dreams, which is morphine, God its name. And that's where the mu receptors sort of nomenclature came from. And since it was related back to Greek mythology, they gave it the Greek symbol mu. And then when they found these other receptors, capa and delta, they just maintained that Greek sort of nomenclature. We all know that mu is the primary target for clinically used analgesics.

2:32:30It also causes the euphoria. Capa opioid receptors also have analgesic effects and it was for a long time thought that targeting capa opioid receptors was the holy grail of painkillers because you got the same pain relief as you would get with something like morphine or even more potent opioids. But the animals didn't want to abuse it. So they moved into human clinical trials and we learned something in psychiatry at that moment that capa opioid receptors cause dysphoria instead of euphoria. So people don't like the effect. So people don't like the effect. However, there's a group of people out there that's tend to like whatever that is being miserable.

2:33:10Or that makes them feel better. Maybe they're miserable by nature and that makes them feel bad. I don't know what is there, but there's a whole group of people using salvia, divinorum plant. It's called divinar sage. It's a mint from mohaka, Mexico that was used by shaman there to diagnose people when they couldn't figure things out. They would give it to the subject. And then that would open up their mind and hopefully tell them what was wrong with them. And then if the patient couldn't tell the shaman what was wrong, the shaman would resort to taking it himself to go into the spiritual world to figure out what was wrong.

2:33:50So this is a fascinating plant. And that plant is the plant that led me to metragonispecies. And so I was funded by Nida, National Institute of Drug Abuse to study salvia, divinorum. And my program officer, who's the person that manages your grant from the institute contacted me and said, hey, I'd like to invite you to this neuroscience meeting and give a talk on naturally occurring pain medications or substances. And so I said, that sounds cool. That should be easy. There's aspirin. There's morphine. There's this. And so I dove into the literature and started looking for all these different sources of naturally occurring pain medications and lo and behold, there was mitragonispeciesa with an incredible track record of study by Smith Klein and French, which was now glaxo -Smith Klein.

2:34:50Back in the 60s, they isolated mitragonis out of the plant. They did as much and to this day is still the most complete study in the literature. So 19, I think is a 1972 paper by Meko, at all. I can't remember the journal, but it detailed all the clinical development of mitragonis. And at the end of the day, they decided to not pull the trigger on full development because it was no better than coding as an analgesic. And at that time was the emergence of a new class of drugs called the non -steroidal anti -inflammatory drugs, which had no opioid activity, which were much safer, no habit forming properties.

2:35:39We've come to learn their problems with NSAIDs as well, like ibuprofen, liver issues, liver, kidney, GI bleeding. That potent. No, they're from my own pain. And mitragonis was even recognized back then as being very comparable to coding, which is really for more moderate pain. It's not morphine. That's a whole other discussion, but it's much less potent than morphine coding is. It has great antitusoproporties for cough, and that's why they put in cough serps, and works better for that than it really does for pain control. But it was just an equivalent to that. And they said there's no point in trying to compete with this new class that's safe, right?

2:36:26Or thought to be safer. So they shelved the project at Smith Klein and French. Thank God they did, because that's what I found, and that was when I realized nobody's touched this plant. Fantastic, Ark. And one that really reflects a constant curiosity and willingness to see when a door opens and go through it. So it's really wonderful that you did. Clearly that's in your nature. And I think one consistent theme throughout several, but what I heard were themes related to intense curiosity. A real practical grounding, your practical guy, it's clear. You come from your pharmacist father and your mom who impressingly impressed.

2:37:16My wife may not agree with this, but and your mom who impressively is what I meant to say. When back and after raising you guys and became a scientist in her own right and teacher. And then the element of public education, teaching pharmacists, teaching neuroscientists, I've long wanted to do an episode about creatum. And for a variety of reasons, the most important one being that many people ask about it and it's out there and it's having an impact and it's growing in usage. And that there's these very polarized views you hear, this is the greatest thing ever. Help me or someone I know get off opioids.

2:37:57And then you also hear this stuff is dreadfully bad. In the course of you know, researching creatum, it's not hard to find your name because you're responsible for publishing the enormous percentage of the work on on creatum. But I would also hear things from people like got to get Chris McCurdy on. He's the man. I heard he's the man a lot. And so I just really want to thank you for coming here today with with the intention to teach. I've clearly learned everyone's learned so much from this from hearing you today. And your nuanced perspective that when someone says is creatum good or bad, say for not safe, you break it down.

2:38:36Look here are the different things we're talking about when we're talking about creatum. And I list off some of the key takeaways earlier. Serving size matters. Craterum derived products versus isolates. Why are you using creatum? Maybe the F round and find out reason is not a good reason. Is it pain relief? Is it to avoid or trying to alleviate a much more serious condition or addiction? In some cases drug interactions. There's your pharmacist side that the inter this case example of a seizure. And on and on. I mean, you've just done a spectacular job of explaining the nuance that one has to address that question with.

2:39:16I must also highlight that as somebody who's very interested in science and public health, but also the natural world, you've done such a spectacular job of explaining how plants contain these incredible compounds interact with the animal world and with the human world and medicine for better or worse. And that's a beautiful dance. And you're clearly encyclopedic about all of it. Thank you so much for coming here for sharing all this knowledge. So clearly people are going to be safer and are going to make excellent use of this knowledge. I'm sure and as things evolve in the world of creatum and coca leaf and cacao and please come back and share with us what you just covered.

2:39:59Absolutely. Thank you so much for having me. Thank you for giving me your platform as well to get this education out there. It needs to be out there and people need to understand that there may be benefits indeed, but there's risks and there's potentially harm. And we've got to figure out where each of those lie. Well, it's been a pleasure. Thank you. Thank you. Thank you for joining me for today's discussion with Dr. Chris McCurdy. To learn more about his work, please see the links in the show note captions. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel.

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2:41:02I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled Protocols and Operating Manual for the Human Body. This is a book that I've been working on for more than five years and that's based on more than 30 years of research and experience. And it covers protocols for everything from sleep to exercise to stress control protocols related to focus and motivation. And of course, I provide the scientific substantiation for the protocols that are included. The book is now available by pre -sale at protocolzbook .com. There you can find links to various vendors.

2:41:37You can pick the one that you like best. Again, the book is called Protocols and Operating Manual for the Human Body. And if you're not already following me on social media, I am Hubertman Lab on all social media platforms. So that's Instagram, X, Threads, Facebook, and LinkedIn. And on all those platforms, I discuss science and science -related tools, some of which overlaps with the content of the Hubertman Lab podcast, but much of which is distinct from the information on the Hubertman Lab podcast. Again, it's Hubertman Lab on all social media platforms. And if you haven't already subscribed to our neural network newsletter, the neural network newsletter is a zero -cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three -page PDFs that cover everything from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure.

2:42:22We have a foundational fitness protocol that covers cardiovascular training and resistance training. All of that is available completely zero -cost. You simply go to HubertmanLab .com, go to the menu tab in the top right corner, scroll down to newsletter, and enter your email. And I should emphasize that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Chris McCurdy. And last, but certainly not least, thank you for your interest in science.

2:42:52And as mentioned at the beginning of today's episode, we are now partnered with Momentus Supplements, because they make single ingredient formulations that are of the absolute highest quality and they ship international. If you go to livemomentus .com slash Hubertman, you will find many of the supplements that have been discussed on various episodes of the HubertmanLab podcast, and you will find various protocols related to those supplements.