Skip to content
Huberman LabHuberman Lab

Dr. Chris McCurdy on Huberman Lab: Why Kratom Misleads

How kratom alkaloids differ across leaf, extract, and isolate forms; McCurdy maps opioid and serotonin effects, addiction risk, and harm reduction tools.

Andrew HubermanhostDr. Chris McCurdyguest
Jul 21, 20252h 42mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 2:51

    Chris McCurdy

    1. AH

      Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Chris McCurdy. Dr. Chris McCurdy is a professor of medicinal chemistry at the University of Florida, where he directs research on natural products and their pharmacologic effects, most recently the plant-derived compound kratom, which is readily sold in the US and around the world and is now used by tens of millions of people daily, and those numbers are increasing fast. Dr. McCurdy's research focuses on understanding how kratom interacts with our nervous system and affects our physiology and behavior. He also studies its potential for addiction. During today's episode, we discuss the complex effects of kratom and its relationship to the opioid system. Dr. McCurdy explains how kratom's active compounds work in the brain, why it shares certain similarities to opioid drugs, and critically, how kratom products available in the US and elsewhere are largely derivatives and isolates of the kratom leaf, which is very different in terms of the effects it produces when compared to the traditional leaf products. And unfortunately, that has confused and in many cases harmed consumers. So today you'll learn about kratom's effects at different doses and when it's sourced in different ways. You'll learn about how it can be a stimulant, how it can increase focus, how it can be a painkiller, how it can increase euphoria, but also its strong potential for addiction. You'll also learn what is known about kratom in terms of its ability to help people transition off traditional opioid drugs. It has been shown to be effective for that. However, we are also going to explain the potential harms of kratom, in particular in young people whose brains are still developing and in people that don't have a prior opioid addiction. Our discussion about kratom also opens up a broader discussion about other plant alkaloids that have medicinal properties, including those found in things like cocoa and 100% chocolate, and we discuss the incredible history of soft drinks like Coca-Cola, Pepsi, 7UP, and Dr Pepper, which believe it or not, were originally developed as pharmacologic tools before becoming the ultra-popular beverages that we're familiar with today. So I realize many people have heard about kratom, but also many of you perhaps have not. What everyone should know, however, is that kratom products are pretty much everywhere now. You can find them in supermarkets, convenience stores, online, and they're sold under the pretense of having very specific effects related to energy, pain management, or mood. But by the end of today's episode, you'll have a thorough understanding of how this plant compound actually works, yes, its potential effects, but also its serious risks. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Chris McCurdy.

  2. 2:51 – 7:19

    Kratom (Mitragyna speciosa), Origin, Effects, Low vs High Doses

    1. AH

      Dr. Chris McCurdy, welcome.

    2. CM

      Thank you. It's really a pleasure to be here.

    3. AH

      I'm excited to have you here because you work on some incredibly interesting compounds, several of which are very controversial and all of which are impacting health and society in a major way right now, especially in the United States. The most notable of those is kratom. I'm guessing some people have heard of kratom. I'm guessing some people perhaps have not. I'm pretty certain everyone has seen a kratom product because they are everywhere.

    4. CM

      Yeah.

    5. AH

      But it's often in the fine print. So could you just tell us what kratom is, where it's found in nature and in the United States, and some of its properties that people take it in order to achieve certain effects and maybe some of its lesser-known properties? So that's a lot of questions, so maybe just a general description of kratom, where it's found, and what it does.

    6. CM

      Let's just start from the beginning and make it easy. It's, it's a tree that's called Mitragyna speciosa by its botanical name. Um, it's called kratom in Southeast Asia, which is where it's native to. It's actually native to, uh, where peninsular Malaysia and Thailand connect, so at the border of, of those two countries is thought to be ground zero for where this tree species came from. And in that region it's very rural. It's lots of farmers and lots of outdoor laborers, and those outdoor laborers chew the leaves, um, in Thailand or they make a, a tea, uh, more technically what we call a decoction because they boil the leaves for hours. Um, but they'll harvest fresh leaves and boil those leaves and then drink that just like we would drink a coffee drink in the morning to give them energy, to give them sort of sustainability throughout the day to tolerate that heat, humidity, and very harsh tropical environment. And it gives them the stamina to make it, make it through the day. Um, and that's really what the traditional use has, has always been, uh, more or less for energy and to get through that day. Uh, but it also has been used to treat pain, it's been used to treat, um, of all things, uh, uh, erectile dysfunction, it's been (laughs) said to be nature's sort of Viagra. Um, it's used for, uh, mood elevation primarily, um, and so these, these individuals will, will utilize it, uh, like I said, throughout the day. It's (laughs) a Muslim population in that area so there's no, uh, alcohol really and no consumption of alcohol, um, and this is sort of a socially lubricating product, um, and so in the evenings, on Friday, Saturday evenings, the men would generally gather and then increase their consumption of, of the tea, um, just socially, uh, and, and it could get them into a more sedative-like effect. And so there's this always this sort of, um, paradoxical description of, of, uh, kratom, or, or as we say in the United States, kratom.... um, where you get this stimulant effect at lower doses or, or smaller amounts, and you get this more euphoric or sedative-like, opioid-like effect, if you will, at higher doses. And so, they, they tend to use that traditionally, so they'll, they'll take the be- the benefits of it, um, just like we would use coffee, I think, uh, to, to sort of get us moving in the mornings. That's what they sort of use in those regions, and they move into, um, you know, on the weekend evenings, they'll use it as more of a social, uh, beverage. And so, that's where that's been. We got interested in it from the standpoint that there were also reports that this could be utilized when they ran out of heroin or raw opium, um, so that they wouldn't go into withdrawals. And so essentially, they're already using it. They would increase the consumption when they ran out of heroin or opium, and that would stave off withdrawals for them. And that became really interesting to me, uh, as an opioid researcher, a pain researcher. Could this be something that, uh, has potential, uh, and, and obviously would have potential in helping with the opioid crisis, uh, that we're in? And that's, that's kind of what drove us into starting to look at this.

  3. 7:19 – 10:07

    Sponsors: David Protein & Eight Sleep

    1. AH

      I'd like to take a quick break and acknowledge one of our sponsors, David. David makes a protein bar unlike any other. It has 28 grams of protein, only 150 calories, and zero grams of sugar. That's right, 28 grams of protein, and 75% of its calories come from protein. This is 50% higher than the next-closest protein bar. David protein bars also taste amazing. Even the texture is amazing. My favorite bar is the chocolate chip cookie dough, but then again, I also like the new chocolate peanut butter flavor and the chocolate brownie flavor. Basically, I like all the flavors a lot. They're all incredibly delicious. In fact, the toughest challenge is knowing which ones to eat on which days and how many times per day. I limit myself to two per day, but I absolutely love them. With David, I'm able to get 28 grams of protein in the calories of a snack, which makes it easy to hit my protein goals of one gram of protein per pound of body weight per day, and it allows me to do so without ingesting too many calories. I'll eat a David protein bar most afternoons as a snack, and I always keep one with me when I'm out of the house or traveling. They're incredibly delicious, and given that they have 28 grams of protein, they're really satisfying for having just 150 calories. If you'd like to try David, you can go to davidprotein.com/huberman. Again, that's davidprotein.com/huberman. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. One of the best ways to ensure a great night's sleep is to make sure that the temperature of your sleeping environment is correct, and that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees, and in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. Eight Sleep automatically regulates the temperature of your bed throughout the night according to your unique needs. Eight Sleep has just launched their latest model, the Pod 5, and the Pod 5 has several new important features. One of these new features is called Auto Pilot. Auto Pilot is an AI engine that learns your sleep patterns to adjust the temperature of your sleeping environment across different sleep stages. It also elevates your head if you're snoring, and it makes other shifts to optimize your sleep. The base on the Pod 5 also has an integrated speaker that syncs to the Eight Sleep app and can play audio to support relaxation and recovery. The audio catalog includes several NSDR, non-sleep deep rest, scripts that I worked on with Eight Sleep to record. If you're not familiar, NSDR involves listening to an audio script that walks you through a deep body relaxation combined with some very simple breathing exercises. It's an extremely powerful tool that anyone can benefit from the first time and every time. If you'd like to try Eight Sleep, go to eightsleep.com/huberman to get up to $350 off the new Pod 5. Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eightsleep.com/huberman to save up to $350.

  4. 10:07 – 17:00

    Kratom, Traditional Use vs Commercial Kratom Products, Absorption

    1. AH

      When we see a kratom product in the United States, and I realize there are a variety of those, but, um, let's just take for example, I'm aware of, uh, a product that's very popular nowadays. It's a small blue bottle. Um, it includes kava and kratom-

    2. CM

      Right.

    3. AH

      ... as its primary ingredients. I have zero financial relationship to this company. I actually had the opportunity to be an early investor. I turned it down.

    4. CM

      (laughs)

    5. AH

      Um, when somebody takes a bottle of that, when they drink a bottle of that, how concentrated and how much kratom are they getting compared to, say, the typical adult user in Malaysia who drinks, uh, I don't know, what, a mug of this concoction, um, i- are they comparable? Um, are they even the same compound? Can we think about them the same way? Because this is very much, in my mind, uh, like comparing, um, smoked cannabis, uh, let's just say there is no typical variety, but-

    6. CM

      Right.

    7. AH

      ... um, compared to a highly concentrated, uh, uh, THC tincture, for instance.

    8. CM

      Right, yes.

    9. AH

      W- Uh, I mean, the same chemical structure, but at some point, you- the pharmacokinetics changes, and you're basically looking at different brain circuits, different bodily organs engaged. There's a kind of different experience altogether.

    10. CM

      Correct, and I, and I think it's an important distinction to make at the outset of this is that, you know, what I described as the traditional use is, is freshly picked leaves that day. They're either chewing them directly when they pull it off the tree, or they're brewing this decoction right away. Um, in the, in the United States and in the Western world, it's a very different product from day one because it's a dried leaf material, um, that's been exposed to the air, the sun, whatever environmental factors are there, plus shipping it all the way across the world from Indonesia, which is the primary country where most of this is grown. Um, the last I heard a year ago was there's about 250,000, uh...... kratom farmers in, in Indonesia that are producing and exporting, um, raw materials a- a- around the globe, but primarily to United States. So that leaf material comes in, and then leaf material has been ground and put into capsules, put into, um, various products, even just powdered product, uh, where people use tablespoons of powder and, you know, couple grams of powder in their, in their warm water or however they like to do. Um, so, uh, it- it's an interesting product because f- that's as close to the traditional use that you can get in, in the Western world, right? Because you're s- you're still using leaf. You're ingesting it, um, or, or you're making a tea from it. Water is the worst, uh, least efficient extractor of chemicals (laughs) out of a plant material, and even if we don't make a tea out of it, if we just take the leaf material internally, our body has to work incredibly hard to pull those active ingredients out of the plant material. So it's a, it's a active process for us as humans or as, uh, animals, if we wanna talk about the animal research too and where we've learned most all of this from, that, that our body has to work hard to get that into our system. Now, you take that leaf material and then you do something like you mentioned, put it into a tonic, or you put it into a concentrate form, uh, or an extract. And now, the compounds have been already pulled out of the leaf material by the, the, the solvent or the liquid that's being utilized, whether it's ethanol or it's, uh, oil or some other, some other type of, uh, vehicle. I think in the product you mentioned, it's pineapple juice, which again, is not as efficient as something like oil or, or a solvent would be. But you start to pull these compounds into that liquid instead of our body having to pull it out of the leaf. It's already out of the leaf. Now we can ingest that and those compounds are absorbed much faster into our body, into our system, and it totally changes the dynamics of what our body is exposed to, um, from that sort of more traditional based product. And this is also where we feel that things have become problematic. And so if we go back to Paracelsus, you know, the hundreds of years ago talking about the poison is in the dose, um, where we, where we've seen somewhat, um, (clicks tongue) non-problematic use, I would say, the majority of non-problematic use is with that leaf material, more of that closer to traditional use. But as you start to make these concentrates and extracts and, and, and now isolates, which are even, uh, a whole nother discussion because they're no longer even kratom products, um, you, you start to move ever so far across that spectrum. And I like to equate it to the, the alcohol world where we talk about seltzers or light beers being, um, more comparable in an alcohol beverage to that traditional use of kratom, whereas we get to things like almost pure alcohol, Everclear, 190 proof, 95% alcohol. Now you're talking about these isolate products, and we have products in the, in the alcohol industry through that whole span. But we've classified all of them. We don't call them alcohol in general. Well, we'll define them. (laughs)

    11. AH

      Beer, wine.

    12. CM

      Beer, wine, craft beer.

    13. AH

      Cider. Yeah.

    14. CM

      Yeah. And, and into spirits and then into very fortified, um, beverages. And so we don't have that delineation in the, in the kratom space and so all kratom products get dumped into a single bucket, and so whether or not it's a benign product or something that's highly, highly concentrated, um... And I shouldn't say benign but, uh, you know, something that i- is much more close to that traditional use that you're not gonna have a risk of getting a great exposure when you take some of it versus a, a shot that might be 15 milliliters and it tells you on the bottle it's nine servings, but nobody reads that part and just downs the entire bottle.

    15. AH

      Is that what we're talking about when we talk about this little blue, little blue bottle?

    16. CM

      So no, the little blue bottle is more... it actually is more similar in terms of what is dosed in there to a traditional exposure of a beverage, so-

    17. AH

      One bottle.

    18. CM

      One bottle.

  5. 17:00 – 23:16

    Kratom Products, Serving Size, Kids; Semi-Synthetics; Tool: Understand Kratom Product Labels

    1. CM

    2. AH

      One bo- I say one bottle-

    3. CM

      Yeah.

    4. AH

      ... and forgive me for interrupting because about a year and a half ago, I ran into a friend and, um, (smacks lips) his assistant, she came running out and knowing what I do she said, "Hey, well, do you know about this, like, little blue bottle product?" And I, I said, "Yeah, I've seen it, not tried it." And, um, "Why? What do you think?" And she said, "Well, I, I liked it because I drank one, but now I'm drinking six a day and I can't seem to whittle it back. Like when I went to three, I did not feel well. Headaches, k- feeling..."

    5. CM

      Yeah.

    6. AH

      "... anxiety, not well," was how sh- basically how she described it.

    7. CM

      Yeah.

    8. AH

      And, um, I said, "Well, sounds like, uh, either addictive or, or habit-forming," and I don't know where she's at with that but this seems very common. People start with one, not unlike nicotine patch- pouches.

    9. CM

      Right, right.

    10. AH

      Uh, start with 3 milligrams and they're up to 6 milligrams and then pretty soon it's a tin a day or a canister a day. So, um, one bottle of that, uh, of kratom kava-

    11. CM

      That's a-

    12. AH

      ... is comparable to the, to the plant use?

    13. CM

      I think if I remember right, a bottle is two servings. So we've tested, we've tested almost every single product in the marketplace and we've analyzed it for the content of alkaloids to see what's, what's there and what they consider a serving. Um, but if we only look at a serving-... they're pretty much all equivalent.

    14. AH

      Mm-hmm.

    15. CM

      Again, it's what's in that bottle, right? Is it one serving, two servings, nine servings, 15 servings-

    16. AH

      Wow. Okay.

    17. CM

      ... in a single bottle? So, most people aren't gonna look at it from the standpoint of, "Hey, I've got- I've got this bottle here, which is actually smaller than the- the blue bottle."

    18. AH

      Mm-hmm.

    19. CM

      But it's- it's 10 times more servings (laughs) , right? And so if you're used to consuming that blue bottle all at once, which is two servings, I think, and then if you pick up one of those bottles that's 15 servings, and you consume the whole thing at once, you're- you're getting a much greater exposure immediately and it's in a much easier vehicle for our body to, um, welcome those compounds in, if you will. So, it- it- it becomes a very, very slippery slope, in my opinion, um, um, with these different products that are out there in the marketplace. And so y- if- if someone is not paying attention to what the actual serving is supposed to be, then this is where problems become. And the other thing I would add to that is, that y- a lot of times, and I've seen this, I've- I've stopped in, um, so o- of all places, I stopped at a Murphy USA gas station, Walmart's gas station, and they had, uh, kratom energy shots right next to the 5-Hour Energy shots.

    20. AH

      Mm-hmm.

    21. CM

      And so if- if you were in a hurry and you weren't even paying attention, you might accidentally grab something that you thought was a 5-Hour Energy shot, right? And suddenly, you ... and I- I took, I normally take two of those and I do it right back, back and throw 'em right back. And, um, so if you, if you get these, and generally what we worry about is kids getting these, right? And getting these and then taking a- a shot, a whole bottle, uh, which may be multiple servings. A- and they don't feel anything right away and somebody told them, "You're gonna get high from this. You- y- y- you can't believe it, but you'll get high from this thing you can buy in the gas station." And then they don't feel anything, and then suddenly they have another one, right? And then all of it gets absorbed and hits them harder almost all at once. And you can think of it, like if you sat down and you drank a light beer, and you drank that 12-ounce beer, um, i- in a short period of time, just y- you could really drink it fast, you're not gonna get very much alcohol exposure because there's only 3.5% in that 12 ounces. But if you sit down and you do three shots of tequila in a row, in that same timeframe, your body is getting exposed to m- significantly more alcohol in that timeframe. And that's what- that's what our concerns are around some of these products. And so, when you look at the specific serving, yeah, they- they dial it in to say, "Yep, this is what, uh, is comparable to a traditional full glass of tea." Um, but- but they're- they're very, very concentrated. And now, as I mentioned, you know, moving- moving outside of this space into semi-synthetics and products that are no longer kratom products, are no longer traceable back to the plant material. They're actually semi-synthetically produced. That means they're chemically modified, um, into other things that they're calling, in some cases, kratom product, again, this is that trash can (laughs) . Or they're actually calling them kratom derived products.

    22. AH

      Two things that I'm taking from what you've said thus far is that anyone considering kratom products of any kind needs to carefully consider serving size. And it's, uh, interesting that those small bottles, and frankly the packaging of most, uh, things is pretty small.

    23. CM

      Yeah.

    24. AH

      And, uh, I don't think it's just my age. Uh, you need a compound microscope to- to read some of the- the print. Like literally fine print has become so fine that- that- that I think i- it's below the- the threshold of a- of a f- you know a Air Force, um, fighter pilot's-

    25. CM

      (laughs)

    26. AH

      ... uh, high acuity vision.

    27. CM

      The 2015, yeah.

    28. AH

      So in all seriousness, you need to look at the serving size and- and know how many servings are in there.

    29. CM

      Absolutely.

    30. AH

      So, check serving size. And the other thing is, uh, to look for kratom derived or kratom extracted versus actual kratom plant product.

  6. 23:16 – 32:53

    Kratom Products & Various Desired Effects; Physical Dependence

    1. AH

      um, maybe we, just for the moment, let's step back in light of that, and let me just ask, you said earlier that when people use the plant at lower dosages, it's a bit of a stimulant.

    2. CM

      Right.

    3. AH

      Might even have some aphrodisiac, um, qualities to it.

    4. CM

      Right.

    5. AH

      Which suggests to me, I'm not a- a medicinal chemist as you are, but suggests that there might be some dopaminergic, um, maybe some cholinergic, maybe some vasodial- uh, dilation activity given the aphrodisiac part, et cetera. Okay. Um, but then in higher doses, it starts to become more of a sedative.

    6. CM

      Yeah.

    7. AH

      When people take kratom derivatives, or these, uh, more manufactured or processed kratom products in the United States, the small blue bottle, let's say t- one or two servings, or um, the- the ones that are in the energy shot, let's say they take one or two servings, which would be basically a- a quarter of a sip-

    8. CM

      (laughs)

    9. AH

      ... of one of those (laughs) little- little thimble-sized things-

    10. CM

      Right.

    11. AH

      ... are they seeking the stimulant aphrodisiac effect? Or do you think that most ... Do we have any data, rather, as to whether or not users in the US are really going for that kind of se- sedative numbing out effect? Because those are two very different things.

    12. CM

      Very, very different. And- and I don't think we have good, strong definitive data. So I will say that, um, with my colleague, uh, Dr. Kirsten Smith at Johns Hopkins, um, and- and-... others on our team, we've done pretty extensive surveying of, of users. Um, these users, y- you know, volunteer themselves into the study, so (laughs) I think we have to, uh, we have to look at that from a standpoint of, you know, we're not, we're not just putting out random people on the street and asking them questions. These are people that choose to a- answer. Uh, but what we found in the largest study that we've done to date is most users are using it in a very responsible, um, and directed way where they're not using it to get this high or euphoria or, or sedative feel.

    13. AH

      Really?

    14. CM

      Really. Uh-

    15. AH

      Okay. I want, uh, could you repeat that? Uh, you said-

    16. CM

      So-

    17. AH

      ... it very clearly, but I think-

    18. CM

      (laughs)

    19. AH

      ... the world needs to hear this. Um-

    20. CM

      The estimated number of users right now, we, we don't really have a good thumb on this, all right? So the most recent literature report was around two million, two and a half million users. But if you look at sales of products and you talk to the manufacturers, the estimates are well over 20 million users in the United States. And if you look at the availability of product, it's gotta be closer to those numbers. So-

    21. AH

      On a daily basis?

    22. CM

      On a daily basis.

    23. AH

      Daily basis? So this isn't, you know, two to 20 million people per year-

    24. CM

      No.

    25. AH

      ... ingest a kratom product?

    26. CM

      This is-

    27. AH

      This is 20 million people a day.

    28. CM

      This is what is the estimate right now.

    29. AH

      Wow.

    30. CM

      Based on the amount of material that's been imported, or if, if you will, exported, um, to the US and then manufactured, and so in 2019, then, when we actually had solid data, it is 1,950 metric tons per month coming in.

  7. 32:53 – 36:59

    Different Kratom Usage Patterns, Opioid Dependence

    1. CM

      on yet.

    2. AH

      I'm gathering, at this point, that there are basically three paths of kratom usage in the United States. One group of people is using kratom products to achieve an energetic lift not dissimilar from the lift they're seeking with caffeine or an energy drink.

    3. CM

      Right.

    4. AH

      Sounds like they're using kratom products pretty regularly to achieve that. And if they don't use their kratom product, they feel a little bit more lethargic, maybe a little bit minor headache, not as energized and clear as they would otherwise. Sounds a lot like caffeine to me.

    5. CM

      Right.

    6. AH

      With one caveat, I should add. When somebody consumes a lot of caffeine, at some point, the, the effect starts to drop off because they, they gain a tolerance. The, the effect of caffeine doesn't shift from a stimulant to an, to a more opioid-like effect the more you take. It tends to just make you less, uh, sensitive to caffeine over time. It's more of a inverted U-shape function as opposed to a, two different curves, right?

    7. CM

      Right. But you will, you will become, you know, you'll get jittery with caffeine.

    8. AH

      Mm-hmm.

    9. CM

      And you get... It actually causes anxiety when you get into higher amounts of it. And so, yeah, I mean, point well taken. It's just a matter of where you are in that sort of U-shaped curve, right?

    10. AH

      Mm-hmm.

    11. CM

      You, you gotta get over that sort of jittery anxiety point before it really starts to, y- y- it doesn't bother you, right?

    12. AH

      Mm-hmm.

    13. CM

      I, I mean, when I was a young assistant professor, they would see me come in the restaurant with our, our guests, and they would immediately put a pot of coffee on because they knew I was gonna sit there until 9:00, 10:00 at night and drink coffee the whole time.

    14. AH

      Oh.

    15. CM

      Right? And I'd go to bed, no problem.

    16. AH

      Yeah. I was same way.

    17. CM

      I can't do that today. (laughs)

    18. AH

      Recently on a podcast I was a guest on, I shared that I drink, and I do not suggest people do this, but-

    19. CM

      (laughs)

    20. AH

      ... I legitimately drink somewhere between 600 and probably 900 milligrams of caffeine per day.

    21. CM

      Wow.

    22. AH

      And people say, "Well, that's impossible." But I'll drink five zero sugar cold brew yerba mates, 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 2:00 PM.

    23. CM

      Yeah.

    24. AH

      But no problem. But most people who get their commercial vendor coffee-

    25. CM

      Right.

    26. AH

      ... let's say, uh, venti coffee, take that away from them for two, for two days, and they will be complaining of headache and maybe even nausea because it, there's so much caffeine in those.

    27. CM

      Mm-hmm.

    28. AH

      Okay, so we got this first case, uh, caffeine-like usage.

    29. CM

      Right, right, right.

    30. AH

      Let's just bin that. Um, second path of kratom usage seems to be people who use fairly high doses or, or concentrates to achieve an opioid-like effect, a, a mild sedative effect, um, euphoric effect. Um, this sounds a lot like opioid use or higher dosage alcohol use, for instance.

  8. 36:59 – 47:47

    Alkaloid Compounds, Nitrogen, Nicotine; Animals & Self-Experimentation

    1. CM

      we can't just say kratom because it's... That's just like just saying alcohol, right?

    2. AH

      Mm-hmm.

    3. CM

      So there's, there's a variety of different forms of product-

    4. AH

      Mm-hmm.

    5. CM

      ... 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. Um, as I mentioned, we don't have good strong data to suggest one way or the other, but you can assume and 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. Um, one is, is that, uh, kratom itself contains multiple compounds, multiple chemical compounds, so it's not just one thing.

    6. AH

      It's an alkaloid.

    7. CM

      It has at least 20 to 40 alkaloids in it.

    8. AH

      Can you, um, explain to people what an alkaloid is-

    9. CM

      Sure.

    10. AH

      ... and some other examples of alkaloids they might be familiar with?

    11. CM

      Sure. So alkaloid is a organic molecule that has at least a nitrogen in its structure. So i- it has to be, uh, nitrogen, carbon, hydrogen. It can or cannot have oxygen. Um, but those are essentially the, the template for what we would define as an alkaloid. And then there's various classes of alkaloids. Um, many things that people are familiar with, dopamine, serotonin, these are alkaloids. Um, but we could go further. We've just talked about caffeine. Caffeine's an alkaloid. Uh, cocaine's an alkaloid. Morphine's an alkaloid. Um, so all of these molecules contain a nitrogen, um, that, that is core to part of their activity, what we believe is essential for them to interact with the proteins in the body.

    12. AH

      Can I ask a question about nitrogen-

    13. CM

      Mm-hmm.

    14. AH

      ... and protein interactions-

    15. CM

      Sure.

    16. AH

      ... given this is a science/health podcast?

    17. CM

      Yeah.

    18. AH

      Without getting too far down in the weeds, uh, a number of people will hear, okay, it's got a nitrogen, okay, that probably have, uh, vague or, or clear memories of, of chemistry class. But the fact that you have this, this N, this nitrogen-

    19. CM

      Right.

    20. AH

      ... and you have cells that have proteins, it... For the non-chemists, could you explain how the nitrogen allows th- that molecule to do something? Does it bind with more affinity? Does it ch- change the gene expression? What is it about having a nitrogen that really changes the properties of a molecule?

    21. CM

      Yeah, so there's, there's a couple of important pieces here. Nitrogen is a element that can act as a base, so it can... In, 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 charged magnet face and a negative charged 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. That'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, a, 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 molecule's floating around and it, 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 gonna cause, whether it activates that protein or whether it blocks that protein from doing its function. It is a key element of life. All our amino acids, amino is nitrogen. (laughs) All of our amino acids, our 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. Um, 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, um, have helped define really our chemical neurotransmitter systems. Nicotine, perfect example.

    22. AH

      Mm-hmm.

    23. CM

      It's an alkaloid. We have an entire acetylcholinergic nervous system in... Which is the exclusive nervous system in insects. But nicotine binds to nicotinic acetylcholinergic receptors. That whole system was defined by nicotine.

    24. AH

      Right, and people, uh, just to take a step back, um, what, uh, Dr. McCurdy's explaining is that there are receptors throughout the brain and body that are responsible r- for everything from muscle movement and contraction to-

    25. CM

      Correct.

    26. AH

      ... uh, your ability to focus, um, to your memory, um, neuroplasticity, that are so-called nicotinic acetylcholine receptors. They didn't evolve because we thought that people would take nicotine. It just so happens-

    27. CM

      That's right.

    28. AH

      ... that this plant, that, uh, tobacco plant that contains nicotine was used as a experimental probe to understand where these nicotinic receptors are in the body. So this reflects the fact that humans have been, uh, nibbling on plants and seeing what happens for a long time. There's a, um, a- explicative version of this which is F around and find out kind of-

    29. CM

      Right.

    30. AH

      ... uh, experimentation, but this is really what, uh, old world primates, including humans, have been doing for a long time and then just seeing whether or not, uh-... your buddy that ate the plant died.

  9. 47:47 – 51:05

    Sponsors: AG1 & ROKA

    1. CM

    2. AH

      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. I discovered AG1 back in 2012, long before I ever had a podcast, and I've been taking it every day since. I find it improves all aspects of my health, my energy, my focus, and I simply feel much better when I take it. AG1 uses the highest quality ingredients in the right combinations, and they're constantly improving their formulas without increasing the cost. In fact, AG1 just launched their latest formula upgrade. This next gen formula is based on exciting new research on the effects of probiotics on the gut microbiome, and it now includes several clinically studied probiotic strains shown to support both digestive health and immune system health, as well as to improve bowel regularity and to reduce bloating. Whenever I'm asked if I could take just one supplement, what that supplement would be, I always say, "AG1." If you'd like to try AG1, you can go to drinkag1.com/huberman. For a limited time, AG1 is giving away a free one-month supply of omega-3 fish oil along with a bottle of vitamin D3 plus K2. As I've highlighted before on this podcast, omega-3 fish oil and vitamin D3 K2 have been shown to help with everything from mood and brain health, to heart health, to healthy hormone status, and much more. Again, that's drinkag1.com/huberman to get a free one-month supply of omega-3 fish oil plus a bottle of vitamin D3 plus K2 with your subscription.Today's episode is also brought to us by ROKA. I'm excited to share that ROKA and I recently teamed up to create a new pair of red lens glasses. These red lens glasses are meant to be worn in the evening after the sun goes down. They filter out short wavelength light that comes from screens and from LED lights, which are the most common indoor lighting nowadays. I want to emphasize, ROKA red lens glasses are not traditional blue blockers. They do filter out blue light, but they filter out a lot more than just blue light. In fact, they filter out the full range of short wavelength light that suppresses the hormone melatonin. By the way, you want melatonin high in the evening and at night, makes it easy to fall and stay asleep. And those short wavelengths trigger increases in cortisol. Increases in cortisol are great in the early part of the day, but you do not want increases in cortisol in the evening and at night. These ROKA red lens glasses ensure normal, healthy increases in melatonin and that your cortisol levels stay low, which is again, what you want in the evening and at night. In doing so, these ROKA red lens glasses really help you calm down and improve your transition to sleep. ROKA red lens glasses also look great. They have a ton of different frames to select from, and you can wear them out to dinner or concerts and you can still see things. I don't recommend you wear them while driving just for safety purposes, but if you're out to dinner, you're at a concert, you're at a friend's house, or you're just at home, pop those ROKA red lens glasses on, and you'll really notice the difference in terms of your levels of calm and all the sleep stuff I mentioned earlier. So it really is possible to support your biology, be scientific about it, and remain social at the same time if you like. If you'd like to try ROKA, go to roka.com, that's R-O-K-A .com and enter the code Huberman to save 20% off your first order. Again, that's roka.com and enter the code Huberman at checkout.

  10. 51:05 – 59:00

    Medicine Development, Disconnection from Nature, Product Concentrations

    1. AH

      What's clear to me now is that, uh, what we're talking about, scientists and, um, everyday, uh, apes (laughs) -

    2. CM

      (laughs) .

    3. AH

      ... uh, that we call humans, um, smelling stuff and tasting stuff and experimenting, uh, on, on one end of the spectrum. And that, on the other end of the spectrum, somebody going into a convenience store or looking online and buying a little bottle and, and slugging it down-

    4. CM

      Yeah.

    5. AH

      ... and getting some effect. And I actually think i- in between those is w- some important experiential stuff that's missing that perhaps is, explains a bit of where we are with kratom at this point in time, which is historically or what you call the traditional use, people would harvest the plant, they have knowledge of kind of the, the coloration of the plant, the texture, the feel, a lot of unconscious knowledge too. Um, maybe it's passed down through generations, maybe they just learn it, you know, 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, um, avenues of information coming in about the concentration. You're not just going from product purchase-

    6. CM

      Right.

    7. AH

      ... ingestion, effect.

    8. CM

      Right.

    9. AH

      And I think that perhaps this explains a lot of how we end up with, um, the highly processed food industry where, you know, much of what we're talking about today is paralleled. You know, sugar is, we have an innate desire for sugar.

    10. CM

      Yeah.

    11. AH

      Uh, who doesn't like sugar? Uh, 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, right? So you're ingesting far more calories, far more preservatives, et cetera, in trying to get some effect, but what happens is your threshold changes-

    12. CM

      Right.

    13. AH

      ... and the next thing you know, you're going to the highly concentrated version. We, in other words, we don't go through this process of stepping through and, and getting familiar with a molecule. And, and I think that could explain why people... You know, you're prescribed an opioid, next thing you know, you need that opioid.

    14. CM

      Right.

    15. AH

      I mean, good, good people have been very willing, it's clear, to do bad things to other people-

    16. CM

      Right.

    17. AH

      ... in effort to try and avoid the withdrawal symptoms of opioids.

    18. CM

      Right.

    19. AH

      And often the person they're harming the most is themselves.

    20. CM

      I think what you hit on is, uh, is a really deep philosophical conversation on a whole nother level, because I just had this conversation with a, a colleague. We'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. And-

    21. AH

      Aspirin.

    22. CM

      Aspirin is one perfect example.

    23. AH

      Salicylic acid.

    24. CM

      Salicylic acid. It comes from salicin, which is in the bark of the willow tree, and people used to chew on the bark of willow tree and that salicin is the active form. And, you know, you get salicylic acid, makes it more stable, and there's a long story there, but, um, uh, i- i- it's, it's important because, um, w- we've lost that sort of connection to nature, that connection we just talked about with the animal world, right? The watching the animals do things and learning from the animals.

    25. AH

      Metformin, berberine-

    26. CM

      Yeah.

    27. AH

      ... a tree bark-

    28. CM

      Yeah.

    29. AH

      ... that lowers blood glucose and works for all the world as well as metformin.

    30. CM

      Well, look at, look at the biggest selling weight loss drugs right now, the GLP-1s. You know, you know that story. They actually came from the saliva of the, the Gila monster. So this is a lizard that eats only a few times a year. Um, but in its saliva it has, uh, GLP-1 peptides and, um, this was, this was learned to help control glucose and help do all these things, and that was modified and now we have Wegovy and whatever, uh, Ozempic, uh, out there as, as blockbuster drugs that are really changing, um, you know, the shape of, of our society for, hopefully for-... a, a good benefit and, and getting people away from some of these sugary things (laughs) you mentioned earlier too. But yeah, there's, there's just this history, rich history of dr- how drugs have gotten to where they are, and most of us, including myself, uh, you know, we 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 gonna give us this effect, and boom. And so, you're, 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, we've lost that whole understanding of where things are coming from, and that's, that's one of the things that I've always loved. In my training originally as a pharmacist, I've always felt like for every disease that presents itself on this planet, there's gotta be a solution, there's gotta be this balance in nature, and natural products has always attracted me because of that.

  11. 59:00 – 1:09:06

    Alkaloids & Natural Products, Opium Poppy, Coca Leaf, Tool: Kratom Leaf vs Extracts (Kratom-Derived/Kratom Isolates)

    1. AH

      has been using supplements since I was in my teens, um, and I know it's a less well-regulated, um, industry, I've, I've long been interested in, in herbs. Like, I, I use and I'm open about the fact that I've used tongkat ali, um, as a, like, for vitality for a long time, things like fadogia, um, I continue to use these and my blood work says, um, it's fine and I, I enjoy them and, and it, it works well for me. But if those were put into a, um, pharmacologic agent, very high concentration, I can bet that it's an entirely different molecule and experience and might cause shutdown of the, of, uh, certain hormone pathways and things like that. There seems to be something kind of, um, unregulated and yet, uh, more nuanced (laughs) and, um, staid about the use of, of medicinals in their more natural form, and this is kind of the, the yin yang of it. It's like, yeah, you can't get an exact milligram dosage and concentration, but you're also not playing at very high concentrations.

    2. CM

      Right. Right. I a- I, I look at it like a... Natural products, i- i- they have evolved in Mother Nature's kitchen for, you know, millennials. I mean, they've, they've been there for thousands of years. Um, it, it only took humans coming along to figure out how to manipulate all that, right, and mess it up. (laughs) So Mother Nature's kinda got it right in many cases. Uh, couple examples, just, just to bring this back to more of a discussion around alkaloids, um, opium, opium poppy, uh, 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.

    3. AH

      Mm-hmm.

    4. CM

      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 in indigenous tribes and cultures there and still used today. It's one of the only places on the face of the earth that it's legal. Um, when cocaine was isolated and discovered, the, the rest of the leaf was criminalized and thrown out like the baby's bathwater, um-... yet there seems to be great medical potential with coca leaf, uh, and, and this is something that my lab is getting ready to embark on next as kind of, like, our new, our new challenge. We still, uh, we still have a lot (laughs) of work to do, um, with kratom and understanding that. But, um, you get, 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 wanna come back to some of that initial excitement project-type work again, and that's why we're embarking on that. Um, we've... 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, um, which it's a very nutritious plant. It's utilized by, um, tribes in the, in the high mountains, uh, high elevations in South America where they don't have much dairy in their diet. There's tons of calcium, uh, in this, um, in the coca leaf. There's tons of vitamins. It's so nutrient-rich, um, and, and just a remarkable plant in and of itself. But again, we've forgotten about this because we found this, you know, smoking bullet, uh, cocaine, and we don't want people to mess with that plant because there's a chance they're gonna get that out of it. And this has been a somewhat of a cautionary tale bringing this back to kratom because what we're seeing now is these kratom-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. Th- they're chemically changing these molecules, um, and these are n- now products that are out in the market that are available, easily purchasable, um, and unfortunately in the same places you can buy the more, you know, benign leaf, if you will, and it's not benign, and please don't m- m- think that I'm saying kratom 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. Uh, we don't have a good scientific history of, of how that evolves, but what we do know is that if we go down the same pathway that we have for things like the identification of morphine, identification of co- of cocaine, to a product that we started from nature again, kratom, uh, and now we're whittling down and figuring out actually it's a metabolite in our bodies, it's a, um, a metabolite controversially that may or may not exist in the plant. We've never found with all the work that we've done, um, with expert biosynthetic, um, biosynthetic, uh, plant folks, we've never found enzymes that will produce this compound 7-hydroxymitragynine, and that's a metabolite of mitragynine, which mitragynine is the major alkaloid within the plant, uh, kratom, and as I mentioned, there's more than 20 alkaloids within this plant. And I, I, I really wanna come back to this discussion about the differences in some of these alkaloids because they're, they're very, very different. I, I, I look at this plant as almost a pharmaceutical shotgun. It's got different alkaloids that are targeting different systems in our body, and this is what makes kratom different. You referred to it in the past as it's opioid, but it's different opioid, right? It's a different because it's interacting with multiple other systems in our brains, and so we need to come back and, and revisit that, but before we do that, what we know is that this 7-hydroxymitragynine, this metabolite that our bodies produce naturally from the major alkaloid, is being chemically produced now and sold in commerce, and the... These are now kratom-derived products or isolates or synthetically derived products. Um, we know that that molecule is pure opioid in its activity.

    5. AH

      Mm.

    6. CM

      It only interacts with opioid receptors.

    7. AH

      You said these are kratom-derived or kratom isolates. If they're gonna experiment with or use kratom products, they need to pay attention to serving size-

    8. CM

      Yeah.

    9. AH

      ... and also pay attention to whether or not the product is contains kratom-derived products within it or kratom isolates because those more closely mimic powerful opioids-

    10. CM

      A pure drug, right.

    11. AH

      A pure drug. And I actually am of the belief that many people taking kratom products are not aware that they're not taking the leaf-type product.

    12. CM

      Correct. I-

    13. AH

      Even if they're drinking it, they, they, it's because we just call it one thing.

    14. CM

      I agree, and that's where, uh, you know, we've-

    15. AH

      Mm-hmm.

    16. CM

      ... we've, we've published commentaries, um, on this because we feel 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, um, that are dealing with patients, humans firsthand, they show up in an emergency department, um, you know, they, they don't know to ask, "Did you take leaf? Did you take (laughs) a, a extract? Did you take a concentrate? What, what product is it that you actually take?" Because most people if they know, if someone was with them and they g- got intoxicated by a product, they're, they're probably just gonna generically say it's kratom. They're not gonna specify what, 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 kratom is the same, right?

    17. AH

      Mm-hmm. Well, fortunately, uh, we have the ear-... um, on this podcast from some of the folks like Jay Bhattacharya at NIH and, and others who are, um, thinking seriously about revising, uh, laws around packaging of, uh, food and drugs. Um, I don't have any direct relationship to them, but we have their ear. So, um, uh, I think one thing that I can't imagine anyone would oppose would be the careful wording of warnings about, "This contains kratom-derived products or kratom isolates." In the same way that, um, you'd like... You know, cannabis is legal in many places now, or at least decriminalized. As I learned from a guest on this podcast who's an expert in, uh, cannabis science, um, people who smoke cannabis are pretty good at regulating the dose, um, based on number and duration of inhales. But people that take edibles are often the ones that end up, uh, in psychotic episodes, um, or anxiety attacks due to overconsumption because you can eat something very fast before it hits you. There's that-

    18. CM

      Correct.

    19. AH

      ... there's this delay.

  12. 1:09:06 – 1:12:19

    Is It Safe for Kids to Consume Kratom Products?

    1. AH

      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, uh, tick off really quick as we-

    2. CM

      Mm-hmm.

    3. AH

      ... as we head into that. And 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 kratom? And, and here we're talking about leaf kratom or kratom products, and we're talking about kids in the US so we're, we're not... uh, and, and in Europe. We're talking about outside of Malaysia-

    4. CM

      Right.

    5. AH

      ... where they have a, have a more innate, um, historical understanding of, of the, of the plant.

    6. CM

      I will preface it by saying I am not familiar with anybody young using this in Southeast Asia in the traditional sense, right?

    7. AH

      Well, that's good to know.

    8. CM

      So it's, it's mostly used by people that are laborers that are out doing this, you know, more adult, if you will. Most 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.

    9. AH

      Do you agree with that generally?

    10. CM

      I agree with that from the standpoint that the brain is still developing until we're 24, 25. We know from studies with cannabis that, you know, that can slow brain development and people can have lower IQs if they start at a younger age versus people that never smoked and developed their brain fully. So we have no idea what the impact is of kratom on developing brain. A lot of people will hate me for saying this-

    11. AH

      (laughs)

    12. CM

      ... but my (laughs) feeling is, you know, the drinking age should be 24, 25, just like when your insurance rates go down for your car. It's 25. It's because you have a prefrontal cortex, (laughs) -

    13. AH

      Mm-hmm. Yep.

    14. CM

      ... right? 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 24, 25. But I would be okay with people saying 18 or 21, um, because that seems to be more acceptable in society as to where we've set barriers in, uh, in, you know, historical precedent. So yeah, I don't... I- I- I have great fear, um, as a parent that my own child would go into one of these gas stations not knowing what, what they're getting because one of their buddies told them, "Hey, this is cool. Try it," um, you know, and, and consume it and, and something, something happens. Um, and, and as you're well aware, there's a, there's a big difference between someone who's naive to any substance and takes it for the first time, um, versus someone who's gained some experience, um, with those substances. And so young people are, again, because there's not that executive control of the prefrontal cortex, are, are much more likely to take those risks, but not because they're being dumb. They just don't... they don't understand. Um-

    15. AH

      Well, they're not getting the information and-

    16. CM

      Correct.

    17. AH

      ... and, uh, thanks to you, they're getting the information now.

  13. 1:12:19 – 1:16:56

    Kratom, Energy, Mood & Pain Management, Dose; Caffeine

    1. AH

      The second cohort that I'll ask about would be, you know, people, let's just say, you know, 18 to, uh, 25 and older who are seeking a caffeine, um, stimulant-like effect. Um, assuming they can get ahold of the more plant-like product, so the, uh, you know, where it, it's not a kratom-derived product or isolate, are most people able to use a kratom 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, they would have a couple of days of, of mild discomfort, but they'd be okay? They could drink caffeine instead and get over the, the hump, so to speak?

    2. CM

      Yeah. So it's a... that's a definite maybe question. (laughs)

    3. AH

      Mm-hmm. So it depends-

    4. CM

      Right?

    5. AH

      ... on the person?

    6. CM

      It depends on the person. As you know, that we're all so different and we all respond differently to different... or the same thing. Um, but I, I think that... Uh, let's just say, um, the, the most frequent thing I hear from people that are using kratom, and particularly kratom leaf products on a regular basis, they always say less is more. They always say that the lower amounts they take, they seem to derive more benefit from it.

    7. AH

      Mm-hmm.

    8. CM

      And I've, 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 gotta take more to, 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...... s- mood lifting, elevating, um, energy-derived, uh, thing, then, then, th- the recommendation, the... And I would say this for anything, is s- stay low and stay slow and, and you know, never increase things. What I've been told (laughs) , 'cause again, e- this is not something that I use, uh, i- is, is that, um, people benefit from this on a consistent basis, just like most people benefit from a cup of coffee or two a day. Um, and, uh, yeah, if you go a couple of days without it, you're gonna have a headache. Where people start to develop problems is, if they are using this for, um, t- 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 timescale looks like, so we have no idea, and it, it'll differ for everyone. Um, we've not done these studies in animals to tell you that, uh, you know, a- a mouse or a rat is going to take this much time, and therefore, we can s- 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, they'll develop these, 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. It's something off target or off, off of that original frame that we're focused on that gives us into the problems. Um, 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, um, 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... Y- y- you, you can get too stopped up, and this could be worse. Same thing with respirations. Of course, the mo- main reason that individuals die from opioid overdose is because they stop breathing, um, and that respiratory depression is nothing to do with the analgesia. It has nothing to do with the pain relief. It's just this off, offside-

    9. AH

      Yeah.

    10. CM

      ... target.

    11. AH

      Yeah, it's these receptors in the brainstem. I mean, I think-

  14. 1:16:56 – 1:20:16

    Respiratory Depression & Kratom Products

    1. AH

    2. CM

      That's right.

    3. AH

      ... um, it raises the question whether or not kratom can cause respiratory, uh-

    4. CM

      Uh-

    5. AH

      ... suppression.

    6. CM

      It's a good, it's a good segue to-

    7. AH

      Well, kratom-

    8. CM

      ... our paper that should be coming out in the next week or two.

    9. AH

      Oh, great. Well-

    10. CM

      (laughs)

    11. AH

      ... since it's already accepted, uh, it... Yes or no?

    12. CM

      It's complicated.

    13. AH

      Is it dose-

    14. CM

      So-

    15. AH

      ... dependent?

    16. CM

      So, I will say this. In kratom as a whole, we've not studied in respiratory depression, so 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 kratom 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, um, and it should be in the Journal of Pharmacology & Experimental Therapeutics. Um, it's already on bioRxiv right now, but bioRxiv is not a peer-reviewed site. Uh, we just wanted to get this information out as soon as possible 'cause we think it is vitally important for public safety. Um, these 7-hydroxymitragynine, um, products that are now being sold, as I mentioned, as semi-synthetics or isolates, um, are actually causing respiratory depression equivalent to opioids.

    17. AH

      Wow. Okay, so these are the, the, um, the specific alkaloid metabolites. So to back up again for folks-

    18. CM

      Yeah.

    19. AH

      ... that the alko- uh, kratom contains, uh, somewhere between 20 and 40 alkaloids. Um, one of them i- is most abundant. The metabolite of that, um, is what's active in the body. Chemi- 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, um, on par with, uh, opioids. And s-

    20. CM

      Uh, i- in a rat, so I will, I will caveat that, but, you know, it's one of these things that we d- uh, we t- talk about all the time.

    21. AH

      Sure.

    22. CM

      If it walks like a duck, if it quacks like a duck, if it looks like a duck, it's a duck.

    23. AH

      Yeah, I think when it comes to translating animal studies to humans, it, um, it's hard, often, to take a dosage by kilogram of body weight and translate, 'cause the 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-

    24. CM

      Mm-hmm.

    25. AH

      ... these two nuclei in the brain, pre-Botzinger and parafacial nucleus, which have ar- abundant receptors for these things that control breathing, um, th- that machinery is so highly conserved from mice to rats to non-human primates, as we always say, rat, cat, monkey, bat, um, and human, um, that it would be e- it would be remarkable and extraordinary t- for the system to work much differently-

    26. CM

      No, and I, a-

    27. AH

      ... than human.

    28. CM

      And I think in humans, it's gonna have exactly the same effect, you know, but I can't say that definitively, and, 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 naloxone. So it's, it's-... also highly opioid, um, receptor involved.

  15. 1:20:16 – 1:22:04

    Sponsor: Function

    1. CM

    2. AH

      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. Function provides over 100 advanced lab tests that give you a key snapshot of your entire bodily health. This snapshot offers you with insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFASs or forever chemicals. Function not only provides testing of over 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas. For example, in one of my first tests with Function, I learned that I had elevated levels of mercury in my blood. Function not only helped me detect that, but offered insights into how best to reduce my mercury levels, which included limiting my tuna consumption, I'd been eating a lot of tuna, while also making an effort to eat more leafy greens and supplementing with NAC, N-acetylcysteine, both of which can support glutathione production and detoxification. And I should say by taking a second Function test, that approach worked. Comprehensive blood testing is vitally important. There's so many things related to your mental and physical health that can only be detected in a blood test. The problem is blood testing has always been very expensive and complicated. In contrast, I've been super impressed by Function's simplicity and at the level of cost. It is very affordable. As a consequence, I decided to join their scientific advisory board, and I'm thrilled that they're sponsoring the podcast. If you'd like to try Function, you can go to functionhealth.com/huberman. Function currently has a wait list of over 250,000 people, but they're offering early access to Huberman podcast listeners. Again, that's functionhealth.com/huberman to get early access to Function.

  16. 1:22:04 – 1:26:59

    Kratom Leaf vs Derivatives, FDA Regulations, Usage Guidelines

    1. AH

      So let me ask you this. If I were in charge of the FDA, and I'm not, um-

    2. CM

      That makes two of us.

    3. AH

      (laughs) But if I were, I would say, okay, based on everything I've learned thus far, um, the plant-based kratom products that were still close to the plant pro- 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, um, or two, or an energy drink or two. I mean, some of these energy drinks now, I mean, they pack a serious punch.

    4. CM

      Oh, yeah.

    5. AH

      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-

    6. CM

      Right.

    7. AH

      ... that serve to amplify the, the neuromodulator effect-

    8. CM

      Right.

    9. AH

      ... like increased dopamine, epinephrine. I mean, they've got huperzine, um, alpha-GPC. They've got, um, things to enhance the serotonin pathway. They've got things to take away the jitters like L-theanine, plus the caffeine-

    10. CM

      Right.

    11. AH

      ... plus some additional stimulants and pretty soon you go, yeah, the caffeine count isn't that high, but what you've got is a, is a neuromodulator cocktail in there. So, um, and 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.

    12. CM

      Right.

    13. AH

      Something like that, but then I would probably also create a third category which is, and I'm gonna get the pronunciation wrong, but the 7-hydroxymetabolite of mitro- mitragynine?

    14. CM

      Mitragynine.

    15. AH

      Yeah. Mitragynine. Um-

    16. CM

      Or mitragynine some people call it. (laughs)

    17. AH

      Mitragynine. 7-Hydroxymitragynine. (laughs) Um, tragynine, tragedy, okay?

    18. CM

      (laughs) Oh.

    19. AH

      Should be, um, if I were FDA commissioner, I'd say this just sounds all bad, let, just flat out make it illegal.

    20. CM

      Yeah, I mean-

    21. AH

      Um, so you're not making kratom illegal, you're making the, the opioid-like derivative, uh, illegal or extremely hard to get or maybe you need some additional, um, barriers there. Why isn't it that way? I mean, wh- why did we sit down here today, me ready to ask you should kratom be illegal-

    22. CM

      Right.

    23. AH

      ... when we're really talking about two different use categories, younger and adult people, and we're talking about basically two completely different compounds?

    24. CM

      Yeah. Well, even very different products period, right? So, uh, it's, it's, 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.

    25. AH

      I see. Okay.

    26. CM

      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, um, nonprofit organizations out there. Um, there's American Kratom Association, there's a Global Kratom Coalition, there's a Holistic Alternative Recovery, um, Group, uh, HEART.

    27. AH

      What's their role? Are these people who are looking at this as a, as a good alternative to opioid abuse?

    28. CM

      So in, in many of the cases, yes. All of the cases, yes. So I should say that. Um, the, the American Kratom Association and Global, uh, Kratom Coalition are much more, um, advocating for science-based information and knowledge around kratom and kratom products and putting actual guidelines in place that will give some regulation to the industry, um, that they claim the FDA is, is not doing right now. The FDA is just letting it exist in the marketplace in whatever form, shape, size it wants to. Um, some of these groups are, 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. Um, there's this other group, the HEART group, which is really, uh, a proponent for this 7-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? It, but it is purely an opioid, but it's not a prescription opioid and they're saying it's reducing harm. Wait, 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, um, suggesting that there's no mention of these in the FDA's databases of adverse events, the FEARS database. Um, but then again, it makes you wonder, if these products have only been in the marketplace for a couple of years, um, is there even a coding to put it into the FEARS database (laughs) so they can even be recognized?

    29. AH

      If

  17. 1:26:59 – 1:29:09

    Kratom, Alcohol Consumption, Respiratory Failure?

    1. AH

      somebody were to take, um, a kratom product, either an isolate or the plant product, and then drink alcohol, are they at greater risk for, uh, dying, um, from respiratory failure in the same way that if somebody takes an opioid and drinks, um, they can die?

    2. CM

      Yeah.

    3. AH

      A- actually, sadly, I know a lot of cases of this, of people who even took a prescription opioid a day before, um, a- an afternoon or night of drinking and were pretty good drinkers, if I'm, if I'm gonna say it wasn't, it was not, uh, someone real close to me, but from what I understand were good drinkers and then end up dying in their-

    4. CM

      Mm.

    5. AH

      ... typically in their sleep-

    6. CM

      In their sleep, yeah.

    7. AH

      ... after a night of drinking. This is not uncommon.

    8. CM

      Yeah.

    9. AH

      And this is independent of all the fentanyl issues.

    10. CM

      Correct, correct.

    11. AH

      Right? Um, d- does kratom have the same potential risk?

    12. CM

      So kratom as a whole, uh, it, it's hard to say. No- 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 kratom actually reduces alcohol consumption.

Episode duration: 2:42:52

Install uListen for AI-powered chat & search across the full episode — Get Full Transcript

Transcript of episode gyE6Z4GLEeM

Get more out of YouTube videos.

High quality summaries for YouTube videos. Accurate transcripts to search & find moments. Powered by ChatGPT & Claude AI.

Add to Chrome