0:00:07 Delay your intuition. Don’t try to form an intuition quickly, which is what we normally do.
0:00:12 Focus on the separate points, and then when you have the whole profile,
0:00:15 then you can have an intuition and it’s going to be better.
0:00:26 Welcome to The Knowledge Project. I’m your host, Shane Parrish. In a world where knowledge is power,
0:00:30 this podcast is your toolkit for mastering the best of what other people have already figured out,
0:00:33 so you can use their insights in your life.
0:00:42 Before we get into the interview, I want to tell you about a moment that didn’t make it into the episode.
0:00:49 I first came across Daniel Common’s work in the early 2000s. His impact on me and so many people
0:00:55 around the globe has been unbelievable. By the time I sat down with him in his New York City home in
0:01:01 2019, I had so many questions for him. Condon won a Nobel Prize in Economic Sciences in 2002,
0:01:08 yet he never took an economics course. His central message was very simple. If we want to make better
0:01:15 decisions, we need help. Danny died last year on March 27th, 2024. He was 90. This conversation is
0:01:22 now one of the final opportunities to hear directly from one of the most influential thinkers of our time.
0:01:28 I get messages about this episode every week. People come away with new insights on everything from life
0:01:36 to decision making. I re-listened to it recently and it’s timeless. That’s exactly why I’m republishing it.
0:01:42 Consider loss aversion, one of his most important discoveries. Why does losing $100 hurt twice as much
0:01:49 as gaining $100 feels good? The asymmetry affects everything. It affects your stock portfolio, your golf
0:01:55 game. Check your portfolio when it’s down and you’ll start making emotional decisions. A golfer putts better
0:02:02 for power than for birdie. But here’s what happened near the end of our interview. Danny’s phone rang and it
0:02:07 was loud. He’d forget to turn it off. We’re almost done the interview at this point but he answered and
0:02:13 someone obviously wanted him to give a talk or review a book. He ended the call with words that have stayed
0:02:19 with me since then. My rule is I never say yes on the phone. I’ll get back to you tomorrow. I wanted to
0:02:26 discuss that on air but we ran out of time. As I packed up my gear, I asked him about that. This rule was a trick
0:02:32 to avoid saying yes intuitively. It gave him time to think. He’s always bombarded with requests and he
0:02:38 often says yes when he didn’t want to. At first, he would try saying no. That date doesn’t work. That
0:02:43 timeline doesn’t work. But what happened in those moments was it turned into a negotiation. What about
0:02:50 another date? Another timeline? So he hit on this rule. And to me, this is his most practical discovery.
0:02:57 Most people don’t even know about it. This rule lets you reprogram your unconscious mind. Your desired
0:03:03 behavior becomes your default behavior. And that’s incredibly powerful. It changed my life. I now
0:03:08 exercise every day. It’s actually easier than three times a week. The activity, duration, and scope can
0:03:15 change but working out and exercising doesn’t. I think I’ve missed five days in five years at this point.
0:03:20 And I talk about this in my book, Clear Thinking. And the concept has changed so many lives, including
0:03:26 my great friend, Brent Beshore. In episode 196, we talk about this a little. Several parts of this
0:03:31 conversation stuck out when I was re-listening to it. First, we talk about happiness versus satisfaction.
0:03:38 Happiness is feelings. It’s mostly social. Am I with the people who love me and whom I love back?
0:03:43 Satisfaction, on the other hand, is how you feel about your life, your job, your career,
0:03:50 conventional aspects. Danny argued people want satisfaction more than happiness. Second,
0:03:57 changing behavior. Make good behavior easier and bad behavior harder. The insight? All behavior is
0:04:04 equilibrium. Rather than pushing people to change, ask why they aren’t doing it already. Third, behavior
0:04:11 is situational. Want to understand behavior? Look at the situation. When someone acts in ways that don’t
0:04:16 make sense, ask yourself, ask yourself, what would the world have to look like for that behavior to make
0:04:24 sense? Fourth, agents making decisions on your behalf beat you at certain types of decisions. They have no
0:04:31 sunk costs. They have no emotions. Brian Johnson talks about this in episode 188. He turned his health
0:04:38 decisions over to effectively an algorithm because that algorithm makes better decisions than he does.
0:04:44 Fifth, our beliefs are formed by people more than facts. We agree with people we like,
0:04:49 despite the facts. It’s easier to believe a lie from someone you like than a truth from someone you
0:04:57 dislike. We form identity beliefs. Liberal, conservative, Democrat, Republican. They can do no wrong. If they’re
0:05:03 wrong, we’re wrong. And we can’t handle that. Finally, intuition. Danny had talked about this so much,
0:05:08 his answers sounded repetitive. So I framed my question on this to include his typical answer
0:05:15 in the question, forcing him to think a little deeper. Whether this is your first listen or your
0:05:18 third, you’ll come away with ideas that you can use in life.
0:05:40 Daniel, I’m so happy to give it a chance to talk to you.
0:05:43 Well, I’m happy to have you here.
0:05:47 What was your childhood like? What were you like as a child?
0:05:56 Oh, my God. That was a long time ago. I was, I was an early child, as you might expect, I suppose.
0:06:04 I was, I thought I’d be a professor when I was like three or four years old because people told me I would
0:06:12 be because I probably spoke with long words and stuff like that. So, and then the rest of my childhood,
0:06:21 I mean, I was five when World War II began. So, and I was a Jew in France. So, I’ve had a difficult
0:06:28 childhood, but from that point on. But, but I was, was I like, yeah, I was a, I was a nerdy child.
0:06:36 I was quite inept physically. Very fortunately for me, when I’d finally moved to Israel at age 12,
0:06:43 they held me up a grade in them. And that was all right. But that’s, that’s what I was like.
0:06:47 Are there any particular lessons or memories that stand out for you?
0:06:55 There are two of them that I speak about. So, one is that I was, I was a psychologist very early on.
0:07:04 That was, that was very clear. I, I wrote an essay before I was 11. I remember where, because it was,
0:07:11 it was a German counterattack. It was during that period we were in Paris. And I wrote an essay about
0:07:19 faith and religion. And it was a very pompous essay. I had a little book that was, that was titled
0:07:28 what I, what I write about what I think, something pompous like that. But the essay started with
0:07:36 another pompous thing that I quoted Pascal. My, my sister had passed her exams and I had read,
0:07:44 she’s, you know, she’s studied some Pascal and I had read it. And Pascal had said that faith
0:07:56 is God made sensible to the heart. And, you know, little me, I said, how true. That’s what my essay said.
0:08:04 And then, and then, but then I said, but faith is really hard to get. You don’t say it’s God all the time. So, that’s what
0:08:12 that’s what religious pomp is for. Cathedrals, organ music. They give you, and I call that urzat faith,
0:08:21 sort of a substitute faith, because it’s a, it’s a similar feeling. It’s got to do with God. And that’s what you
0:08:30 must do with me. That’s, that’s a psychologist. So, it’s clear that, you know, that was my calling. And so,
0:08:35 that’s one significant memory of my childhood.
0:08:36 So you wanted to be a psychologist?
0:08:46 I think so. I think so. I mean, I, you know, it’s always had that point of view that later, as a
0:08:52 teenager, I was, you know, interested in all the philosophical issues, like, you know, does God
0:08:58 exist? And what’s good and bad? And stuff like that. And why shouldn’t we masturbate? You know, serious
0:09:06 questions. But, but I discovered that, actually, I was less interested in the question of whether or
0:09:13 not God exists, then in why do people believe that he exists? That I thought was interesting. And I
0:09:18 wasn’t particularly interested in the question of what’s good or bad, but I was really interested in
0:09:24 what makes people angry and indignant. So, you know, I’ve had the psychological point of view since,
0:09:26 turns out, since my childhood.
0:09:33 Was there anybody that sort of influenced you to go on to study this? I mean, it’s one thing to have
0:09:39 these dreams as like a 12, 13, 14-year-old boy. It’s another to turn this into, you know, probably
0:09:43 the most eminent career that’s ever happened for a psychologist.
0:09:50 No, not the most eminent career. You know, and I wasn’t sure, actually, that I would do psychology.
0:09:59 And when I took a vocational exam to tell me what I was good at, and psychology and economics stood in
0:10:07 out. But, you know, that was unexpected. And then I took psychology as an undergraduate and mathematics,
0:10:13 at which I was not particularly good. So, and no, it’s not that I knew at the time that, you know,
0:10:19 I had that calling to be a psychologist. It didn’t occur to me. I thought, you know, I thought I’d be a
0:10:26 professor in one thing or another. I mean, I thought I’d be an academic, but not psychology specifically.
0:10:32 You worked with Amos Tversky for a long time. Are there any particular stories that you remember
0:10:34 about working with him that bring a smile to your face?
0:10:44 Almost everything about working with him brings a smile to my face. You know, he was a very unusual
0:10:51 person. Most people who knew them thought that he was the smartest person that I’ve ever met.
0:10:57 And in fact, the famous psychologist, Nick Nesbitt, said that it’s sort of an intelligence test when
0:11:03 you said that when you’re with Amos, how long does it take you to figure out that he’s smarter than you
0:11:09 are. And the faster you figure that out, the smarter you are. So, you know, he was, uh, he was
0:11:17 super bright and very, very funny. He joked a lot. He laughed a lot at his own jokes. And that was
0:11:25 infectious. When I was with him, I was very funny too. More than half of my, the last of my, of my lifetime
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0:12:49 You have an interesting distinction between happiness and satisfaction. Can you walk us through that?
0:12:58 Yeah, sure. I mean, the word happiness is so ambiguous and it means so many things to many people,
0:13:06 but one sensible interpretation of it is that it’s got to do with your emotions, with how you feel,
0:13:12 with the emotional tone of your life, whether it’s a happy life, you know, it’s pleasant to be you.
0:13:19 Life satisfaction is a completely different thing. I mean, life satisfaction is how you feel about your
0:13:24 life when you think about your life. And most of the time, you don’t think about your life, you just live.
0:13:33 But, you know, sometimes you sort of look and that’s when you determine how satisfied you are.
0:13:38 That’s life satisfaction. It’s not satisfaction, it’s life satisfaction.
0:13:43 Should we balance the two? Or how would you think about them? Should we be more happy when we’re younger,
0:13:44 more satisfied when we’re older?
0:13:51 That thought had never occurred to me. When I began to work on this, I started out thinking that
0:14:00 happiness, in that sense of how you feel when you live, that was reality. And that
0:14:07 life satisfaction was just stories that people tell themselves. And the important thing was to be
0:14:13 happy in real time. But later, when we did more research, it turned out that
0:14:19 the circumstances that make people happy and the circumstances that make them satisfied with their
0:14:25 life are not the same. So happiness is mostly social. It’s, you know, it’s being with people
0:14:33 you love and who love you back. That’s, that’s a lot of what happiness is. Life satisfaction is much more
0:14:39 conventional. It’s to be successful. And, you know, so it’s money, education, prestige,
0:14:46 that sort of thing is what life satisfaction is about. So those are two very different things.
0:14:53 I thought that life satisfaction is irrelevant. You know, that’s how I began. And we, we had a research
0:15:00 program where we were, we were trying to, you know, to show that this is the case. But then after a few
0:15:09 years, I realized that what people really want in their life is they don’t seem to care about how happy
0:15:14 they’ll be. They seem to want to be satisfied with their life. They seem to want to have a good story
0:15:21 about their life. And then I was in the position of saying that to define wellbeing in a way that people
0:15:28 didn’t seem to care particularly about. So that was not a tenable position. So I, I dropped back into
0:15:31 saying that I had no idea how to deal with it.
0:15:37 Was this a result of the research? You did some research that was, I think it said above 70,000,
0:15:40 you don’t become happier, but do you become more satisfied?
0:15:51 No. The research I did with Angus Deaton at Princeton, famous economist, we showed that in terms of
0:15:58 happiness, in terms of emotional tone, positive and negative, having a lot of money doesn’t make you
0:16:06 happier. But being poor makes you miserable. So that’s above the threshold that was like $70,
0:16:15 $50,000 approximately in the U.S. Then extra money didn’t make you emotionally happier. But with life
0:16:21 satisfaction, it was a different story. With life satisfaction, that doesn’t satiate. So it’s always
0:16:29 good to have more. Because basically, I think, money is a proxy for success. And it’s a proxy for
0:16:31 subjective success in many cases.
0:16:35 So it’s not necessarily about spending it or doing something with it. It’s just a measure.
0:16:41 Just getting it. I mean, you know, you look at all those people, those billionaires working their heads
0:16:46 off. And they’re clearly not doing this because they need more money. They’re trying to get more
0:16:51 money. And they’re trying to get more money because that would be an indication that they’re good at what
0:16:54 they do. I think mostly it’s a proxy.
0:16:59 Do either of those variables correlate to longer living, happiness, or satisfaction?
0:17:06 Both, apparently. But you know, it’s hard to separate. And I haven’t been followed. You know,
0:17:14 shortly after deciding that I didn’t know what well-being was, I sort of stopped doing research
0:17:22 on this. So I haven’t been following. But I think there’s clear evidence that being effectively happy,
0:17:27 you know, is very good for you. And you do live a little longer, and you live better, and so on.
0:17:34 And life satisfaction works in the same direction. Whether it’s separable, which of them, you know,
0:17:36 is it more important that I don’t?
0:17:44 I want to switch gears a little bit and talk about behavior. And I’d love your insider expansion
0:17:49 upon the idea of we can change behavior. And how do we go about changing our behavior?
0:17:56 Well, you know, I’m not sure I buy the premise. I think changing behavior is extremely difficult.
0:18:02 There are a few tips and, you know, a few guidelines about how to do that. But anybody who is very
0:18:10 optimistic about changing behavior is just deluded. It’s hard to change other people’s behavior. It’s very
0:18:12 hard to change your own. Not simple.
0:18:14 This is what marriage is all about, right?
0:18:19 Yeah, among other things. You know, people, when, when, you know, married people try to
0:18:21 change each other’s behavior.
0:18:23 It’s a lot of dissatisfying.
0:18:26 They are not on their way to a good marriage, I think.
0:18:28 We’d all be happier with lower expectations.
0:18:34 Yes. I mean, and, and even if you have expectation, don’t try to change because, you know,
0:18:38 it’s very unlikely to work in a significant way.
0:18:43 I can think of the common ways that we would sort of go about behavior change and it would be,
0:18:48 you know, making good behaviors more easy or negative behaviors harder.
0:18:55 And that’s the main, the main insight. You know, when you want to influence somebody’s behavior,
0:19:01 that’s a very big insight. I’ve always thought that this is the best psychological idea ever,
0:19:08 you know, so far as I’m concerned. But it’s that when you want somebody to move from A to B in terms of
0:19:15 their behavior, you can think of it that there are two ways of doing it. You can push them or you can ask
0:19:22 the question, “Why aren’t they doing B already?” Which is an unusual question, but you know, why?
0:19:32 So then when you ask, “Why, why not? Why aren’t they doing B?” as they ought to, as they think they ought to,
0:19:40 then you get a list of what’s got to win. That’s the psychologist who my guru and that’s my hero and
0:19:45 many people’s hero. He spoke of restraining forces. I mean, so there are reasons.
0:19:52 why they’re not where you want them to be. So he spoke of behavior as an equilibrium. There are
0:19:58 forces that are pushing you one way, forces that are pushing you the other way. So how loud you speak,
0:20:06 how fast you drive. It’s easy to think of it as an equilibrium. And what we tend to do when we want to
0:20:17 move people from A to B is we push them. We add to the driving forces. And Kurt Lewin’s insight was that
0:20:23 this is not what you should do. You should actually work on the restraining forces and try to make them
0:20:31 weaker. And that’s a beautiful point. And he showed, he had that image that, you know, I’ve had since I was an
0:20:37 undergraduate. And I’m not sure actually whether it was his image or something that I drew from
0:20:44 reading him. But it’s like you have a plank and it’s being held by two sets of springs. You know,
0:20:50 you want it to move one direction. And so you could add another spring that would push it that way, or
0:20:56 could remove one of the springs that are holding it back. And the interesting thing, and that’s the
0:21:04 striking outcome, is when it moves, if it moves because of the driving force you’ve added to the
0:21:12 driving force, then at equilibrium, it will be in a higher state of tension than it was originally.
0:21:17 That is because you’ve compressed one spring and such pushing back harder. But if you remove
0:21:23 a restraining force, at equilibrium, there’ll be less tension in the system. I must have been 20 years
0:21:30 old. I thought that’s just so beautiful. What do you wish that everybody knew about psychology that you
0:21:34 don’t think that they do? If that was class one, what’s class two?
0:21:41 You know, class two, which is a development from class one, you know, it’s the same idea extended.
0:21:51 Class two is that behaviors don’t necessarily reflect the personality, but behaviors have a lot to do with
0:21:58 the situation. And so if people behave in strange ways, look at the situation they’re in and what are
0:22:05 the pressures in the situation that make them act as well. So there is a bias that the social
0:22:11 psychologist, well-known social psychologist, call the fundamental attribution error. And that means
0:22:17 that when you see people acting in some way, you think that it’s because of their personality that they
0:22:23 do it. That may not be the case. It’s quite likely that the situation is making them do it.
0:22:31 I’d like people to know that motivation is complex and that people do good things for a mixture of
0:22:37 good and bad reasons. And they do bad things for a mixture of good and bad reasons. And I think that
0:22:43 there is a point to educating people in psychology is to make them less judgmental. Just have
0:22:50 more empathy and more patience and being judgmental doesn’t get you anywhere.
0:22:55 When you talk about situational, one of the things that comes to mind is it’s so easy for us to give
0:23:00 our friends advice. But if we were in that situation, we might not necessarily see it.
0:23:04 Why is that the case? Why is it so much easier to give other people advice?
0:23:11 I mean, feelings get in the way of clear thinking. There is a phenomenon that we call the endowment effect,
0:23:18 which is that when I’d ask for more money to sell you my sandwich than I’d pay to get it. I mean,
0:23:24 that’s essentially the endowment effect. And our explanation of it, there are many explanations,
0:23:30 but a story I like to tell about it is that it’s more painful to give something up than to get something.
0:23:37 But there is an interesting result that if you have an agent making decisions on somebody’s behalf,
0:23:43 that agent doesn’t have loss of those. So that agent sells and buys at the same price,
0:23:48 which is the economically rational thing to do. Where this goes into policy and governments and
0:23:54 really important things is that governments are like agents or people who think about the good of
0:24:00 society. And agents, they take the economic view. They take the view of what things will be like at
0:24:06 the end. They don’t figure out that there are some people are going to be losing because of the reform
0:24:13 that they make. And it turns out that you can really expect losers, potential losers to fight a lot
0:24:20 harder than potential winners. And that’s the reason that reforms are frequently fair. And that when they
0:24:27 succeed, they’re almost always way more expensive than anticipated. And they’re more expensive because
0:24:35 you have to compensate the losers. And that frequently is not anticipated. So that’s an example of a story
0:24:46 that incorporates behavior change. And the difference between perspective, between being, you know, in the
0:24:52 situation, feeling the pain of giving up the sandwich, and not feeling the pain of giving up the sandwich.
0:24:59 That would have huge public policy sort of implications too, right, that we don’t tend to think about or discuss.
0:25:05 That’s a really interesting angle there. I want to come back to sort of situational decision-making based on
0:25:10 sort of like what we see is all there is. And we have these feelings that we can’t sort of disassociate
0:25:17 with. How does environment play a role like the physical environment in sort of what we decide or does it?
0:25:25 I mean, you know, there are sort of obvious things that we know. If people are hot and bothered and
0:25:34 distracted, and there is a lot of noise and so on, then they’ll think as well. And that we know that’s…
0:25:39 But even there, there are puzzles. I mean, many people think and work a lot better in cafes,
0:25:46 you know, where there is actually ambient noise and activity around them, and it helps them concentrate
0:25:52 better. So there isn’t a very simple story of the environment. But certainly, you can make the
0:25:58 environment tough enough so that people won’t be able to think properly. That’s feasible.
0:26:05 Are there things that we could do to, I guess, push the environment to be more conducive to
0:26:09 to clear thinking, the physical environment in this case?
0:26:16 Oh, there are all sorts of, you know, odd findings, you know, the color of the color of the room.
0:26:22 Some colors are better than others. And you would expect that some colors are more calming than others.
0:26:25 So you wouldn’t want to be in a red room.
0:26:26 Making decisions.
0:26:26 Making decisions.
0:26:32 Making decisions. But, you know, those are extreme and minor effects.
0:26:38 I want to come to intuition and noise later. Is there anything else that stands out that gets in
0:26:43 the way of clear thinking that we can sort of bring to the surface now?
0:26:51 Well, you know, what gets in the way of clear thinking is that we have intuitive views of
0:26:57 almost everything. So as soon as you present a problem to me, I have, you know, I have some
0:27:02 ready-made answer. And what gets in the way of clear thinking are those ready-made answers.
0:27:08 And we can’t help but have them. So that’s one thing that gets in the way. Emotions get in the
0:27:19 way. I would say that independent clear thinking is, to first approximation, impossible. In the sense
0:27:25 that, you know, we believe in things most of the time, not because we have good reasons to believe
0:27:31 them. If you ask me for reasons, I’ll explain you. I’ll always find a reason. But the reasons are not
0:27:38 the causes of our beliefs. We have beliefs because mostly we believe in some people and we
0:27:45 trust them and we adopt their beliefs. So we don’t reach our beliefs by clear thinking,
0:27:50 something, you know, unless you’re a scientist or doing something like that.
0:27:52 But even then, it’s probably a very narrow…
0:27:57 But that’s very narrow. And there is a fair amount of emotion in neuroscientists as well
0:28:02 that gets in the way of clear thinking. You know, commitments to your previous views,
0:28:08 being insulted that somebody thinks he’s smarter than you are. I mean, lots of things get in the way
0:28:14 even when you’re a neuroscientist. So I’d say there is less clear thinking than people like to think.
0:28:22 Is there anything that we can do at the belief formation stage? Like it sounds almost as though
0:28:29 when you say that we’re reading a newspaper, we read this op-ed, and it’s well constructed and fits
0:28:37 with our view of the world. Therefore, we adopt that opinion. And we forget the context that we didn’t
0:28:42 learn it through our own experience or reflection. We learned it sort of from somebody else. So we don’t
0:28:48 know when it’s sort of likely to work or not work. But we just proffer that as our opinion, is there?
0:28:54 That’s how I believe in climate change. You know, I believe in the people who tell me there is climate
0:28:59 change. And the people who don’t believe in climate change, they believe in other people.
0:29:04 So, but similarly, there’s like fake news and all this other stuff that we would have the same
0:29:12 reaction to you. You know, but I’m much more likely to believe fake news on my side than the fake news
0:29:22 on the other side. I mean, it’s true that there is a huge degradation in public discourse in the recent
0:29:28 10, 15 years in the United States. I mean, there used to be an idea that facts matter.
0:29:33 What would be your hypothesis as to why that is playing out? Are they getting into politics?
0:29:37 because I don’t want to talk politics. But like, why is that? Well, I mean, it’s hard to,
0:29:44 it’s hard to answer that question without, without politics, because it’s a general political
0:29:54 polarization has had a very big effect. And the fact that people can choose the sources of information.
0:30:01 Let’s switch gears a little bit and talk about intuition. I think one of the,
0:30:07 the things that strikes me the most about some of the work that you’ve done is the
0:30:15 cases where we’re likely to trust our intuition and when we’re not. And so if I’m, correct me if I’m
0:30:21 getting this wrong. So it’s sort of like a stable environment, repeated attempts and rapid feedback.
0:30:31 It strikes me that most decisions made in organizations do not fit that environment.
0:30:39 And yet we’re making a lot of these decisions on judgment or experience. What are the ways that we can
0:30:43 sort of make better decisions with that in the context?
0:30:48 : Well, in the first place, I think, you know, you shouldn’t expect too much.
0:30:50 : And pat to low expectations. : And pat to low expectations.
0:30:53 : I shouldn’t think too young. You should have low expectations
0:30:59 about improving decisions. I mean, there is, you know, one basic rule is slow down,
0:31:05 especially if you, if you have that immediate conviction, slow down. There are procedures,
0:31:11 you know, there are ways of reaching better, better decisions, but reaching better reverence,
0:31:13 and we can talk about them. : I would love to hear.
0:31:19 : If you really want to improve the quality of decision-making, use algorithms. I mean,
0:31:27 whenever, wherever you can, if you can replace judgments by, by rules and algorithms, they’ll do
0:31:36 better. And there’s big social costs to trusting, allowing algorithm to make decisions, but, but the
0:31:42 decisions will likely to be better. So that’s one thing. If you can’t use algorithms, then you slow
0:31:48 yourself down. And then there are things that you can do for certain types of problems. And there are
0:31:55 different types of problems. So one class of problems, like forecasting problems. A friend,
0:32:03 Phil Tetlock, you know, has that book on super forecasters, where he identifies with people who are
0:32:10 good at forecasting the future, what they do that makes them good. And, you know, he tries to train
0:32:16 people and he can improve people. So that’s one classic problem. I’m interested specifically in
0:32:23 another kind of problem, judgment problems, where basically you’re considering options or you’re
0:32:30 evaluating a situation and you’re trying to give it a score. There, there, there is advice, I think,
0:32:39 on how to do it. For me, it goes back to something I did in the Israeli army when I was like 22 years
0:32:46 old. So that’s a long time ago, like 63 years ago. I was a psychologist in the Israeli army. And I was
0:32:54 assigned the job of setting up an interviewing system for, for the army. That’s ridiculous. But you know,
0:32:59 this was the beginning of the state of Israel. So people were improvising all over the place.
0:33:06 So I had a BA and I was, I think I was the best trained psychologist in the army. My, my boss was a
0:33:15 chemist. Brilliant. But anyway, and the, the existing system was one where people would interview and try to
0:33:23 form an intuitive global image of how well that recruits would do as a combat soldier, which was
0:33:29 the objective of the, the object of the interview. And because I had read a book, I told me, I took a
0:33:38 different tack. And the different tack was, I identified six traits that I sort of made up. And I had them
0:33:45 ask questions and evaluate each of these traits independently and score it and write down the score,
0:33:51 then go on to the next trait. And they had to do it for all six traits. And that was, that’s all I asked
0:33:58 them to do. And the interviewers who were about one year younger than I, or recruits, but very,
0:34:04 very smart, selected for being good at it. They were furious with me. And they were furious with me
0:34:09 because they wanted to exercise their intuition. And I still remember that one of them said,
0:34:16 you’re turning us into robots. So I compromised with them. And I said, okay, you, you do it my way.
0:34:23 And I told them, you try to be reliable, not valid. You know, I’m in charge of validity. You be
0:34:30 reliable, which was pretty arrogant, but that’s, that’s how I presented it. But then when you’re done,
0:34:39 close your eyes and just put down a number of how good a soldier is that guy going to be. And when we
0:34:47 validated the results of the interview, it was a big improvement on what had gone on before. But the
0:34:54 other surprise was that you have an interesting distinction between happiness and satisfaction.
0:35:03 Can you walk us through that? Yeah, sure. I mean, the word happiness is so ambiguous and it means so
0:35:10 many things to many people, but one sensible interpretation of it is that it’s got to do with
0:35:16 your emotions, with how you feel, with the emotional tone of your life, whether it’s a happy life that,
0:35:22 you know, it’s pleasant to be you. Life satisfaction is a completely different thing. I mean, life
0:35:29 satisfaction is how you feel about your life when you think about your life. And most of the time,
0:35:34 you don’t think about your life, you just live. But you know, sometimes you sort of look,
0:35:43 and that’s when you determine how satisfied you are. That’s life satisfaction. It’s not satisfaction.
0:35:48 It’s life satisfaction. Should we balance the two or how would you think about them? Should we be
0:35:53 more happy when we’re younger, more satisfied when we’re older? That thought had never occurred to me
0:36:02 when I began to work on those. So I started out thinking that happiness in that sense of how you feel
0:36:10 when you live. And that was reality. And that life satisfaction was just stories that people tell
0:36:17 themselves. And the important thing was to be happy in real time. But later, when we did more research,
0:36:25 it turned out that the circumstances that make people happy and the circumstances that make them satisfied
0:36:32 with their life are not the same. So happiness is mostly social. It’s, you know, it’s being with people
0:36:39 you love and who love you back. That’s, that’s a lot of what happiness is. Life satisfaction is much more
0:36:48 conventional. It’s to be successful. And you know, so it’s money, education, prestige, that sort of thing,
0:36:55 is what life satisfaction is about. So those are two very different things. I thought that life satisfaction
0:37:00 is irrelevant. You know, that’s how I began. And we, we had a research program where we were,
0:37:07 we were trying to, you know, to show that this is the case. But then after a few years, I realized
0:37:16 that what people really want in their life is they don’t seem to care about how happy they’ll be.
0:37:21 They seem to want to be satisfied with their life. They seem to want to have a good story about their
0:37:28 life. And then I was in the position of saying that to define well-being in a way that people didn’t seem
0:37:36 to care particularly about. So that was not a tenable position. So I, I dropped back into saying that I had no
0:37:41 idea how to deal with it. Was this a result of the research? You did some research that was,
0:37:46 I think it said above 70,000, you don’t become happier, but do you become more satisfied?
0:37:58 No. The research I did with Angus Deaton at Princeton, famous economist, we showed that in terms of happiness,
0:38:05 in terms of emotional tone, positive and negative, having a lot of money doesn’t make you happier,
0:38:13 but being poor makes you miserable. So that’s above the threshold that was like 70,000 dollars
0:38:22 approximately in the US. Then extra money didn’t make you emotionally happier. But with life satisfaction,
0:38:28 it was a different story. With life satisfaction, that doesn’t satiate, so it’s always good to have more.
0:38:38 Because basically I think money is a proxy for success, and it’s a proxy for subjective success in many cases.
0:38:42 So it’s not necessarily about spending it or doing something with it. It’s just a measure.
0:38:47 It’s just getting it. I mean, you know, you look at all those people, all those billionaires working
0:38:53 their heads off, and they’re clearly not doing this because they need more money. They’re trying to get
0:38:57 more money. And they’re trying to get more money because that would be an indication that they’re
0:39:00 good at what they do. I think mostly it’s a proxy.
0:39:05 Do either of those variables correlate to longer living, happiness, or satisfaction?
0:39:13 Both, apparently. But you know, it’s hard to separate. And I haven’t been followed, you know,
0:39:20 shortly after deciding that I didn’t know what well-being was, I sort of stopped doing research
0:39:28 on this. So I haven’t been following. But I think there’s clear evidence that being effectively happy,
0:39:34 you know, is very good for you. And you do live a little longer, and you live better, and so on. And
0:39:40 life satisfaction works in the same direction. Whether it’s separable, which of them, you know,
0:39:45 isn’t more important that I don’t. I want to switch gears a little bit and talk about
0:39:53 behavior. And I’d love your insider expansion upon the idea of we can change behavior, and how do we
0:40:00 go about changing our behavior? Well, you know, I’m not sure I buy the premise. I think changing
0:40:07 behavior is extremely difficult. There are a few tips and, you know, a few guidelines about how to do that.
0:40:14 But anybody who is very optimistic about changing behavior is just looted. It’s hard to change other
0:40:18 people’s behavior. It’s very hard to change your own. Not simple.
0:40:20 This is what marriage is all about, right?
0:40:25 Yeah, among other things. You know, people, when, you know, married people try to
0:40:27 change each other’s behavior.
0:40:29 It’s a lot of dissatisfying.
0:40:32 They are not on their way to a good marriage, I think.
0:40:34 We’d all be happier with lower expectations.
0:40:38 Yes. I mean, and even if you have expectation, don’t try to change,
0:40:44 because, you know, it’s very unlikely to work in a significant way.
0:40:49 I can think of the common ways that we would sort of go about behavior change, and it would be,
0:40:55 you know, making good behaviors more easy or negative behaviors harder.
0:41:02 I think that’s the main, the main insight. You know, when you want to influence somebody’s behavior,
0:41:07 that’s a very big insight. I’ve always thought that this is the best psychological idea ever,
0:41:15 you know, so far as I’m concerned. But it’s that when you want somebody to move from A to B in terms of
0:41:22 their behavior, you can think of it that there are two ways of doing it. You can push them. Or you can
0:41:29 ask the question, why aren’t they doing B already? Which is an unusual question, but you know, why?
0:41:38 So then when you ask why, why not? Why aren’t they doing B as they ought to, as they think they ought to,
0:41:46 then you get a list of what’s going to win. That’s a psychologist who, my guru on this, my hero,
0:41:52 and many people’s hero. He spoke of restraining forces. I mean, so there are reasons why they’re
0:41:59 not where you want them to be. So he spoke of behavior as an equilibrium. There are forces that
0:42:06 are pushing you one way, forces that are pushing you the other way. So how loud you speak, how fast you
0:42:13 drive. It’s easy to think of it as an equilibrium. And what we tend to do when we want to move people
0:42:24 from A to B is we push them. We add to the driving forces. And Kurt Lewin’s insight was that this is
0:42:30 not what you should do. You should actually work on the restraining forces and try to make them weaker.
0:42:37 And that’s a beautiful point. And he showed, he had that image that, you know, I’ve had since I was an
0:42:43 undergraduate. And I’m not sure, actually, whether it was his image or something that I drew from
0:42:50 reading him. But it’s like you have a plank and it’s being held by two sets of springs. You know,
0:42:56 you want it to move one direction. And so you could add another spring that would push it that way,
0:43:01 I could remove one of the springs that are holding it back. And the interesting thing,
0:43:10 and that’s the striking outcome, is when it moves, if it moves because of the driving force,
0:43:15 you’ve added to the driving force, then at equilibrium, it will be in a higher state of
0:43:21 tension than it was originally. That is because you’ve compressed one spring and such pushing back
0:43:28 harder. But if you remove the restraining force at equilibrium, there’ll be less tension on the
0:43:32 system. I must have been 20 years old. I thought that’s just so beautiful.
0:43:38 What do you wish that everybody knew about psychology that you don’t think that they do?
0:43:40 If that was class one, what’s class two?
0:43:48 You know, class two, which is a development from class one, you know, it’s the same idea extended.
0:43:57 Class two is that behaviors don’t necessarily reflect the personality, but behaviors have a lot to do with
0:44:04 the situation. And so if people behave in strange ways, look at the situation they’re in and what are
0:44:11 the pressures in the situation that make them act as well. So there is a bias that the social
0:44:17 psychologists, well-known social psychologists call the fundamental attribution error. And that means
0:44:23 that when you see people acting in some way, you think that it’s because of their personality that they
0:44:29 do it. That may not be the case. It’s quite likely that the situation is making them do it.
0:44:37 I’d like people to know that motivation is complex and that people do good things for a mixture of
0:44:43 good and bad reasons. And they do bad things for a mixture of good and bad reasons. And I think that
0:44:50 there is a point to educating people in psychology is to make them less judgmental. Just have
0:44:56 more empathy and more patience and being judgmental doesn’t get you anywhere.
0:45:01 When you talk about situational, one of the things that comes to mind is it’s so easy for us to
0:45:07 give our friends advice. But if we were in that situation, we might not necessarily see it. Why is that
0:45:11 the case? Why is it so much easier to give other people advice?
0:45:17 I mean, feelings get in the way of clear thinking. There is a phenomenon that we call the endowment effect,
0:45:24 which is that when I’d ask for more money to sell you my sandwich than I’d pay to get it. I mean,
0:45:30 that’s essentially the endowment effect. And our explanation of it, there are many explanations,
0:45:36 but a story I like to tell about it is that it’s more painful to give something up than to get something.
0:45:44 But there is an interesting result that if you have an agent making decisions on somebody’s behalf,
0:45:49 that agent doesn’t have loss of urge. So that agent sells and buys at the same price,
0:45:55 which is the economically rational thing to do. Where this goes into policy and governments and
0:46:01 really important things, that governments are like agents or people who think about the good of society.
0:46:07 And agents, they take the economic view. They take the view of what things will be like at the end.
0:46:13 They don’t figure out that there are some people who are going to be losing because of the reform that
0:46:20 they make. And it turns out that you can really expect losers, potential losers to fight a lot harder
0:46:27 than potential winners. And that’s the reason that reforms are frequently fair. And that when they succeed,
0:46:33 they’re almost always way more expensive than anticipated. And they’re more expensive because
0:46:42 you have to compensate the losers. And that frequently is not anticipated. So that’s an example of a story
0:46:52 about that incorporates behavior change and the difference between perspective, between being in the
0:46:58 the situation, feeling the pain of giving up the sandwich, and not feeling the pain of giving up the
0:46:58 sandwich.
0:47:05 That would have huge public policy sort of implications too, right? That we don’t tend to think about or
0:47:10 discuss. That’s a really interesting angle there. I want to come back to sort of situational decision
0:47:16 making based on sort of like what we see is all there is. And we have these feelings that we can’t sort of
0:47:23 disassociate with. How does environment play a role like the physical environment in sort of what we
0:47:24 decide or does it?
0:47:32 I mean, you know, there are sort of obvious things that we know. If people are hot and bothered and
0:47:41 distracted and there is a lot of noise and so on, then they’ll think as well. That we know. But even
0:47:48 there, there are puzzles. I mean, many people think and work a lot better in cafes, you know, where there is
0:47:54 actually ambient noise and activity around them. And it helps them concentrate better. So there isn’t
0:48:00 a very simple story of the environment, but certainly you can make the environment tough enough so that
0:48:04 people won’t be able to think properly. That’s, that’s feasible.
0:48:11 Are there things that we could do to, I guess, push the environment to be more conducive to
0:48:15 clearer thinking? The physical environment in this case?
0:48:21 Oh, there are all sorts of, you know, odd findings, you know, the color of the
0:48:27 color of the room. Some colors are better than others. And you would expect that some colors are
0:48:31 more calming than others. So you wouldn’t want to be in a red room.
0:48:39 Making decisions. Making decisions. But, you know, those are extreme and minor effects.
0:48:44 I want to come to intuition and noise later. Is there anything else that stands out that
0:48:49 gets in the way of clear thinking that we can sort of bring to the surface now?
0:48:54 Well, you know, what, what gets in the way of clear thinking is that we have,
0:49:01 we have intuitive views of almost everything. So as soon as you present a problem to me,
0:49:07 I have, you know, I have some ready-made answer. And what gets in the way of clear thinking are
0:49:13 those ready-made answers. And we can’t help but have them. So that’s one thing that gets in the
0:49:22 way. Emotions get in the way. And I would say that independent clear thinking is, to first
0:49:29 approximation, impossible. I mean, in the sense that, you know, we believe in things most of the time,
0:49:34 I’m not because we have good reasons to believe them. If you ask me for reasons, I’ll explain you.
0:49:39 I’ll, I’ll always find a reason, but the reasons are not the causes of our beliefs.
0:49:47 We have beliefs because mostly we believe in some people and we trust them and we adopt their beliefs.
0:49:54 So we don’t reach our beliefs by clear thinking something, you know, unless you’re a scientist or
0:49:56 doing something like that.
0:49:59 But even then, it’s probably a very narrow…
0:50:03 But that’s very narrow. And there is a fair amount of emotion in neuroscientists as well
0:50:08 that gets in the way of clear thinking. You know, commitments to your previous views,
0:50:12 being insulted that somebody thinks he’s smarter than you are. I mean,
0:50:18 lots of things get in the way than the neuroscientists. So I’d say there is less
0:50:20 clear thinking than people like to think.
0:50:27 Is there anything that we can do at the belief formation stage? Like, it sounds
0:50:35 almost as though when you say that we’re reading a newspaper, we read this op-ed, and it’s well-constructed
0:50:42 and fits with our view of the world. Therefore, we adopt that opinion. And we forget the context that
0:50:48 we didn’t learn it through our own experience or reflection. We learned it sort of from somebody
0:50:53 else. So we don’t know when it’s sort of likely to work or not work. But we just proffer that as
0:50:54 our opinion is there.
0:51:01 That’s how I believe in climate change. You know, I believe in the people who tell me there is climate
0:51:05 change. And the people who don’t believe in climate change, they believe in other people.
0:51:11 But similarly, there’s like fake news and all this other stuff that we would have the same reaction to.
0:51:19 You know, but I’m much more likely to believe fake news on my side than the fake news on the other
0:51:29 side. I mean, it’s true that there is a huge degradation in public discourse in the recent
0:51:34 10, 15 years in the United States. I mean, there used to be an idea that facts matter.
0:51:39 What would be your hypothesis as to why that is playing out? Are they getting into
0:51:42 politics because I don’t want to talk politics? But like, why is that?
0:51:46 Well, I mean, it’s hard to, it’s hard to answer that question without,
0:51:55 without politics, because it’s a general political polarization has had a very big effect.
0:52:01 And the fact that people can choose the sources of information.
0:52:08 Let’s switch gears a little bit and talk about intuition. I think one of the,
0:52:16 things that strikes me the most about some of the work that you’ve done is the cases where we’re
0:52:22 likely to trust our intuition and when we’re not. And so if I’m, correct me if I’m getting this wrong,
0:52:29 so it’s sort of like a stable environment, repeated attempts and rapid feedback. It strikes me that
0:52:40 most decisions made in organisations do not fit that environment and yet we’re making a lot of these
0:52:49 decisions on judgement or experience. What are the ways that we can sort of make better decisions with that in the context?
0:52:54 Well, in the first place, I think, you know, you shouldn’t expect too much.
0:52:56 And pat to low expectations.
0:53:02 I shouldn’t think too young or should have low expectations about improving decisions. I mean,
0:53:08 there is, you know, one basic rule is slow down, especially if you, if you have that immediate
0:53:13 conviction, slow down. There are procedures, you know, there are ways of reaching better,
0:53:18 better decisions, but reaching better judgment and we can talk about them.
0:53:20 I would love to hear.
0:53:25 If you really want to improve the quality of decision making, use algorithms. I mean,
0:53:33 whenever, wherever you can, if you can replace judgments by, by rules and algorithms, they’ll do
0:53:42 better. And there’s big social costs to trusting, allowing algorithm to make decisions, but, but the
0:53:48 decisions will likely to be better. So that’s one thing. If you can’t use algorithms, then you slow
0:53:54 yourself down. And then there are things that you can do for certain types of problems. And there are
0:54:02 different types of problems. So one class of problems, like forecasting problems, a friend,
0:54:09 Phil Tetlock, you know, has that book on super forecasters, where he identifies with people who
0:54:16 are good at forecasting the future, what they do that makes them good. And, you know, it tries to train
0:54:21 people and we can improve people. So that’s one class of problem. I’m interested specifically
0:54:29 in another kind of problem, judgment problems, where basically you’re considering options or you’re
0:54:36 evaluating a situation and you’re trying to give it a score. There, there, there is advice, I think,
0:54:45 on how to do it. For me, it goes back to something I did in the Israeli army when I was like 22 years
0:54:52 old. So that’s a long time ago, like 63 years ago. I was a psychologist in the Israeli army. And I was
0:55:00 assigned the job of setting up an interviewing system for, for the army. That’s ridiculous. But you know,
0:55:06 this was the beginning of the state of Israel. So people were improvising all over the place. So I
0:55:13 had a BA and I was, I think I was the best trained psychologist in the army. My, my boss was a chemist.
0:55:22 Brilliant. But anyway, and the, the existing system was one where people would interview and try to form an
0:55:30 intuitive global image of how well that recruit would do as a combat soldier, which was the objective,
0:55:37 the object of the interview. And because I had read a book of Paul Neal, I took a different talk. And
0:55:45 the different talk was, I identified six traits that I sort of made up and I had them ask questions and
0:55:52 evaluate each of these traits independently and score it and write down the score, then go on to the
0:55:58 next trait. And they had to do it for all six traits. And that was, that’s all I asked them to do. And
0:56:06 the interviewers who were about one year younger than I, all recruits, but very, very smart, selected
0:56:12 for being good at it. They were furious with me. And they were furious with me because they wanted to
0:56:18 exercise their intuition. And I still remember that one of them said, “You’re turning us into robots.” So I
0:56:26 compromised with them. And I said, “Okay, you do it my way.” And I told them, “You try to be reliable,
0:56:33 not valid. You know, I’m in charge of validity. You be reliable.” Which was pretty arrogant, but that’s,
0:56:41 that’s how I presented it. But then when you’re done, close your eyes and just put down a number of
0:56:49 how good a soldier is that guy going to be. And when we validated the results of the interview,
0:56:55 it was a big improvement on what had gone on before. But the other surprise was that
0:57:05 the final intuitive judgments added, it was good. It was as good as the average of the six straights,
0:57:11 and not the same. It added information. So actually, we ended up with a score that was
0:57:18 half, was determined by the specific ratings, and the intuition got half the way. And that,
0:57:22 by the way, stayed in the Israeli army for well over 50 years. I don’t know whether it’s,
0:57:28 I think it probably, some version of it was still being forced, but around 15 years ago,
0:57:36 a visit of my old base. And, and the commanding officer of the research unit was telling me how
0:57:43 they run the interview. And, and then she said, and then we tell them, “Close your eyes.” So that,
0:57:50 that had stayed for 50 years. Now, the “Close your eyes” and that whole idea is not the basis of the
0:57:57 book that I’m writing. So actually, I have the same idea really, that when you are making decisions,
0:58:03 you should think of options as if they were candidates. So you should break, break it up into
0:58:10 dimensions, evaluate each dimension separately, then look at the profile. And, and the key is,
0:58:19 delay your intuition. Don’t try to form an intuition quickly, which is what we normally do. Focus on the
0:58:25 separate points. And then when you have the whole profile, then you can have an intuition and it’s going to
0:58:32 be better because people make form intuitions too quickly. And the, the rapid intuitions are not
0:58:38 potentially good. So if you delay intuition until you have more information, it’s going to be better.
0:58:40 I’m curious how we delay intuition.
0:58:49 You delay intuition by focusing on the separate problems. So our advice is that if you have, you know,
0:58:56 a board of directors making decisions about an investment, we tell them you do it that way. Take
0:59:04 the separate dimensions and really think about each dimension separately and independently and don’t
0:59:11 allow, you know, if you’re the chair, don’t allow people to give their final judgment. Say, we’ll wait
0:59:18 until we cover the whole thing. I mean, if you find a deal breaker, then you stop. But if you haven’t found
0:59:27 a deal breaker, wait to the end and look at the profile and then your decision is almost certainly going to be better.
0:59:33 Does that include weighting the different aspects of the problem differently or do you highlight that in advance or do you?
0:59:42 Yeah. I mean, it makes you see the trade-offs more clearly. Otherwise, when we don’t follow that discipline,
0:59:50 there is a way in which people form impressions. Very quickly you form an impression and then you spend
0:59:58 most of your time confirming it instead of collecting evidence. And so if accidentally your impression was
1:00:04 in the wrong direction, you’re going to confirm it and you don’t give yourself a chance to correct
1:00:14 it. Independence is the key because otherwise, when you don’t take those precautions, it’s like having a bunch of
1:00:23 witnesses to some crime and allowing those witnesses to talk to each other. They’re going to be less valuable if you’re
1:00:29 interested in the truth than keeping them rigidly separate and collecting what they have to say.
1:00:37 What have you seen work in a repeatable way? It may be a particular organization or across organizations
1:00:48 to not only reliably surface disconfirming evidence, but then place a value on what is surface instead of
1:00:52 being dismissive. Is there a framework for that? Is there?
1:00:58 Well, yeah. There are many, you know, there are many procedures like red team, blue team,
1:01:05 a devil’s advocate. I mean, there have been, you know, many attempts. In general, you know,
1:01:12 if you are the head of a group that makes decisions, one of your missions would be to protect the dissenters
1:01:21 because they’re very valuable and you should make it painless to be sent or as painless as possible.
1:01:29 Well, it’s hard to be sent. It’s painful and costly. So protecting dissenters is important.
1:01:37 I’m curious about the distinction between intuition and judgment. You had mentioned intuition, judgment,
1:01:43 intuitive judgment. Can you walk me through some of like how those differ?
1:01:53 It’s a bit hard to separate and judgment is what you do when you integrate a lot of information informally
1:01:56 into a score of some kind.
1:02:03 I, we speak, we being my co-authors and I in the book we’re writing, we speak of judgment as
1:02:10 measurements. But it’s measurement where the measuring instrument is your mind. But you do it informally.
1:02:17 And because you do it informally, people are going to, are not necessarily going to agree. So wherever we
1:02:22 say it’s a matter for judgment, we’re allowing for differences, for variability.
1:02:32 Now, judgment can be more or less slow, more or less systematic. So at one end, you have pure intuition,
1:02:38 where you allow the judgment to go very quickly and so on. And at the other end, you try to delay
1:02:44 intuition. But ultimately, if you’re making it by judgment, you’re going to have a judgment and it’s
1:02:51 going to be like an intuition and you’re going to go with it. So the more or less deliberate judgment,
1:02:56 intuition is always involved at one point or another.
1:02:59 You’re either sort of like listening to it or fending it off?
1:03:03 Yeah. And our recommendation is fend it off.
1:03:07 Are there ways to judge the quality of somebody’s judgment?
1:03:12 Yeah, sure. I mean, some of them would be unique to the actual scenario,
1:03:15 but what are the sort of other ways that we could?
1:03:22 Well, I mean, you may require people to explain their judgments and evaluating the quality of the
1:03:29 explanation is, you know, whether it’s logical, whether it uses the evidence, whether it uses all
1:03:39 the evidence, whether it is strongly influenced by wishes, whether the conclusion was reached before
1:03:48 the judgments supposedly is made. You know, there are lots of ways for judgment to fail that can be
1:03:53 recognized. So it’s harder to recognize very good judgment, but it’s really easy to see, you know,
1:03:57 what goes wrong. And there are quite a few ways for judgment to go wrong.
1:04:04 And I think some of those ways are the cognitive biases, like overconfidence and sort of using
1:04:11 small or extrapolating from small sample sizes. And one of the interesting things that I’ve heard you
1:04:18 say in interviews before, so correct me if I’m off here, is that you’ve studied cognitive biases
1:04:23 effectively your whole life and you’re no better at avoiding them than anybody else.
1:04:27 Yeah, certainly. Not much better, no.
1:04:29 What hope do the rest of us have?
1:04:37 Not much. I mean, I never, you know, I think, you know, the quality of people’s judgment is affected
1:04:46 by education. But, so in general, you know, more educated people make better judgments, I think,
1:04:53 on average. But people decide I’m going to make better judgments. I don’t think that’s very hopeful.
1:05:01 I’m much more hopeful about organizations because organizations think more slowly and they have
1:05:08 procedures for thinking. And so you can control the procedures. Individual judgment is really hard to fix.
1:05:10 Not impossible.
1:05:16 One of the things that I see people do in response to cognitive biases and trying to account for them
1:05:23 is to sort of make a list of them, almost like a checklist, and then go through that checklist and
1:05:29 explain or rationalize why those things don’t apply in this situation. It also strikes me that the more
1:05:35 intelligent you are, the more stories you’d be able to conjure up about why you’re avoiding this.
1:05:42 I really think that’s not very hopeful because there are so many biases. And the biases work in
1:05:50 different directions anyway. So sometimes you can recognize a situation as one in which
1:05:59 you’re likely to be wrong in a particular way. So that’s like illusions. If you recognize a particular
1:06:05 pattern as something that gives rise to a visual illusion, then you don’t trust your eyes.
1:06:13 You know, you do something else. And the same thing happens when you recognize this is a situation where
1:06:22 I’m likely to make an error. So sometimes you can recognize the importance, for example, of what we’ve called
1:06:31 an anchor. So you’re going to negotiate a price with somebody. They start very high. And that has an effect.
1:06:39 So you know, or you should know, that the person who moves first in a negotiation has an advantage.
1:06:50 Because the first number changes everybody’s view of what is considered plausible. So it moves things
1:06:57 in that direction. That’s a phenomenon. People can learn that. And they can learn to resist it.
1:07:05 So when I was teaching negotiations, I would say, somebody does that to you, comes up with a number
1:07:14 that’s absurd. I would say, lose your temper. Make a scene. Say, I will not start the conversation from
1:07:20 that number. It’s an absurd number. I don’t want to let’s erase that number. So that’s something that,
1:07:27 you know, you know, you can improve if you recognize it. I think people are aware of the fact that you
1:07:34 shouldn’t make a decision about road safety within a short interval of a terrible accident.
1:07:42 So you should allow things to settle down and cool down. There is a more subtle error and harder,
1:07:51 harder to fix. But that, the best prediction, the best guess is always less extreme than your impression.
1:07:56 intuitive prediction. Intuitive prediction is, as we say, not regressive. It doesn’t recognize
1:08:04 regression to the mean. But statistics is statistics. And in statistics, things are less extreme.
1:08:11 Should I give you my favorite example of a bias? Yeah, please. Okay. I have been unable to think of a
1:08:19 better one. But the story is about Julie. That’s part of the story. That’s her name. She is a
1:08:25 graduating senior at university. And I’ll tell you one fact about her, that she read fluently when she
1:08:33 was four. But it’s a GPA. And the interesting thing here is that everybody has a number. As soon as I
1:08:39 told you that thing, her number came to mind. Now, we know where that number came from. We really,
1:08:45 that’s one of the few things that I’m reasonably sure I understand perfectly. And this is that when you
1:08:53 hear she read fluently at age four, you get an impression of how smart she is, of how precocious
1:09:00 she was at age four. And you could put that in percentiles. You know, where did that put her on a
1:09:06 percentile for sort of aptitude, ability? And it’s high. It’s not, you know, if she had read fluently
1:09:13 at age two and a half, it would be more extreme. But age four is pretty high. So say at the 90th percentile.
1:09:23 And then the GPA that comes to your mind is around the 90th percentile in the distribution of GPA.
1:09:28 So you pick something, your prediction is as extreme as your impression.
1:09:40 And it’s idiotic statistically, completely stupid, because clearly the age at which a child learned
1:09:47 to read is not all that diagnostic with respect to GPA. So it’s better than nothing. If you didn’t
1:09:55 know anything, you would predict the mean GPA, whatever it is, 3.1, 3.2. Now, she’s bright,
1:10:04 so probably a little higher, but not 3.7. You don’t want to. So that’s cool. That’s a bias. That’s
1:10:13 non-regressive prediction. And that’s very hard to resist. Sometimes I’m able to resist it,
1:10:19 but never when it’s important. You know, when I’m really involved in something, I don’t think about it,
1:10:25 but sometimes I will recognize, oh, you know, that’s the situation. I should moderate my prediction.
1:10:31 And if you’re conscious of it, that’s an example of one you can sort of talk yourself into.
1:10:38 Yeah. Yeah. You can talk yourself into. Although, you know, you usually will find a way to cheat
1:10:47 and end up with your intuition. It’s remarkable. You know, when you’ve been in academic life for a long
1:10:56 time, so you’ve been in many situations where people discuss a job candidate. And absurdities of that kind
1:11:05 are very common. So somebody, a job candidate gives a talk, and people evaluate the talk, and this is
1:11:11 something happens, you know, at Berkeley when I was teaching there, that somebody gave a talk. It wasn’t
1:11:20 a very good talk. Stammered a bit. Now, that person had teaching prizes, and yet what was said about him
1:11:28 in the discussion? He can’t teach. You know, we heard the talk. So that’s a mistake. But the funny
1:11:33 thing is you can point out to people that that’s a mistake. They still don’t want to hire him because
1:11:40 he gave a lousy talk. So it’s hard to resist. It’s interesting. I think one of the ways I probably
1:11:46 got my job is using psychology in the interview, which is asking why I was there, and then reinforcing
1:11:54 those beliefs throughout the interview. I want to come back just one second to the immediacy of sort
1:12:02 of having a stimulus and then making a decision. So we use the example of roads, and a tragic accident
1:12:08 happens, and you’re rethinking sort of policy or laws around the roads. How much of that do you think
1:12:16 is social pressure? And I’m wondering if we could even extrapolate that a little more to we’re taught
1:12:22 to answer questions on a test right away, right? So we see this question, then we answer it. We’re
1:12:29 taught that we, or maybe it’s reinforced, taught is probably the wrong word, that politicians need to
1:12:35 have a response, an immediate response to, and even if they know the best thing to do is like, okay,
1:12:43 let this settle, take some time. It’s society writ large seems to demand it, like the environment is
1:12:50 not conducive. I think it’s pretty clear that people prefer leaders who are intuitive and who are
1:13:00 overconfident. Leaders who deliberate too much are viewed with suspicion, you know. So I think Obama
1:13:05 Obama was at a certain disadvantage relative to George Bush, you know.
1:13:07 Because he was seen as more deliberate.
1:13:12 Yeah, he was more deliberate. And then when you’re very deliberate, you look as if you don’t know what
1:13:20 you’re doing. But when you act with confidence, so people want leaders who are intuitive, I think,
1:13:24 they’re very much. Provided they agree with me.
1:13:28 I’m just working my way back through some of these rabbit holes that we’ve gone down. You taught
1:13:36 negotiations. I’m curious what would be in your sort of syllabus for negotiations that everybody should
1:13:41 learn about negotiations when it comes to your work in psychology.
1:13:49 Well, you know, that goes back to a theme that we started with, the essence of teaching
1:13:56 negotiations, that negotiations is not about trying to convince the other guy. It’s about trying to
1:14:01 understand them. So again, it’s slowing yourself down. It’s not doing what comes naturally,
1:14:11 because trying to convince them is a prime pressure. Arguments, promises, and threats are always a prime
1:14:17 pressure. And what you really want is understand, you know, what you can do to make it easy for
1:14:25 them to move your way. Very non-intuitive. That’s a surprising thing when you teach negotiation. It’s not
1:14:30 obvious. You know, we are taught to apply pressure. I mean, socialize that way.
1:14:36 You mentioned that there was procedures for thinking in organizations. Are there any that
1:14:43 stand out in your mind that we could use to elevate thinking, and if not elevate,
1:14:49 but give feedback on the quality of thinking to improve it? Well, I think one of the ideas that
1:14:58 people like the most is an idea by Gary Klein, what he calls the premortem. And that’s the universal
1:15:03 winner. People really like that idea. And this is that when you’re about to make a decision,
1:15:10 a group, not quite, because if you’ve made it, it’s too late, but they’re approaching you. And then
1:15:19 you get people in a room who can be the people who are making the decision. And you said, suppose it’s two
1:15:26 years from now. And we made the decision that we’re contemplating. And it turned out to be a disaster.
1:15:32 Now, you have a page in front of you, write the history of that disaster in bullets. That’s the
1:15:40 pre-mortem. And it’s beautiful as an idea. It’s beautiful because when people are coming close to a
1:15:49 decision, it becomes difficult to raise doubts or to raise questions. People who are slowing the group
1:15:56 down when the group is nearing a decision are procedures really, you know, it’s annoying. You
1:16:03 know, you want to get rid of them. And the pre-mortem legitimizes that sort of dissent and that sort of
1:16:11 of doubts not only legitimizes it, you know, it rewards it. And so that’s a very good idea. I don’t,
1:16:17 you know, I don’t think that it’s going to prevent people from making mistakes, big mistakes,
1:16:25 but it could certainly, it will alert people to possible loopholes, to things that they ought to
1:16:30 do to make a safer decision. So that’s a good procedure. And there are many others.
1:16:37 What comes to mind. What comes to mind is, is to make intelligence, I mean,
1:16:46 the collection of, of the information independent of the decision-maker’s wishes. And you really want
1:16:54 to protect the independence of the people collecting the evidence. And I would add to, you know, a procedure
1:17:01 that really people don’t like, but if it were possible to implement it, I think would be good.
1:17:09 And that’s, that when you’re going to be discussing a topic, and it’s done in advance on people in sense
1:17:16 and material to think about the topic, that you may want them to write down their decision, the decision they
1:17:24 are in favor of before the discussion starts. That has many advantages. It’s going to give you a broader
1:17:33 diversity of points of view, because people tend to converge very quickly in a, in a group discussion.
1:17:40 And it forces people to be better prepared. It’s, except people don’t want this.
1:17:47 So I, I don’t know whether it’s even possible to implement it, but clearly, if you could,
1:17:49 it would be a good idea.
1:17:51 What are the reasons people don’t want it?
1:17:52 It’s too much work.
1:17:57 Right. Forces you to do a lot rather than the signaling you can sort of get away with.
1:18:02 Yeah. And then, you know, there’s somebody who is going to prepare the case. And so I glanced at
1:18:13 the material and then, you know, so a lot of meetings are a tremendous, a sink for wasted time.
1:18:17 And improving the quality of meetings would be a big thing.
1:18:19 Do you have any insights on how to do that?
1:18:26 Keeping them short. You know, I’m not a professional at fixing meetings. So I have,
1:18:35 I have a few ideas, but not an incomplete view. The, the question of structuring the meetings to
1:18:43 be discussing topics one at a time, that I think is, is really useful. I’ll give you an example. I mean,
1:18:48 it’s something that I suggested when I was consulting, but for some reason,
1:18:54 people didn’t buy that suggestion. So you, when an investment is being discussed,
1:19:01 say by an investment firm, some staff people, if it’s a big investment, staff people will prepare
1:19:11 a briefing book with chapters. Now, our recommendation would be that the staff should end each chapter with
1:19:19 a score. How does that chapter taken on its own independently of anything else affect the likely
1:19:26 decision? And then you could structure the meeting that discussed this and the meeting of the boards,
1:19:33 say, to discuss these scores one at a time. That has the effect that I was talking about earlier,
1:19:40 making the decision, making the judgments about the dimensions. We call them mediating assessments,
1:19:47 is a drogen tube. The mediating assessments come first, and then you have the profile of them,
1:19:55 and then you make a global judgment. And you can structure it. So if the staff has presented a score,
1:20:03 and you discuss in the board, do we accept their score? You’re forcing people to have a look at
1:20:09 the evidence. And think about why they would accept or reject. And then they feel like they have to
1:20:16 construct an argument that might be less intuitive. That’s it. So, you know, there are ways of doing this,
1:20:24 but if you’re going to be too rigid about it, it won’t work either. I’m curious what other advice
1:20:29 you gave as a consultant that nobody followed. Oh, I mean, virtually all the advice I gave,
1:20:34 people don’t follow. I mean, you know, I think that’s, that’s not, you shouldn’t, you know,
1:20:40 you’re not going to be a consultant if you expect your advice to be taken. You have to give the best advice
1:20:46 you can. What would be other examples of something you think could be widely applicable that you would advise,
1:20:51 you would have advised people and you just sort of like saw them drop the ball?
1:20:58 Well, I mean, you know, I would advise people who make a lot of decisions to keep track their
1:21:09 decisions and of how they turned out so that later you can come and evaluate your procedures and see
1:21:15 whether there is anything that is in common with those decisions that turned out well and didn’t,
1:21:18 not so well and so on. People hate doing this.
1:21:20 Why do you think people hate doing it?
1:21:27 Oh, because, because retrospectively, they may look foolish, some of them or all of them,
1:21:33 or in particular, the leader. So they really don’t like keeping track. I mean, there are exceptions.
1:21:43 Ray Dalio and his firm, and where everything is explained. Bridgewater, yeah. Bridgewater. But in
1:21:51 general, in my, I haven’t consulted with Bridgewater, they don’t mean me. But in general, when I suggested
1:21:56 that, it never went anywhere. What are the variables that you would recommend people keep track of?
1:21:59 Like, what would your decision journal look like?
1:22:02 Oh, I mean, I, my, my decision journal would be a mess.
1:22:08 I don’t, I’m not putting myself as an example, but…
1:22:11 So obviously the outcome, but you’ve got to do that post after.
1:22:20 Yeah, but no, no. You, you would want to say, what were the main arguments, pro and con? What were
1:22:22 the alternatives that were considered?
1:22:29 You know, it doesn’t have to be very detailed, but it should be enough so that you can come later and
1:22:31 debrief yourself.
1:22:34 So do you have a calibration, like what degree of confidence you are?
1:22:40 That would be good. Then, you know, it would depend on something that you could evaluate later.
1:22:49 It strikes me that decision journals and premortems are a way to identify people that are sort of,
1:22:55 perhaps, suppressed by their manager, where you have somebody who’s actually a better,
1:23:01 better at exercising judgment than the person that is, you know, that they’re working for.
1:23:07 And this would be a pain-free sort of way to calibrate that score over time and identify
1:23:11 the quality of judgment in a consistent way.
1:23:16 Oh, yeah. I mean, that strikes me as worth a lot of money to an organization.
1:23:23 Yeah. But, but also very costly. And you, you will see that certainly anything that threatens the
1:23:30 leader is not going to be adopted. And, and leaders may not want something that threatened their
1:23:34 subordinates either. People are really very worried about embarrassment.
1:23:36 You’re writing a book now on noise.
1:23:37 Yeah.
1:23:40 Tell me about noise and decision-making. Can you explain the concept?
1:23:47 Yeah. I can really explain it by saying what, you know, was the beginning of it,
1:23:56 and which was a consulting assignment in an insurance company where we, I had the idea of running a test
1:24:05 to see whether people in a given role who were supposed to be interchangeable agreed with each other.
1:24:11 So, you know, when you come to an insurance company and an underwriter gives you a premium,
1:24:17 the underwriter speaks for the company. And so it’s, you expect that any underwriter,
1:24:23 that it doesn’t matter which underwriter you get to afford a premium. And the company has that
1:24:30 expectation. It shouldn’t make much difference. So we tested that. And they constructed some cases.
1:24:35 And then we had some like 50 underwriters assess a premium for the case.
1:24:37 With the same information.
1:24:37 Hmm?
1:24:43 Yeah. With a really very realistic, we didn’t construct it. They constructed the case.
1:24:48 So, and they conducted the experiment. But now, the interesting question is,
1:24:56 how much variation do you expect there to be? So, we asked the executives the following question.
1:25:01 Suppose you take two underwriters at random. By what percentage do they differ? I mean,
1:25:06 you look at the difference between their premium, divide that by the average premium. What number do you
1:25:14 get? And people expect 10%. By the way, it’s not only the executives in that company. For some reason,
1:25:22 people expect 10%. And it was roughly 50%, 5-0. So that’s, you know, that’s what made me curious about
1:25:28 noise. That and the fact that the company was completely unaware that it had the noise. It took
1:25:35 them completely by surprise. So now we’re writing a book because there’s a lot of noise. So wherever
1:25:43 a rule is that wherever there is judgment, there is noise. And more of it than you think. So that’s the
1:25:44 pattern.
1:25:50 Are there procedures to reduce noise? And conversely, it strikes me that the variation would be good,
1:25:52 but maybe only in an evolutionary concept.
1:26:00 Well, we call that noise is useless variability. I mean, variability can be very useful if you have
1:26:07 a selection mechanism and some feedback. So evolution is built on variability, but of course,
1:26:13 it’s useful, it’s useful. But noise among ambient writers is useless. There’s nothing. Nothing
1:26:22 gets learned. There’s no feedback. It’s just noise. And it’s costly. The first advice, of course, would be
1:26:30 algorithms, as I said earlier. So algorithms are better than people, than judgment. That’s not intuitive,
1:26:40 but it’s really true. And after that, then the procedure that I mentioned earlier for making
1:26:46 decisions in an orderly way by breaking it up into assessments. That’s the best that we can do.
1:26:54 And there is one very important aspect that I haven’t mentioned. And this is training people in what the
1:27:02 scale is. So there is one piece of advice that you’d have for underwriters, that they should always
1:27:12 compare the case to other cases. And if possible, if you can have them share the same frame of
1:27:17 reference with other underwriters, you’re going to cut down on the noise.
1:27:19 Oh, that’s a clever idea, yeah.
1:27:30 And that exists in human resources, where performance evaluation, which is one of the scandals of modern
1:27:36 commerce, how difficult it is. But performance evaluation, they have the thing that’s called
1:27:44 frame of reference training, which is teaching people how to use the scale. There’s a lot of variability in
1:27:52 the scale. And a part of what the super forecasters do, they make judgments in probability units,
1:28:00 and they teach them to use the probability scale. So learning the scale is a very important aspect of
1:28:01 reducing noise.
1:28:07 I know we’re coming up to the end of our time here. What have you changed your mind on in the past 10 years?
1:28:08 Oh, a lot.
1:28:09 Anything big?
1:28:17 Yeah. There’s been a replication crisis in psychology. And some of the stuff that I really
1:28:24 believed in, when I wrote “Thinking Fast and Slow”, some of the evidence has been discredited. So I’ve had to
1:28:25 change my mind.
1:28:27 What are the, what’s the biggest?
1:28:35 Some of the sexiest stuff, priming and unconscious priming, and so it just hasn’t held up in replication.
1:28:43 And I believed it, and I wrote it as if it were true, because the evidence suggested it. And in
1:28:52 fact, I thought that you had to accept it, because that was published evidence. And I should have,
1:28:58 I blame myself for having been a big gullible. That is, I should have known that you can publish
1:29:05 things, even if they’re not true. But I just didn’t think that through. So I changed my mind.
1:29:13 I’m now much more cautious about spectacular findings. I mean, very recently, I’ve come,
1:29:21 I think I have a theory about why psychologists are prone, or social scientists generally are prone to
1:29:29 to exaggerate, to be overconfident about their hypotheses. So I’ve done quite a bit of learn.
1:29:30 What’s the theory?
1:29:39 Well, the theory, the one element of the theory is that all these hypotheses are true. In what sense?
1:29:46 That, you know, if I, there’s a famous study that you mentioned wrinkles to people, and then
1:29:52 you measure the speed at which they walk, and they walk more slowly. Turns out that hasn’t held up in
1:29:59 replication, which is very painful. It’s one of the favorite studies. But actually, you know, that if
1:30:04 you mention wrinkles, and it’s going to have any effect on the speed of walking, it’s not making to make,
1:30:09 it’s not going to make people faster. If it has any influence, it’s going to make them slower. So
1:30:19 directionally, all these hypotheses are true. But what there is, is what people don’t see, is that
1:30:28 then huge number of factors that determine the speed at which individuals walk, and the differences in the
1:30:36 speed of walking between individuals. And that’s noise. And people neglect noise. And then there is
1:30:43 something else, which is, touches on both philosophy and, and psychology. When you have intuitions about
1:30:51 things, there are clear intuitions, and there are strong intuitions. Another thing. So clear intuition is if I
1:31:00 offer you a trip to Rome, or a trip to Rome and an ice cream cone, you know what you prefer. It’s easy. But it’s very
1:31:06 weak, of course. I mean, the amount of money you would pay to get a trip to Rome, a trip to Rome and an ice cream cone,
1:31:15 nothing. But when you are a philosopher, and I should add one thing, to see the clear intuitions,
1:31:20 you have to be in this kind of situation that psychologists call within-subject. That you
1:31:28 have both. You have both with the ice cream cone and without the ice cream cone. So in a within-subject
1:31:34 situation, that’s an easy problem. In a between-subject situation, it’s an impossible problem. But now,
1:31:40 if you’re a philosopher, you’re always in a within-subject situation. But people live in a
1:31:46 between-subject situation. They live, you know, in one condition. And the same thing is true for
1:31:55 psychologists. So psychologists live in a, when they cook up their hypotheses, they’re in a within-subject
1:32:01 situation. But then they make guesses about what will happen between subjects. And they’re completely
1:32:09 lost between clear intuitions and strong intuition. We have no way of calibrating ourselves. So that makes
1:32:17 us wildly overconfident about what we know and reluctant to accept that we may be wrong.
1:32:23 That’s a great place to end this conversation, Danny. Thank you so much.
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0:00:06 Welcome to the Next Wave Podcast. I’m Matt Wolfe, and I could not be more excited to
0:00:11 share today’s episode with you. So we’ve gone from AI that can chat with you to AI that
0:00:18 can work for you. And the difference? Well, this new AI can actually think through problems,
0:00:24 catch its own mistakes, and complete complex tasks from start to finish, just like a human
0:00:30 employee would. This is what everyone in the AI world calls AI agents. You’ve probably heard the
0:00:36 term. But here’s why this breakthrough changes everything for regular people. If you’re someone
0:00:41 who codes, there’s no more debugging AI hallucinations. It can actually check its own
0:00:48 work. If you run a business, these AI agents can actually plan out and finish complex tasks,
0:00:53 just like one of your employees might. And the implications for humanity? Well,
0:00:59 with these new tools, drug discoveries, testing, and real-world trials can now take weeks instead
0:01:05 of decades. In fact, Isometric Labs is already gearing up for human trials of AI-discovered drugs
0:01:11 right now. And we’re also already getting stories about how AI has successfully diagnosed human
0:01:19 illnesses when human doctors couldn’t. These things are accelerating insanely fast. But this isn’t just
0:01:26 about better chatbots. We’re talking about AI that understands the physical world, plans weeks ahead,
0:01:31 and even works while you’re asleep. And the company that’s leading the charge in all of this
0:01:38 is Google DeepMind. They’ve already used this thinking AI to predict protein structures that used to take
0:01:45 years. Now it just takes seconds. It’s called AlphaFold. They’ve also invented AI that can invent new
0:01:53 algorithms, including AI algorithms. It’s called AlphaEvolve. It’s insane stuff. Two million researchers
0:02:00 worldwide are using their tools right now. But with this power comes some pretty big questions. Can we
0:02:07 trust it? What happens to privacy? What about our jobs? Can we trust Google with our data?
0:02:13 So I sat down with Google DeepMind CEO Demis Hassabis to get answers straight from the source
0:02:22 about how we got from autocomplete to actual thinking and what comes next. He’s a Nobel laureate,
0:02:28 a knight, and one of the most influential pioneers in the world of AI. And somehow,
0:02:34 I managed to get him to sit down and chat with me about all of this. What he told me will change
0:02:42 how you think about AI forever. So without further ado, here’s my conversation with Sir Demis Hassabis.
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0:03:21 Hey Demis, great to see you again. So my first question for you is, can you sort of describe
0:03:26 what’s happening under the hood with an LLM? Like what’s kind of going on? Can we sort of demystify
0:03:33 it for people a little bit? I can try. So I mean, at the basic level, what these LLM systems are trying
0:03:38 to do is very simple in a way. They’re just trying to predict the next word. And they do that by obviously
0:03:46 looking at a vast training set of language. But the trick is not just to regurgitate what it’s already seen, but actually
0:03:52 generalize to something novel that you are now asking it. And it seems like, you know, we’ve managed with the
0:03:55 modern day systems is to get that generalization to work.
0:04:01 Gotcha. So at IO, you announced the new DeepThink, right, which is so much more powerful, and it’s topping all of the
0:04:06 benchmarks for things like coding and math and all that. What happened under the hood that caused that new leap?
0:04:12 Well, new techniques have been brought into the foundational model space where there’s called
0:04:16 pre-training, where you sort of train the initial base model based on, you know, all the training
0:04:21 corpus. Then you try and fine tune it with a bit of reinforcement learning feedback. And now there’s this
0:04:27 third part of the training, which is we sometimes call inference time training or thinking, where you’ve
0:04:34 got the model, and you give it many cycles to sort of go over itself and go over its answer, maybe do use
0:04:40 some tools. For example, it could fact check with search, something like that, before it outputs the
0:04:45 answer to the user. So it gets a chance to sort of correct itself and adjust what it’s going to
0:04:50 output. And of course, if you do that, you get a much better answer. And then what Deep thinks about
0:04:56 is actually taking that to the maximum and giving it loads more time to think and actually even doing
0:05:01 parallel thoughts and then choosing the best one. And it turns out it works really well. And, you know,
0:05:07 we pioneered that kind of work in the past, actually nearly a decade ago now with AlphaGo and our games
0:05:12 playing programs, because in order to be good at games, you need to do that kind of planning and
0:05:14 thinking. And now we’re trying to do it in a more general way here.
0:05:20 Right, right. So it almost kind of thinks of a whole bunch of potential responses and then goes
0:05:23 through reviews all the potential responses and then figures out what the best response from those
0:05:28 potential responses. Exactly. And it can go over and correct some parts of it and use tools to check
0:05:33 some aspects of it. So, you know, especially in certain areas like maths and the coding, it really
0:05:39 improves the answers. Amazing. Very cool. So you’ve mentioned that the long term goal is to sort of
0:05:45 let these AIs have like a world model. Right. So can you sort of explain what you mean by a world
0:05:51 model and what does that open up to us? Well, so we’re all familiar with large language models now,
0:05:57 but of course, we have five sensors and we operate in the real world. And language is only one aspect,
0:06:04 very important aspect of our world and human civilization, but only one aspect. And so I think for a model,
0:06:09 what we mean by a world model is a model, sometimes we call it a multimodal model that can understand
0:06:16 not just language, but also audio, images, video, all sorts of input, any input, and then potentially
0:06:22 also output any kind of token as well. And the reason that’s important is if you want a system to be a good
0:06:27 assistant, it needs to understand the physical context around you. Or if you want robotics to work
0:06:32 in the real world, the robot needs to understand the physical environment. Right. So in order to do that,
0:06:35 you have to have what we sometimes like to call a world model.
0:06:40 Cool. So what sort of new things do you think that’ll open up to people once they have that ability?
0:06:45 I think robotics is one of the major areas. I think that’s what’s holding back robotics today. It’s
0:06:49 not so much the hardware, it’s actually the software intelligence. You know, the robots need to understand
0:06:54 the physical environment. But I think that that’s also what will make today’s sort of nascent
0:06:58 assistant technology and things like you saw with Project Astra that we show in Gemini Live.
0:07:04 For that to work really robustly, you want as accurate as world models you can. And then the
0:07:10 other thing is, if you want to do planning in the real world, you need to sort of plan multiple
0:07:15 steps with your world model. So in order for that to be good for long range planning, your world model
0:07:20 has to be very accurate as well, which is pretty hard when you’re talking about real world situations.
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0:08:05 So you’ve mentioned things like AI will be able to, most likely in the future, solve things like
0:08:10 room temperature superconductors and, you know, more energy efficiency and curing diseases.
0:08:15 Out of the sort of things that are out there that it could potentially solve, what do you think the
0:08:20 sort of closest on the horizon is? Well, as you say, we’re very interested and we actually work on
0:08:25 many of those topics, right? Whether they’re mathematics or things like material science, like
0:08:30 superconductors, you know, we work on fusion, renewable energy, climate modeling. But I think
0:08:35 the closest if you think about and probably most near term is building on an alpha fold work.
0:08:41 And we spun out a company called Isomorphic Labs to do drug discovery. We think that we sort of
0:08:46 the whole drug discovery process from first principles with AI. And normally, you know,
0:08:52 it takes the rule of thumb is around a decade for a drug to go from sort of identifying why a disease
0:08:57 is being caused to actually coming up with a cure for it. And then finally being available to patients.
0:09:02 It’s a very laborious, very hard, painstaking and expensive process. And I would love to be able
0:09:09 to speed that up to a matter of months, maybe even weeks one day and cure hundreds of diseases like that.
0:09:14 And I think that’s potentially in reach. It sounds maybe a bit science fiction like today,
0:09:19 but that’s what protein structure prediction was like, you know, five or six years ago before we
0:09:24 came up with alpha fold and used to take years to find painstakingly with experimental techniques,
0:09:29 the structure of one protein. And now we can do it in a matter of seconds with these computational
0:09:34 methods. So I think that sort of potential is there. And it’s really exciting to try and make that happen.
0:09:40 Amazing. So you guys just announced Alpha Evolve recently, which looks amazing, right? It’s an AI
0:09:46 that essentially can help you come up with new algorithms, right? So how close are we to AIs that
0:09:51 are sort of designing new AIs to improve the AIs and then we start entering the cycle?
0:09:56 Yes. I mean, it’s a baby step in that direction. I think it’s really cool breakthrough piece of work
0:10:02 where we’re combining kind of, in this case, evolutionary methods with LLMs to try and get
0:10:08 them to sort of invent something new. And I think there’s going to be a lot of promising work actually
0:10:13 combining different methods in computer science together with these foundation models like Gemini
0:10:18 that we have today. So I think it’s a great, very promising path to explore just to reassure everyone
0:10:22 when it still has humans in the loop, scientists in the loop to kind of, it’s not directly improving
0:10:28 Gemini. It’s using these techniques to improve the AI ecosystem around it, slightly better algorithms,
0:10:32 better chips that the system’s trained on versus it’s the algorithm that it’s using itself.
0:10:38 Right, right. So AI agents, they’ve been sort of a big talk in the AI community recently.
0:10:43 And this week at IO, we saw Project Mariner, which can go and open up 10 different browsers and
0:10:48 go and do a whole bunch of things on your behalf. How far off do you think we are to
0:10:52 being able to give an agent like a week’s worth of work and then goes and executes that for us?
0:10:57 Yeah, I mean, I think that’s the dream to kind of offload some of our mundane admin work and
0:11:01 also to make things like much more enjoyable for us. You know, you have maybe have a trip to
0:11:06 Europe or Italy or something, and you want the most amazing itinerary sort of built out for you and
0:11:11 then booked. I love our assistance to be able to do that. You know, I hope we’re maybe a year away or
0:11:16 something from that. I think we still need a bit more reliability in the tool use. And again,
0:11:21 the planning and the reasoning of these systems, but they’re rapidly improving. So as you saw with
0:11:26 the latest Project Mariner, and so it’d be great for that to come together with some of the other
0:11:29 advances we’re making with the Gemini Live and the Astro technology.
0:11:34 Yeah. What do you think the biggest bottleneck is right now to sort of getting that long-term agent?
0:11:38 I think it’s just the reliability of the reasoning processes and the tool
0:11:45 And making sure because each one, if it has a slight chance of an error, if you’re doing like
0:11:50 a hundred steps, even a 1% error doesn’t sound like very much, but it can compound to something
0:11:55 pretty significant over a hundred, you know, 50 or a hundred steps. And a lot of the really interesting
0:12:00 tasks you might want these systems to help you with will probably need multi-step planning and action.
0:12:05 Gotcha. So I want to shift gears a little bit here and talk a little bit about some of the
0:12:09 sort of fears and concerns that have come up in like my YouTube comments and things like that.
0:12:14 You know, people are worried about things like privacy and losing their jobs to AI and all of
0:12:20 that kind of stuff. And so I’m curious, how does a company like DeepMind build the trust of the general
0:12:23 public that you can trust them with this kind of technology?
0:12:26 Yeah. Well, look, I think we’ve tried to be, and I think we try to be responsible role
0:12:31 models actually with these frontier technologies. Partly that’s showing what AI can be used for,
0:12:36 for good, you know, like medicine and biology. I mean, what better use could there be for AI than
0:12:42 to cure, you know, terrible diseases. So there’s always been my number one thought there, but there’s
0:12:45 other things, you know, where it can help with the climate, energy and so on that we’ve discussed.
0:12:50 But I think we’ve got to, you know, companies is incumbent on them to behave thoughtfully
0:12:55 and responsibly with this powerful technology. We take privacy extremely seriously at Google,
0:12:59 always have done. And I think, you know, most of the things we’ve been discussing with the
0:13:03 assistants, they would be opt-in. They’ll make the universal assistant much more useful for you,
0:13:08 but you would be, you know, intentionally opting into that very clearly with all the transparency
0:13:13 around that. And what I want us to get to is a place where the assistant feels like it’s working
0:13:19 for you. It’s your AI, right? Your personal AI, and it’s working on your behalf. And I think that’s
0:13:22 that’s the mode, you know, that’s the, at least the vision that we have and that we want to deliver
0:13:25 and that we think users and consumers will want.
0:13:31 So all of those are incumbent. And actually I would say to your viewers as well, you have a lot of
0:13:36 say in this in the sense of like, you should exercise your consumer choices and buy services
0:13:41 and products from companies that you feel are acting responsibly and the leadership is acting
0:13:45 responsibly and you like the type of work that they’re doing. Because now we’re entering this sort
0:13:51 of commercialization, productization era of AI now. Right. And you know, I think your viewers
0:13:55 and everyone has a big say in that. Right, right. So one of the things that you guys also demoed at
0:14:01 IO that I got a chance to actually test out a little bit earlier was the Android XR glasses. And those were
0:14:06 absolutely mind blowing when I tried them the first time. And so I guess the flip side of this sort of
0:14:12 privacy thing is if everybody’s sort of walking around wearing glasses that have microphones and cameras on
0:14:18 them, how do we ensure that the sort of privacy of the other people around us is secure?
0:14:21 I think it’s a great question. I mean, first thing is to make it very obvious that you’re
0:14:26 it’s on or off in these types of things, you know, in terms of the user interfaces and the form factors.
0:14:30 I think that’s number one. But I also think this is the sort of thing where we’ll need
0:14:36 sort of a societal agreement and norms about how do we do we all want if we have these devices,
0:14:41 they’re popular and they’re useful. What are the guardrails around that? And I think that’s why we’re
0:14:45 only entrusted tester at the moment is partly the technology is still developing, but also we need
0:14:50 to think about the societal impacts like that ahead of time, you know, not just with the technology,
0:14:55 but also society in general and civil society kind of inputting into what might be the right way to
0:14:59 handle that type of world. Right. So I’ve got one last question here. It’s kind of a two-parter
0:15:05 question. So what excites you most about what you can do with AI today? And what excites you most about
0:15:10 what we’ll be able to do in the very near future? Cool. Well, today, I think it’s the AI for science work is my,
0:15:15 you know, always been my passion. And I’m really proud of what AlphaFold and things like
0:15:18 that have empowered. They’ve become a standard tool now in biology and medical research, you know,
0:15:23 over two million researchers around the world use it in their incredible work and vital work. So that’s
0:15:30 fantastic to me. In the future, you know, I’d love a system to basically enrich your life and work for
0:15:36 you on your behalf to protect your mind space and your own thinking space from all of the digital world
0:15:41 that’s bombarding you the whole time. And I think actually one of the answers to that is that we’re
0:15:45 all feeling in the modern world with social media and all these things is maybe a digital assistant
0:15:50 working on your behalf that only at the times that you want surfaces the information rather than
0:15:54 interrupting you at all times of the day. Amazing. Well, thank you so much, Demers. This has been
0:16:10 absolutely fascinating. I really, really appreciate the time that you spent with me today. So thank you
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0:00:03 It’s like faster than light speed travel has just been invented.
0:00:06 For many of the developers and programmers I talk to today,
0:00:11 they’re like going to Disneyland just because how many great tools there are to help them move faster.
0:00:14 We do spend a lot of time just trying to be very honest with ourselves.
0:00:17 What is the new behavior being created? Where is stuff getting used?
0:00:20 Infrastructure never goes away. It just gets layered.
0:00:24 In this case, it’s definitely all the infrastructure that we’ve been using and leveraging in the past
0:00:27 are still very relevant, but it’s definitely getting layered by having this fourth pillar.
0:00:30 Software was always the disruptor.
0:00:33 One of the most exciting things about the AI wave is like software is being disrupted.
0:00:34 Like we’re being disrupted.
0:00:36 This is a pretty big deal.
0:00:38 It’s by far the biggest thing that I’ve seen happen sort of in my life.
0:00:42 Is AI the fourth pillar of infrastructure?
0:00:46 Today on the podcast, we’re joined by Martine Cassato, Jennifer Lee,
0:00:52 and Matt Bornstein from A16Z’s Infra team to unpack how infrastructure is evolving in the age of AI.
0:00:56 From compute, storage, and networking to models, developer tools, and agents.
0:01:00 We get into what infra actually means today, how it differs from enterprise,
0:01:03 and why software itself is being disrupted.
0:01:06 We also talk through the rise of technical users as buyers,
0:01:08 what makes an infra company defensible,
0:01:14 and how past infra waves from cloud to COVID to the current AI boom have shaped how we invest and build.
0:01:16 Let’s get into it.
0:01:21 As a reminder, the content here is for informational purposes only.
0:01:25 It should not be taken as legal, business, tax, or investment advice,
0:01:27 or be used to evaluate any investment or security,
0:01:32 and is not directed at any investors or potential investors in any A16Z fund.
0:01:37 Please note that A16Z and its affiliates may also maintain investments in the companies discussed in this podcast.
0:01:40 For more details, including a link to our investments,
0:01:44 please see A16Z.com forward slash disclosures.
0:01:51 We’re here today to discuss the state of infra.
0:01:53 First, can we get a definition of infra?
0:01:55 Where does infra differ from enterprise?
0:01:56 How do we think about it internally?
0:01:59 I would say infra is basically what makes software work.
0:02:02 We’ll probably get pretty deep into a set of technical definitions.
0:02:04 You mentioned sort of networking, storage, compute.
0:02:06 Where does AI fit into that?
0:02:09 But I think at the simplest possible level, if you want software,
0:02:13 infra is what engineers are using behind the scenes to make all this possible.
0:02:17 And our formal definition internally is technical buyer, right?
0:02:21 So it’s the stuff you use to build the stuff, the stuff you use to build apps.
0:02:25 And if it’s used by a technical user, we consider it infrastructure,
0:02:29 whereas something like, let’s say, vertical SaaS could be used by a flooring company
0:02:31 or by a marketer or by sales.
0:02:32 That would not be considered infrastructure.
0:02:36 And technical user, for the record, is developer,
0:02:39 data scientist, analyst, cybersecurity professor.
0:02:40 Yeah, right.
0:02:41 There’s a DevOps, right?
0:02:43 There’s a wide range of sort of like people.
0:02:44 These are our people, right?
0:02:46 Like the kind of nerds behind the scenes.
0:02:50 And in the system terms, I think about it as compute, networking, and storage,
0:02:54 but also all the tooling that goes around the developer’s day of what you’re using
0:02:58 to build software and what are the tools and products that are operating
0:03:01 this ever-growing, more complex software as well,
0:03:05 all the way to semi-technic users that may want to either prototype
0:03:08 or tinker with building applications.
0:03:10 We’re very interested in anything in the technical domain
0:03:12 and used by technical people.
0:03:15 So you mentioned compute, networking, storage.
0:03:16 How should we think about models?
0:03:18 Is this the fourth layer of how do they interface?
0:03:19 How should we think about that?
0:03:22 I certainly think of it as a fourth layer of infrastructure.
0:03:27 It’s certainly leveraged and built on top of all the three pillars we’re talking about.
0:03:29 It has a lot of demand of compute.
0:03:33 And of course, it’s trained and also producing a large amount of data.
0:03:40 And to leverage and use these models for our purposes, latency and networking capabilities
0:03:41 is also very important.
0:03:45 But it’s going to be as prevalent as any piece of infrastructure software.
0:03:48 I don’t know the analogy these days anymore.
0:03:49 Is it a database?
0:03:51 Is it sort of like a new form of compute?
0:03:55 And so really, to me, it’s like a fourth pillar that incorporates everything,
0:03:59 but also provides intelligence for the software we’re using and building today.
0:03:59 Yeah.
0:04:01 So I think this is exactly right.
0:04:04 I think it’s probably worth asking like why a piece of infrastructure is a piece of infrastructure.
0:04:09 And generally, a new piece of infrastructure changes the way that you program computers
0:04:11 and then changes the stack that’s around it.
0:04:12 Like it’s got different memory requirements.
0:04:14 It’s got different latency requirements.
0:04:19 And so it just requires rethinking how we build software and how we build infrastructure.
0:04:21 You know, I would say in addition to compute networking and storage,
0:04:26 I would say distributed systems would also be included just because things like state consistency
0:04:29 required you to think about like proximity and guarantees.
0:04:33 I would say databases probably did too because it changed our programming model.
0:04:34 You have different guarantees.
0:04:37 And these models very much fit in that for a couple of reasons.
0:04:39 I think Jennifer’s exactly right.
0:04:42 Like you just build different data centers and different chips if you want to build these
0:04:43 models.
0:04:44 So it has that impact.
0:04:47 But programming them is like non-obvious.
0:04:50 Like we’re just still trying to grapple like how you program with them.
0:04:52 Like they don’t really listen to you.
0:04:54 Sometimes they do the coding themselves.
0:04:59 And if I were to try and distill like what is the one biggest difference that these models
0:05:01 provide to infrastructure, it’s the following.
0:05:04 I don’t remember ever in the history of computer science,
0:05:08 where we’ve, from an application standpoint, we’ve abdicated logic.
0:05:10 Like in the past, we’ve abdicated resources.
0:05:12 Like you were like, give me compute.
0:05:13 Give me swords.
0:05:14 Like these abstracted resources.
0:05:18 But the logic, the yes or no, like the what it’s doing, always came from the programmer.
0:05:21 But in these ones, we’re like, come up with the answer for me.
0:05:24 And so it’s requiring us to rethink what does it mean to be a programmer?
0:05:25 What does it mean to be software?
0:05:26 Et cetera.
0:05:28 So it’s clearly very fundamental to computer science.
0:05:34 And I would say, again, to Jennifer’s point, it’s very, very much a new piece of infrastructure.
0:05:37 And I think a lot of people are trying to reason by analogy.
0:05:39 You sort of alluded to this, Jennifer.
0:05:42 It’s like, oh, is it like a database because it can answer queries?
0:05:48 Or is it like a network because it’s sort of non-deterministic and we need to handle retries and weird edge cases?
0:05:52 But like, I think people are really just trying to figure out how to program these things, which you sort of said, Martin.
0:05:58 But like, we’ve got to start from a blank sheet of paper, which is what makes our jobs like really exciting right now.
0:06:01 Because there’s a lot of people trying to figure it out and coming up with new ideas.
0:06:04 Many of us have been in computer science for a long time, right?
0:06:08 We’ve been in our schools and in our operating lives and in our investing lives.
0:06:12 And like software was always the disruptor, right?
0:06:15 Like we disrupt the taxis or we disrupt like sales.
0:06:17 We disrupt the back office or we disrupt everything.
0:06:21 Like one of the most exciting things about the AI wave is like software is being disrupted.
0:06:22 Like we’re being disrupted, right?
0:06:25 Yes, it’s disrupting software and eating software.
0:06:26 I know, I know.
0:06:28 Like, oh, so we have to think about it.
0:06:29 Software is a self-eating.
0:06:30 Yeah, that’s right.
0:06:37 Honestly, I think this is the first time I could honestly say that like the profession that I’ve dedicated my entire life to is being disruptive.
0:06:39 And it’s very exciting because it’s eating itself in a way.
0:06:40 Yeah.
0:06:42 Yeah, and it’s tempting to be a curmudgeon, right?
0:06:44 Because we’ve all been doing this our whole lives.
0:06:47 So it’s like really being open to and embracing the new stuff.
0:06:48 Stuff is like the key thing.
0:06:51 What still applies is infrastructure never goes away.
0:06:52 It just gets layered.
0:06:56 In this case, it’s definitely all the infrastructure that I’ve been using and leveraging in the past are still very relevant.
0:07:00 But it’s definitely getting layered by having this fourth pillar, which is AI and models.
0:07:05 What’s different from past super cycles versus what can we learn as we enter this new one?
0:07:08 So there’s two things that happen.
0:07:14 So one of them is often when you bring the marginal cost of something down, like with compute, we did it for computation.
0:07:17 And for the internet, we did it with distribution.
0:07:20 It increases the TAM a whole bunch.
0:07:23 So for one, you almost always see this massive TAM expansion.
0:07:29 And part of that tends to be because the TAM is bigger, you’ve got new users.
0:07:34 And because you have new users, like there’s normally like a new behavior that happens, right?
0:07:41 This is very much the case with the internet, which is like people weren’t used to going to a computer and talking to everybody around the world on top of the internet.
0:07:46 And existing companies don’t know really how to think about new behaviors.
0:07:50 Like they’ve built these sales motions and operating things around like the old behavior.
0:07:53 And so you see TAM expansion, you see new behaviors.
0:07:59 Those new behaviors provide white space for challengers, new like startup companies to come and to go ahead and fill those models.
0:08:02 And I think we’re seeing exactly that happen with this one as well.
0:08:06 Like clearly this market is massive if you look at how successful these model companies are.
0:08:10 But also you’re seeing use cases that like computers just never really have done before.
0:08:11 And you’re seeing that too.
0:08:16 And so in that way, I think it rhymes very much with say the internet and it rhymes very much with probably even the microchip.
0:08:20 Maybe I’ll answer that question just from my personal experience.
0:08:26 I’m always like sort of a tools person and also wanting to like having tools fulfilling certain creativity.
0:08:36 Because I came to coding and computer science as a late bloomer after my 20s and really enjoyed all the tools available for me at that point of just building software and like learning computer science as well.
0:08:42 Now we just have massive and massive leverage in trying to create anything as long as you have a good idea.
0:08:44 And like Martin laughed at me about this.
0:08:50 Like I was a bigger like local no-code champion for let’s say the last five, 10 years.
0:08:55 Because again, these are tools for people who have good ideas but may not be like educated in the computer science term.
0:09:02 But the real tools of the world, the Wix and Squarespace’s, like you can build applications, can build software easily with these tools.
0:09:12 But now you’re given like the next level of thought partners, tools to really as any role in the company, prototype software interfaces for your end customer, for your end user.
0:09:14 As long as you know what they need, what they want to see.
0:09:19 Like you can really realize these ideas really quickly in like at your fingertips.
0:09:20 So low-code’s finally happening.
0:09:22 It just takes a lot of code.
0:09:23 It just turns out the code is natural language.
0:09:27 I know, it’s so funny because when Jennifer joined the team, she was very excited about low-code.
0:09:29 But from my view, low-code is like Python.
0:09:32 It’s like a scripting language.
0:09:33 Interpreted languages.
0:09:35 And PM is low-code.
0:09:37 So we kind of had to bridge that gap.
0:09:41 And it was in a way like a bit irreconcilable until AI came out.
0:09:45 And it’s very, very clearly like what the promise of low-code was.
0:09:46 And so you’re right.
0:09:47 It really is disrupting software.
0:09:51 So when I was a kid, right, the internet was sort of a new thing.
0:09:55 I just remember really vividly there was this movie with Sandra Bullock called The Net.
0:09:57 And she orders a pizza from her computer.
0:09:59 And this was like completely mind-blowing.
0:10:02 And like now, actually, this is a common user behavior.
0:10:06 But like what we’re dealing with now is just so much bigger than that, right?
0:10:11 I just think it’s really hard to, like I think some of these points about how will the infrastructure evolve,
0:10:14 like how will the companies adapt and things like that are probably transferable.
0:10:15 But this is a pretty big deal.
0:10:17 It’s by far the biggest thing that I’ve seen happen sort of in my life.
0:10:19 Let’s zoom out and take this long view.
0:10:21 And Martina, you’re actually the perfect full circle because
0:10:24 weren’t you the first infra investment ever as a portfolio founder?
0:10:27 I think it was either me or Okta.
0:10:30 But I will say me and Todd were like the infra portfolio.
0:10:35 Fun one LP days when they would trot us out in front of the LPs.
0:10:36 It was like me and Todd from Okta.
0:10:38 So for sure, I was one of the first two.
0:10:41 At what point did we develop a clear infra practice at A’s and Z?
0:10:46 So we always had strong infra people, right?
0:10:48 So like Ben Horowitz is an infra guy.
0:10:50 And honestly, I would say Mark is.
0:10:52 Like he masquerades as a consumer guy.
0:10:56 But he’s actually revolutionized the way we use computers in this deep infrastructure way.
0:10:59 And by the way, many things came from that JavaScript, et cetera.
0:11:02 We had Peter Levine, Zensource.
0:11:03 We had Scott Weiss.
0:11:05 And so like there’s always been deep infra.
0:11:08 But when I joined the firm, we didn’t think of it as infra.
0:11:10 We thought of it as enterprise, right?
0:11:16 And so you’re either in the consumer team, you’re in the fintech team, or you’re in the enterprise team.
0:11:31 And the thing about just classifying this stuff as enterprise, the go-to-market motions for something that touches technology and being able to reason about that is so different than reasoning to the go-to-market motion that’s purely through like sales, right?
0:11:40 And we’ve just learned over time that like we do deep market diligence as a firm, and we do deep diligence on companies before we invest in them.
0:11:47 And that the type of diligence we do if it was deep infrastructure just required a different type of junior partner and type of analysis.
0:11:58 So over time, we realized that companies where you can evaluate more by like the business model, the market buyer, the unit economics, you know, those kind of class of companies are just sufficiently distinct.
0:11:59 So we decided to just pull them apart.
0:12:01 And then that’s why we have the apps fund.
0:12:03 And then, of course, the infra fund.
0:12:14 If you think about enterprise, there is, of course, the horizontal piece of it, but also a lot of vertical enterprise, whether applications, buyers, sectors, where infrastructure is almost always horizontal.
0:12:21 And that’s another thing we realized along the way of we still want to like appeal to these like technical audience and technical buyers.
0:12:28 But we want to think about sort of the space in a horizontal fashion where these technology can be distributed to all these different sectors and verticals as well.
0:12:30 And it impacts how we think about the stack.
0:12:36 It impacts how we think about what is going to drive the form of like how the stacks integrate with each other.
0:12:38 It’s just like different from enterprise generally.
0:12:39 Yeah.
0:12:40 So it’s actually a very, very important distinction.
0:12:41 I’m glad you brought it up.
0:12:46 So like technical buyers tend to be centralized buyers in a way, right?
0:12:48 Like IT will buy compute network and storage.
0:12:51 And yes, you’ve got the compute person, the networking person, but it kind of rolls up to IT.
0:12:53 And developers are kind of a centralized buyer.
0:12:56 So like you can understand IT and you can understand the developers.
0:13:06 But when I was looking at vertical SaaS apps early in my investing career, to understand how to sell into a flooring company, you have to understand the flooring market.
0:13:08 And that’s entirely different than like the pet food market.
0:13:10 And that’s entirely different than the construction market.
0:13:16 So I felt like there was no real central software buyer for these kind of vertical.
0:13:20 So as you get further away from core infrastructure, you get away from this notion of a centralized educated buyer.
0:13:23 And just the level of analysis becomes very different.
0:13:24 I think that’s exactly right.
0:13:32 And there’s even sort of like the horseshoe theory of software buyers happening now where you have like consumers over here and then you kind of work up to like apps.
0:13:36 And like you would think that infra is way over here, but it’s actually that thing back around.
0:13:43 Like developers are making a lot of the decisions and a lot of the like marketing and sales to developers looks more like consumer these days than it used to.
0:13:45 That’s an incredibly important point.
0:13:47 I was researching the stats the other day.
0:13:55 When I first joined venture or maybe even just started thinking about infrastructure developers still like in the low tens of millions and they were becoming like the next generation of consumers.
0:13:58 Now they’re definitely the next generation of consumers.
0:14:01 It’s going above 50 million on the way to even bigger than that.
0:14:04 Now we’re talking about language being a programming language for everybody.
0:14:07 Like they are making decisions just as a consumer.
0:14:17 So we’re, of course, like training ourselves to also understand how developers as individuals adopt tools, but also like IT buying centers as customers and enterprise organizations.
0:14:18 I like evaluating tools.
0:14:24 So there’s just a lot to learn and figure out given these are the technical audience we really care about.
0:14:24 Yeah.
0:14:32 I want to get to how we think about our investable universe and what sort of subcategories are mature versus newer or sort of ripe.
0:14:35 But before that, I want to better trace the evolution a little bit.
0:14:37 So maybe Martin, we can start with you.
0:14:45 If you had to categorize, like since you’ve been investing, like the different waves of infrared or like maybe the different inflection points at which it changed how we even thought about it.
0:14:46 Oh, totally.
0:14:46 How would you characterize it?
0:14:49 Let’s just say for like the life cycle of the firm.
0:14:51 So we started with 2009.
0:14:52 And that was actually pre-cloud.
0:14:57 And so a lot of the early investments were right in the cusp of cloud.
0:15:02 And like, for example, my company, like the cloud was out there, but it wasn’t sufficiently deployed.
0:15:04 You could use it as a core thesis.
0:15:07 And a lot of the early investments were like this.
0:15:11 And we talk about it in terms of tech, but it rips through the entire business model.
0:15:14 Like early software was on-prem with a perpetual license.
0:15:17 That’s just different economics and different analysis, right?
0:15:20 And so like the pre-cloud installable software area was one.
0:15:22 And then we saw the cloud transition, right?
0:15:26 So we went to recurring revenue, totally different deploying model, totally different operating model.
0:15:33 And during that time, we’d see things like net dollar retention being more important, expansion being more important, gross churn being more important.
0:15:34 Gross margin.
0:15:36 Gross margin being more important.
0:15:37 Like everything changed to that.
0:15:41 By the way, meanwhile, of course, we saw consumer being disrupted by mobile, right?
0:15:43 With the rise of the Ubers and the Lyfts and the Airbnb’s.
0:15:55 And then again, we’re seeing it happen again during this AI, which I would say the AI transformation of the last three years has been the most dramatic I’ve seen in the last 30 years of being in this industry.
0:15:59 And there’s one interesting blip along that path, which is COVID.
0:16:07 We come from the realm of like enterprise sales and like being on the ground and deploying things and like that totally evaporated.
0:16:15 So like actually that was a dramatic shift as well, but it was driven by this kind of force majeure as opposed to a secular technical wave like the other two did.
0:16:26 I would say one of the benefits COVID brought is there was already the trend going of like developers buying and adopting tools like this bottom-up motion for infrastructure and for dev tools.
0:16:34 It got accelerated during the COVID time where lots of people just like tinkering, trying out products and tools and also more people building dev tools during that time.
0:16:45 I feel like there was a flourishing ecosystem just of these like PLG or product-led dev tool companies that are giving birth to now where we’re seeing a lot of like AI dev tools are coming up.
0:16:51 There’s nothing developers like better than being forced to stay home and not interact with other people and write code.
0:17:00 Okay, that’s a good overview.
0:17:02 Let’s go deeper into the present a little bit.
0:17:11 Can you guys share how we think about the different subcategories or landscape that kind of makes up and from we could also plug some examples of portfolio companies spaces where we made some bets.
0:17:13 Here’s a few important categories.
0:17:18 Developer tools, meaning anything developers use to make their lives better, easier, faster, more efficient.
0:17:21 Cursor is probably our top developer tool company right now.
0:17:23 And before that, GitHub, right?
0:17:24 Yeah, GitHub before that.
0:17:26 So we’ve seen very much.
0:17:30 And Jennifer, you’ve actually backed a bunch of interesting dev tools companies in the last few years too.
0:17:32 Yeah, from Levi, Stimless.
0:17:35 And there was a long time where the dev tools was written off by VCs, right?
0:17:37 Oh, yeah, the TAM was too small.
0:17:37 Yeah, exactly.
0:17:42 I mean, at the time of GitHub, would you ever have imagined a repository would be a huge company?
0:17:44 It was like almost a joke, yeah.
0:17:47 Right, and people were unsure about the business model and all these things.
0:17:50 Small TAM is the classic like red flag for infra investing.
0:17:53 If you’re at home listening to this and someone tells you small TAM.
0:17:54 They’re not an infra investor.
0:17:56 Infra creates TAM.
0:17:58 If there’s one takeaway from this thing, it’s TAM creative.
0:18:03 So yeah, so like I think dev tools, you’ve got core infra, which is compute networks and storage, right?
0:18:05 This is like to IT.
0:18:08 And then you tend to actually be quite a bit above the core infra stack.
0:18:10 So maybe you talk through kind of the areas you focus on.
0:18:17 I think about both like how developers are like using tools to improve their efficiency, but also how customers are getting value out of that as well.
0:18:21 So a lot of packaging, maybe dev tools into SaaS forms.
0:18:23 Like I’m investing in this company called Pylon.
0:18:28 It is a SaaS company that does customer support, but fundamentally it’s like being a data pipeline.
0:18:34 So that’s like core infrastructure that’s very good at connecting with systems and providing context to a lot of like agents and AI models.
0:18:35 So to me, that’s infrastructure.
0:18:39 And we’re spending a lot of time on, of course, like the cutting edge AI research.
0:18:41 So a lot of foundation model investing.
0:18:44 And we can probably numerate for the next 10 minutes.
0:18:54 I will say the reason that we’re a little bit skittish on this question is early in super cycles, it’s very hard to distinguish between an infra company and the application companies.
0:18:56 And the reason is because the TAM is so small and so new.
0:18:58 The new technology becomes the app, right?
0:18:58 Right.
0:19:02 So let me refer to like the original super cycle that started the firm, which is the internet.
0:19:09 Like Netscape, I remember when it came out, like it was a consumer thing or at least a student in school thing, right?
0:19:16 And so this is one company which everybody was downloading from an FTP server, Netscape, and using it as individuals.
0:19:19 The enterprise didn’t know what to think about it and banned it or whatever.
0:19:24 And the same company that built JavaScript, that’s building this core technology, is also doing the browser.
0:19:26 And over time it matures.
0:19:30 And then, of course, you have all of these internet companies and all the applications show up.
0:19:32 We’re seeing the same thing in the AI wave.
0:19:35 Like, is mid-journey, is that an infra company?
0:19:37 They built a model or is that an app company?
0:19:39 Well, it’s both in this sense.
0:19:42 And so I do think that at this stage, it’s very hard to distinguish.
0:19:44 It’s exactly right.
0:19:48 Like, it’s very hard to answer if OpenAI is an app company or it’s an infra company.
0:19:55 It already is building like infrastructure that’s like a cloud running these models for different sector and different use cases.
0:20:15 But at the same time, they’re also supplying the voices to these large-scale enterprise use case that are like fine-tuning, cloning your own voice and distributing that through API.
0:20:17 So it’s sort of both.
0:20:20 Another area we’ve done a lot of work is data systems.
0:20:22 And this goes all the way back to Databricks.
0:20:24 And there’s sort of been these two branches.
0:20:31 One is this like kind of back-end data-eng driven big data systems, Spark, Kadoop sort of thing.
0:20:35 And the other is this sort of data analyst, more tabular snowflake kind of thing.
0:20:40 And I think as a firm, we’ve been super, super active and super aggressive, you know, investing in companies like Databricks.
0:20:47 I mentioned Fibetran, DBT, which you guys invested in together, Hex, which is doing really, really well, Tabular, which was acquired by Databricks.
0:20:50 So we’re still, I think, really, really bullish on this.
0:20:55 Unfortunately, AI has sucked the air out of the room for a lot of data companies from a bunch of different angles.
0:20:57 But I think we’ll continue to do more of this as well.
0:21:02 How do we think about defensibility for AI companies, whether it’s an app layer or the model layer?
0:21:05 Do they all have their respective sort of areas of defensibility?
0:21:07 Or how has sort of our notion of defensibility evolved?
0:21:11 So we once wrote a blog post that there was no defensibility anywhere in the stack.
0:21:13 For anything?
0:21:13 For anything.
0:21:15 And yet people make lots of money.
0:21:16 Yeah.
0:21:25 You know, the argument at the time was like, okay, like NVIDIA has sort of a moat because chip designs are hard to copy.
0:21:31 But if you go sort of up or down, it’s kind of like, okay, they’re all sort of manufactured at the same place, right, at TSMC.
0:21:36 If you go down, if you go up, the cloud providers provide effectively the same product.
0:21:39 Like the models are training on the same data and have like similar capabilities.
0:21:42 The apps are all kind of like all using the same model.
0:21:46 So that was sort of the naive theory, I think, when we were just trying to understand this at the beginning.
0:21:47 And I think maybe it was true at the time.
0:21:54 What Martine was sort of alluding to a second ago is, meanwhile, every company at every layer of the stack is doing like fantastically well right now.
0:22:00 And during this kind of initial phase of industry development, which we sometimes call the Brownian motion phase,
0:22:05 like I actually think it’s really hard to make sort of pronouncements like this about what’s going to work, what’s not going to work,
0:22:07 where’s value going to accrue, et cetera, et cetera.
0:22:09 App companies are doing really, really well.
0:22:12 And like we’re pretty clear past the sort of wrapper phase.
0:22:14 Like I don’t think there are any wrappers anymore.
0:22:16 Like building good products with AI is really hard.
0:22:20 And the founders doing it now have like really good kind of intuition for how to do it.
0:22:23 The models are clearly like pushing the whole industry forward.
0:22:27 And like they’ve built huge companies from out, you know, so it’s kind of all working right now.
0:22:30 And I think you could actually make a case for how defensibility will work.
0:22:33 It’s quite different from the way defensibility has worked before.
0:22:34 And maybe you guys want to add on to that.
0:22:40 Yeah, on how defensibility worked for infrared companies before, largely it’s really hard to, let’s say,
0:22:47 if you’re building like a new database, like a new framework, it just takes a lot of expertise in the domain of understanding
0:22:52 what has happened in the past, where did the field come through, and what are the innovations that needs to happen
0:22:58 to polish, let’s say, like a software into this new abstraction to provide to developers.
0:23:01 Maybe one example I’m thinking of is like DuckDB.
0:23:06 It’s like such a high-performance, small, but really nimble database.
0:23:08 It took four years for the team to write it.
0:23:10 To replicate that is really hard.
0:23:16 And that’s generally what happened in the past infrastructure space is like it takes these experts a lot of time
0:23:22 to build like a new piece of security software if it’s like YubiKeys or if it’s, again, like Databricks on Spark.
0:23:29 But now as the AI infrastructure comes through, like I think a lot of those defensibilities still stays and are true
0:23:34 because these are earned secrets of what are the downfalls and guarantees other software run into
0:23:39 where these founders know sort of the past and also looking into the future.
0:23:43 But I do feel like the adoption phase is just like really massive.
0:23:48 Who is going to earn the distribution and earn sort of the developer attention is going to be a different game.
0:23:52 Can I just do a quick mental model of what has suited me very well in thinking about this?
0:23:55 I think the sloppiest thinking in our industry is around defensibility.
0:23:57 It’s just we’re just so sloppy about it.
0:24:00 And so maybe this is worth the price of listening to this podcast, like this mental model.
0:24:05 So the industry tends to go through these expansion and contraction phases.
0:24:06 Think of like the Big Bang or something.
0:24:08 Like it expands and then it contracts.
0:24:09 So what happens when it expands?
0:24:14 When it expands, zero-sum thinking is deadly because you’re just getting more market.
0:24:17 We’re clearly in an expanse phase, right?
0:24:21 Everybody is like, oh, NVIDIA can’t like sell more chips, but they keep selling more chips.
0:24:25 Oh, like the hosting platforms can’t continue to get margins, yet they keep continuing to get margins.
0:24:26 I mean, Matt said it perfectly.
0:24:26 I totally agree.
0:24:31 So if you’re in the expansion phase, then there’s just more to sell.
0:24:32 You should be aggressive investing.
0:24:34 So what happens in the collapse phase?
0:24:36 So look at any layer of the stack.
0:24:39 So in the collapse phase, which things start to consolidate again, you have consolidation.
0:24:42 But what is the end state of consolidation?
0:24:46 The end state of consolidation will always be an oligopoly or a monopoly.
0:24:48 It’s not like layers ever go away.
0:24:54 If you have an oligopoly, say the clouds, then you have what is effectively price fixing, but it’s tacit, right?
0:24:58 Which is everybody is like, we’re going to price it this, and we’re going to maintain our 30% margins.
0:25:00 So you still have value there.
0:25:01 You have margins.
0:25:07 Or in the case of like a monopoly, you’ll end up with, say, like an Intel at the time.
0:25:08 Then you can also maintain margins.
0:25:12 So in none of this, do you lose margins, right?
0:25:14 And I just think this is why people think so sloppy about this.
0:25:18 People use the words like commoditization and no defensibility.
0:25:22 That tends to be a battle between layers of the stack.
0:25:28 But the only way you can do that is actually move down the stack and enter somebody else’s layer, which is incredibly hard to do.
0:25:28 And you do see it.
0:25:34 Like, so of course, Google is going to build their own chips and they start moving down the stack.
0:25:39 But that’s a very, very different layer than somehow Google playing the different layers off against each other.
0:25:49 And so I would encourage anybody that does invest at least in infrastructure to not think zero-sum and to realize that historically, every layer of the stack has maintained some level of value and margin.
0:25:55 And if not, it was because a layer above them managed to verticalize themselves.
0:25:58 But then it’s that one player against the rest of the world.
0:26:02 Yeah, I mean, it’s like faster than light speed travel has just been invented, right?
0:26:04 And we’re sending all the spaceships out in all directions.
0:26:06 And there’s plenty of planets and stars to claim for everybody.
0:26:09 Like, you know, we’re not even close enough to each other to fight over one planet.
0:26:10 For the AI wave, yeah, for sure.
0:26:14 But it will slow down and then the consolidation will happen.
0:26:18 But I guarantee you’ll just end up with these great companies that maintain margin.
0:26:21 Like, AWS still has great margins.
0:26:22 Google still has great margins.
0:26:24 And still growing at insane speed.
0:26:26 Databricks, too, is growing at incredible speed for that.
0:26:27 That’s good.
0:26:32 You know, I think people underestimate how hard these problems are in many cases, right?
0:26:35 You’re sort of applying consumer thinking because this is how we live most of our lives.
0:26:41 It’s like, oh, wouldn’t it be relatively easy to move to a different part of the stack or take out your competitor or someone, a customer could just switch back and forth.
0:26:43 And it’s just different laws of physics, I think, in infrared.
0:26:48 It just turns out, in general, the switching cost of the infrastructure piece is so much higher.
0:26:52 Even with, like, API business, people tend to think you can just switch over to another API.
0:26:56 There’s so much logic embedded in calling the API in the software itself.
0:27:00 There’s a lot more switching cost compared to your regular SaaS software consumer software.
0:27:03 Yeah, totally, because you’re actually integrating systems, right?
0:27:06 It’s not necessarily a person who can just have a preference for one thing or another.
0:27:06 You’re sort of integrating.
0:27:07 For sure.
0:27:09 Sam Altman once had the advice to startups last year.
0:27:15 He was like, if you’re worried about us improving our models, you’re in a tough spot.
0:27:19 But if you get more excited about your business by us sort of improving our models, then you’re in a good spot.
0:27:21 Do you think that’s a helpful framework?
0:27:22 I think it’s helpful for open AI.
0:27:27 I want to say that, too.
0:27:35 If, you know, A16Z, if you think us investing in this company isn’t good for you, then if you want to buy from our companies, that’s great.
0:27:40 There’s a very open question that’s actually a technical question.
0:27:46 It isn’t a business question, which is how much does general training generalize, right?
0:27:50 So we know in the pre-training world, it generalized really well.
0:27:56 So you’d create one model, and that model was just as good at code as it was at, like, writing a poem or, right?
0:27:57 So we know that it was very general.
0:28:04 And in that world, sure, as the models get more powerful, then they can do all of the things, so they compete with all of the things, right?
0:28:14 But it seems clear to me, and again, this is an observation and it may not be correct, that as we get more into the RL world, that you make some trade-offs.
0:28:16 And then let’s say I RL something for code.
0:28:18 It’s not going to be as good as something else.
0:28:19 And, like, you’re making these trade-offs.
0:28:24 And in that world, then it’s not the case that the model is going to generally be good.
0:28:26 So I think it’s great to compete at the model layer.
0:28:31 And so, again, I think this is maybe a reasonable rubric, certainly for OpenAI to have people believe.
0:28:35 Maybe a reasonable rubric if you believe that these models are going to be generally great.
0:28:38 But I just don’t think it holds up to how things are going to play out.
0:28:40 This was a debate we had two years ago.
0:28:48 I think whether the general model and the most capable model will rule, or a lot of small, medium-sized models that are very good at specific tasks, that’s going to be the future.
0:28:49 It turns out both are true.
0:28:50 Both, yeah.
0:28:54 When we’re talking about complex systems, you cannot just use one model that drives everything, at least not today.
0:29:11 But you can compose very capable and powerful models to, like, take certain tasks and also chain together processes from, like, processing a document to, like, feeding in a model to have some reasoning and give you back really clean and structured data to make decisions and put it into your application to serve end users.
0:29:17 Like, that’s a complex system that invokes many model calls instead of just, like, one big model’s task.
0:29:23 Did you guys have any reactions, or is it worth talking at all about Karpathy’s talk?
0:29:25 Did that framing resonate with you?
0:29:27 Did you have any sort of differences of how you would frame certain things?
0:29:32 One thing he mentioned is that he thinks it’s not the year of agents, but the decade of agents.
0:29:34 Perhaps it’s not as immediately upcoming as we might have thought.
0:29:36 Probably should have talked about it more.
0:29:44 There’s something he said recently that I thought, and he’s actually responding to somebody else that I thought is actually very insightful.
0:29:49 I actually thought his talk was great, but I thought his talk was kind of an overview of what, you know, a lot of people know.
0:29:51 I thought it was a pretty good general overview.
0:29:54 I saw the tweet today about who knows how old it was.
0:29:57 So there’s this idea of prompt engineering that people have talked about.
0:30:00 And somebody, it wasn’t Karpathy, but Karpathy piled on top is this.
0:30:02 It’s really not about prompt engineering.
0:30:03 It’s context engineering.
0:30:06 And so what is context engineering?
0:30:12 So if you’re going to call a model, you have to know what to put in the context in that prompt.
0:30:14 And what tools do you have to do that?
0:30:18 Well, you could use other models, but at some point you’re probably going to use traditional computer science.
0:30:19 You’re going to use things like indexes.
0:30:21 You’re going to have to do prioritization, et cetera.
0:30:27 And to really drive the best performance out of those models, you do want the context to be correct.
0:30:30 And I do think it’s probably the right framing of this problem.
0:30:38 And the next step is in as much as we’re going to provide formalism to how do you use these models, to how do you use existing tools, to how do you improve the performance.
0:30:42 You should be thinking about what’s the right way to get the right context into those models.
0:30:52 And I bring this up because, like we said before, new infrastructure pieces create new patterns and new methods of software and building systems.
0:30:56 And this is a great example of that kind of emerging before our eyes and people reasoning about it.
0:31:02 And I truly believe in five years, we’ll look back, we’ll come up with a whole new set of formal ways to build software.
0:31:06 And they will have strong guarantees and we’ll understand them and there’ll be all the tools for it, et cetera.
0:31:20 The way I think that relates to our world is if you think about what is the new form factor of infrastructure that needs to become part of this context in engineering, it goes back to a lot of what we’re obsessed about with data pipeline.
0:31:24 How do you feed the right data and context into the models or into the context?
0:31:30 And how do you have agencies’ tools or infrastructure that will provide a discovery and guarantees the observability of these tools as well?
0:31:33 Like it’s the classic infrastructure problem that’s still unsolved.
0:31:34 So it’s a very exciting time.
0:31:38 There’s a few different types of infra founders, right?
0:31:44 There’s the sort of infra founder who loves solving really messy, long tail, like nasty problems, right?
0:31:48 There’s a type that kind of just gets fed up with a problem and they’re like, I’m going to solve this finally.
0:31:49 I’m sick of this.
0:31:53 Then there’s the type that just sees the world in a new way, right?
0:31:55 And it’s kind of like, this is actually how we should marshal these resources.
0:31:57 And like React is a great example of this.
0:32:01 We had all these like kind of progression of front-end development frameworks.
0:32:03 And finally, React was like the way that stuck.
0:32:06 And for years now, it’s been sort of the default front.
0:32:10 So like, I think what Karpathy’s talking about is trying to figure that out, right?
0:32:12 And I think his software 2.0 thing was really interesting.
0:32:15 We were investing in a bunch of like traditional ML companies at the time.
0:32:20 And I think software 3.0, I think he’s sort of right about that too in sort of directionally.
0:32:41 One of the difficulties of having any conversation around AI is it just exploits this weakness in the human imagination to dump all of our fears and hopes and dreams into this anthropomorphic fallacy, right?
0:32:43 And this goes all the way back to the Promethean legend.
0:32:46 And so let’s talk about even this context, right?
0:32:49 We’re building systems to build other systems.
0:32:51 Those systems have constraints, right?
0:32:55 And so you can fail on either side of this when it comes to this anthropomorphic fallacy.
0:32:58 On one side, you can be like, this stuff doesn’t work.
0:32:59 You shouldn’t use it.
0:33:03 You should only use traditional things, which, okay, that’s clearly not the case.
0:33:03 It seems very useful.
0:33:13 But on the other side, you can like believe they’ll solve all of our problems and you don’t need formalism and you just kind of like go to the beach and you come back when AGI is done and it’ll do it for you type thing.
0:33:29 And so part of our job and what we spend a lot of time talking about is trying to find that pragmatic, non-blinkered, non-pessimistic middle despite all of the rhetoric.
0:33:30 And then you hear all the rhetoric, right?
0:33:34 The stuff is going to like, no, we’re not going to have to work and we’re all going to be on.
0:33:35 The beach.
0:33:37 Right?
0:33:39 Or, you know, like it’ll kill us, like the whole thing.
0:33:43 And I think where we’ve landed is this is a real disruption.
0:33:44 It is changing all of software.
0:33:47 It’ll look something, place different, but it is still going to require professionals.
0:33:52 And I do think that the statement it’ll require professionals is a very meaningful one.
0:33:56 It means that you actually still need people that understand the specifications of the systems.
0:33:57 And not everybody agrees that.
0:34:03 Some people are out there like, listen, you will never need a programmer again because people are going to just say some high-level thing and it’ll show up.
0:34:11 And the only one statement I’ll say to that is formal systems came out of natural languages for a reason.
0:34:15 And like either you care about specifying what you’re designing or you don’t.
0:34:17 And if you do, you need to be a professional.
0:34:22 And that’s why every professional discipline, even though they started with a natural language, has ended up with a formal system.
0:34:25 What is your mental model on coding specifically?
0:34:28 Will there be like fewer engineers who are just higher powered?
0:34:33 I think the best way to think about this is simply that we’re going to have more developers.
0:34:40 I think it’s very unlikely that we’re going to shrink development teams because we have amazing new tools.
0:34:43 That’s just not how these markets have worked in the past.
0:34:45 I think exactly the opposite is going to happen.
0:34:51 It’s like we’re going to be creating so much great software and it’s going to be so accessible to so many people who may work at a big company or may just be sort of hacking on the weekend.
0:34:53 I think that’s by far the simplest way to think about it.
0:34:57 And it gets back to Martine’s point of you can’t anthropomorphize these models.
0:35:02 A model is a file on a hard drive in a computer somewhere.
0:35:06 And when you run a Python script, you can transform one piece of data into another piece of data.
0:35:07 Like that’s what this is.
0:35:11 And programming is a fundamentally creative job, right?
0:35:16 You are literally creating things in the most strict sense of the word, which is you’re creating software that doesn’t exist before.
0:35:20 And that’s something only a person can actually do at some level of abstraction.
0:35:26 So I personally think this is a huge boon for programmers and you have to change the way that you’re working.
0:35:28 And it’s like a huge productivity boost.
0:35:29 And I think that creates more, not less.
0:35:31 I cannot agree more.
0:35:44 I feel like for many of the developers and programmers I talked to today, they’re like going to Disneyland just because how many great tools there are to help them move faster, like build things they have always wanted to do on both side projects and also their main job.
0:35:50 I do think it also changes the dynamic of like how people are picking up new languages, picking up new frameworks.
0:35:58 And it is, again, a next level of iteration speed, given what we’re seeing with AI agents and also AI coding tools.
0:36:01 Here’s another, I think, useful mental model on this stuff.
0:36:04 Like I think it’s worth asking the question, why do people buy software?
0:36:07 Like why does someone buy some random SaaS tool?
0:36:09 Is it because it’s so hard to build it?
0:36:10 No.
0:36:12 Like most SaaS tools are like crud.
0:36:15 Like they’re just these basic kind of read-write databases.
0:36:16 They’re all the same.
0:36:17 So why do people buy them?
0:36:30 And Aaron Levy, who’s the CEO of Box, I think said this so beautifully, the reason people buy software is because somebody else made the decisions of what the workflow should be and what the operational logic should be and what data is important.
0:36:31 How you use that data is important.
0:36:40 Like creating a product is a lot of understanding what is being used and guiding the user along that direction.
0:36:42 So if not, I’ll just give you a compiler.
0:36:46 Like you do whatever you want or I’ll just give you a database and you do whatever you want.
0:36:54 There’s a reason that we have a proliferation of vertical SaaS and it is this kind of articulation or this transfer of domain understanding.
0:36:57 And that just doesn’t go away independent of how you create the software.
0:37:08 And so we will still need to design products based on whatever problem is being solved, guide people so that they’re the most effective with them and they can understand the best.
0:37:15 And we did this with assembly before and then we did it with high-level languages and then we did it with high-level frameworks and then we’re going to do it with AI.
0:37:19 But like the fundamental process of that articulation will not go away.
0:37:22 And it’s totally orthogonal to creating the software itself, right?
0:37:28 It turns out to be a much harder problem to go out and collect requirements from an unknown set of users with an unknown set of needs.
0:37:31 And like figuring out what to build, that turns out to be much harder than actually building it.
0:37:35 So what do you think is the average number of lines changed in the PR in the industry?
0:37:36 Two.
0:37:40 But it shows you to the point.
0:37:45 Like it literally is understanding the need from the business and the need from the user and making some minor tweak.
0:37:48 That is the long tail that goes into software.
0:37:49 And by the way, it turns out it’s two.
0:37:50 Well, I think that’s the median.
0:37:51 It’s the median is two.
0:37:55 I’ve written a lot of like GPRs in my life.
0:37:57 Just for the record, by the way, Martine said crud.
0:37:59 Crud is a technical term, right?
0:38:00 Create, read, update, delete.
0:38:02 We actually think applications are great.
0:38:03 We don’t think they’re crudgy.
0:38:04 They just really are crud.
0:38:05 Yeah, crud is it.
0:38:06 Just a footnote.
0:38:08 Good to know.
0:38:12 Jennifer, you were mentioning earlier how two years ago we were having this debate on generalization.
0:38:16 And what are the debates we’re having now internally or with your peers?
0:38:23 Or what are the main questions that we’re asking that we can’t wait to see how they’re going to reveal themselves in the next few months or next year that are going to impact our business?
0:38:24 Oh, gosh.
0:38:25 Every week is different.
0:38:27 What are some recent ones?
0:38:33 Definitely like how realistic are agents today like really producing production level software?
0:38:37 That’s more on the coding agent side, but also in general like the agent evolution.
0:38:42 Where are we in going from demoware to producing real value, tangible value?
0:38:43 What are some other ones?
0:38:46 Synthetic data is one we talk about a lot.
0:38:47 We’ve been talking about that one for 10 years.
0:38:49 Yeah, this is what’s so great about infra.
0:38:52 You can have the same debates for 10 years and they never quite go away.
0:38:54 It’s like change the background.
0:38:55 It’s like everything else is the same.
0:38:57 Yeah, consistency versus availability.
0:38:59 Literally every system has those trade-offs.
0:39:00 So this synthetic data thing, right?
0:39:02 It’s almost an information theory question.
0:39:06 It’s like, can you make models meaningfully better without introducing new information to the system?
0:39:09 And I think it’s now pretty clear you can do a little bit.
0:39:13 But the question is, does this lead to sort of like a self-improving utopia of models or not?
0:39:16 And I think we have some pretty strong opinions on the not side of that.
0:39:19 Generalization, Martine mentioned, is a pretty interesting one.
0:39:22 If you train a model to be really good at math, does that mean it’s going to be really good at other things?
0:39:25 Or is it just like really good at math, which I get excited about.
0:39:27 Not everybody gets excited about this.
0:39:30 Another one that we talk a lot about is like what these things are actually good for.
0:39:35 Just because the path we came from used a lot of AI.
0:39:36 Pre-gen AI used a lot of AI.
0:39:40 So there’s a lot of AI shaped holes in the enterprise, like chatbots and this and that.
0:39:42 And that’s very much on the brain.
0:39:46 And it seems to sometimes confuse the discussions from the new use cases we’re seeing.
0:39:52 Like if you look at the most common use cases of something like chatgpt, I think the top one is like companionship and therapy.
0:39:54 And then it’s like managing my schedule.
0:39:57 It’s like the top of the pyramid of need stuff.
0:40:02 And then number five is professional development, not like low-code development or whatever.
0:40:07 And so I think what is happening is we have this idea of what we thought AI was going to do.
0:40:10 And like just kind of the stilted attempts previously.
0:40:14 And then Jennifer actually ran product for a chat company prior.
0:40:16 And then what it really is good for.
0:40:18 And clearly there’s some overlap and convergence.
0:40:21 But it’s not nearly as big as people say.
0:40:24 And so we do spend a lot of time just trying to be very honest with ourselves.
0:40:26 What is the new behavior being created?
0:40:27 Where is this stuff getting used?
0:40:30 What is it just being trying to cram into places it’s not actually quite good at?
0:40:33 To that point, how do we think about agents right now?
0:40:36 What are they good for, going to be good for soon enough?
0:40:38 What is the state of them? How do we think about the broader conversation?
0:40:39 Coding agents are awesome.
0:40:42 It’s really amazing.
0:40:44 So I have a very simple way to think about this.
0:40:46 And I’m like the anti-agent guy, by the way.
0:40:47 I think it’s kind of a marketing thing.
0:40:49 This is the other thing about infra people.
0:40:51 We are like allergic to marketing, which is not always a good thing.
0:40:53 Which is a good thing you’re here, Eric.
0:40:54 So that’s what you mean.
0:40:56 Yeah, yeah, exactly.
0:40:57 Can you explain?
0:41:02 If you take the simplest definition that basically an agent is an LLM running in a loop,
0:41:08 a very simple way to think about this is errors propagate throughout the loop, right?
0:41:10 So if you have a small error, it gets worse and worse.
0:41:15 And this is why a lot of agents doing, say, general web browsing don’t perform very well yet.
0:41:19 On the flip side, if you have a way to correct those errors in the loop,
0:41:20 which is one thing that you have in code, right?
0:41:23 You can lint, you can interpret, you can try to compile and things like that.
0:41:25 You actually do see good performance over time.
0:41:28 That’s a very simplistic and maybe not quite the right way to look at it.
0:41:29 But if you can do this kind of error correction,
0:41:32 I think you’re seeing a lot of sort of improvement from this iterative approach.
0:41:33 I mean, it’s incredible.
0:41:37 I’m actually on the GitHub mailing list of a lot of the companies that I work with,
0:41:39 just mostly for interest.
0:41:46 And I have, even in the last week, seen a bunch of kind of cursor agent commits.
0:41:51 And even in the last 24 hours, the Slack integration, seeing it come from Slack.
0:41:56 And so I do think for kind of bite-sized tasks, you can articulate very well.
0:41:57 We’re starting to see them really work.
0:42:00 So in the coding space, I would say I’m a convert.
0:42:05 But to Matt’s point, like the, you know, go wander out in the woods and bring back a bear.
0:42:10 I think we’re a lot of errors you can run into.
0:42:15 Will we see more vertical integration or more horizontal specialization?
0:42:18 You know, historically, we’ve seen both.
0:42:21 And what’s interesting is we’re already seeing both now.
0:42:25 Apple, of course, has just been historically vertically integrated.
0:42:28 Microsoft and Intel, historically horizontally.
0:42:33 And often, companies will start horizontal and then go vertical.
0:42:34 So Google is horizontal.
0:42:36 It’s built on top of normal servers, but then they built their servers.
0:42:39 And then, you know, they built their own chips.
0:42:41 They built their own networking gear.
0:42:43 And so I think you always get a mix of the two.
0:42:46 What’s interesting about now is we’re actually really seeing both.
0:42:51 I would say that OpenAI is very much a vertically integrated company now with ChatGPT driving a lot of it.
0:42:54 I would say Anthropic, a lot of the usage really is more horizontal.
0:42:56 And they’re doing a great job of that.
0:42:57 I think we’re seeing this on the model layer, too.
0:43:00 Very interesting discussion we haven’t had, but it’s a very interesting one.
0:43:06 It’s like open source, quote unquote, really seems to work with these models just because you can’t, as a user, recreate it.
0:43:11 So if you look at BFL, they’ve done a great job building like a horizontal layer for these models.
0:43:16 But then you’ve got companies like Ideogram, which have built a great kind of vertical experience as well.
0:43:20 And so I would say for AI, we’ve got already this early on great examples of both.
0:43:22 And I don’t see any reason that that will change.
0:43:22 Yeah.
0:43:28 I think from the business front, it just poses new interesting questions and challenges, too, of how do you capture the value?
0:43:35 You, of course, horizontally can capture the value through being able to address every single use case by providing that to developers or enterprises.
0:43:37 But if you vertically integrate, you kind of have to pick the lane.
0:43:38 Do I want to focus on image models?
0:43:40 Do I want to focus on graphic designers?
0:43:43 Do I want to focus on, you know, people who are generating photographies?
0:43:54 You have to understand the market and the user personas use cases pretty well to capture the maximum value where you probably can take an easier path to just provide APIs so everybody can use it.
0:43:55 I think this is a great place to wrap.
0:43:57 Guys, thanks so much for coming on the podcast.
0:43:58 Thank you for having us.
0:43:59 Thank you.
0:43:59 This is fun.
0:44:04 Thanks for listening to the A16Z podcast.
0:44:10 If you enjoyed the episode, let us know by leaving a review at ratethispodcast.com slash A16Z.
0:44:13 We’ve got more great conversations coming your way.
0:44:14 See you next time.

0:00:04 This episode is presented with limited commercial interruption by Intuit.
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0:00:08 Whether you’re looking to grow a side hustle or switch things up full-time,
0:00:11 Intuit helps tax and bookkeeping professionals chart your own path
0:00:13 and connect with customers in meaningful ways.
0:00:17 Head to intuit.com slash expert to learn more or apply now.
0:00:21 Year after year, without fail, half the people I talk to
0:00:23 are still looking for a side hustle idea.
0:00:26 The other half have too many to choose from.
0:00:29 And it might be surprising that I’ve found myself on both sides of the fence
0:00:30 at various points.
0:00:34 Like if I only had that killer idea to focus on, I know I can crush it.
0:00:37 But what’s been more common lately is being on the other side.
0:00:40 Hey, there are way more ideas than there is time.
0:00:43 And then there’s the challenge of focus and direction
0:00:45 and choosing where to allocate your time and attention.
0:00:48 So last week, we talked about finding your side hustle niche
0:00:51 and some exercises and frameworks to generate those potential ideas.
0:00:54 You can go back and tune in to that one if you missed it.
0:00:58 This week, armed with those ideas, I want to give you a methodology
0:01:04 to pick which one to work on first, to remove the subjective guesswork from it
0:01:10 and help take action and prioritize your limited time for maximum impact and result.
0:01:14 This methodology actually came from a Side Hustle Nation reader years ago
0:01:16 who asked to remain anonymous.
0:01:17 But he sent me this note.
0:01:22 He said, my partner and I keep a running list of potential business ideas.
0:01:24 And then we then baseball score them.
0:01:28 She called single, double, triple, home run on a different criteria.
0:01:32 So for the sake of this exercise, we’re going to assign a number score, one through four,
0:01:37 with four being the best or home run being the best for each of these 10 questions.
0:01:40 So what it’ll look like is a spreadsheet.
0:01:42 And to help you set up this file, you’re going to list your potential
0:01:44 side hustle ideas across the top.
0:01:47 Number one, two, three, four, five, however many options you came up with.
0:01:51 And then down column one is the list of questions that we’ll get into.
0:01:55 And I’ve actually got a free version of this template in a Google Sheet.
0:01:58 If you want to grab that, just head over to the show notes for this episode.
0:01:59 You can make a copy.
0:02:03 You can add it to your drive so it’s customizable, editable, all that jazz.
0:02:06 The show notes link in the episode description will get you right over there.
0:02:11 But the first question, super important one, is just how excited are you about the idea?
0:02:17 Remember Sarah McCaffrey’s line about motivation being temporary, how excitement usually has
0:02:17 an expiration date.
0:02:23 And if you’re not excited about something, how likely are you realistically to give it the effort
0:02:25 necessary to achieve liftoff?
0:02:31 So you’re going to rate your side hustle ideas one through four on how exciting they are to you.
0:02:37 Maybe the niche email newsletter is a two, vending machines are a three, the YouTube channel is
0:02:39 a four, the freelance service is a two.
0:02:39 Do you get the idea?
0:02:44 One through four, four being the best, four being a home run in this baseball scoring methodology.
0:02:49 Question two is, is there a clear path to your first sales or customers?
0:02:50 Step one is the idea.
0:02:52 Step two is the execution.
0:02:56 Is it obvious what you’re going to need to do to make actual sales?
0:02:58 Do you already know your potential customers?
0:03:01 Are people already asking you for this service?
0:03:07 Or is there a more murky question mark filled path on how you’re actually going to monetize?
0:03:12 In this case, the freelance service might be a four, the niche newsletter might be a one.
0:03:13 That’s question two.
0:03:16 Is there a clear path to your first customers or sales?
0:03:22 Question three is, how much time will it realistically take to get off the ground?
0:03:24 Speed can be a weapon.
0:03:28 And making meaningful progress creates this positive feedback loop that helps you keep going.
0:03:30 How much time is it going to take?
0:03:32 Because you don’t want to run out of gas.
0:03:35 You don’t want to run out of excitement before you achieve a liftoff.
0:03:39 In the case of my shoe shopping site, it took months, months of development before we even had
0:03:46 a semi-functional minimum viable product version of the site that I could begin to market and
0:03:46 drive traffic to.
0:03:51 Is there a quick and dirty version of your product, of your service, that you could launch
0:03:52 quickly?
0:03:53 Is there a way to pre-sell something?
0:03:58 Again, you’re going to rate your options one through four on the question of speed.
0:04:02 How long is it realistically going to take to get traction?
0:04:04 Question four is the startup cost question.
0:04:08 How much capital is it going to take to get it off the ground?
0:04:12 And you might be able to fill this in with actual dollar figures if you have an estimate
0:04:12 for that.
0:04:17 Or for the sake of consistency, keep it with that one through four baseball scoring system.
0:04:22 Only for this one, let’s make for a really low startup cost and one being a more expensive
0:04:23 business to start.
0:04:28 And thankfully, most of the side hustles we cover are relatively low startup cost businesses,
0:04:31 especially in the realm of the examples we’ve been talking about.
0:04:36 YouTube channels, email newsletters, freelance services probably would all score a four unless
0:04:40 you need some special new video equipment or something and maybe that bumps it down.
0:04:45 Vending machines have some upfront equipment and inventory costs, but maybe you explore some
0:04:49 financing options and you don’t commit to buying the machine until you’ve secured a location.
0:04:51 So maybe that’s a two or a three.
0:04:53 It’s all relative, but that’s question four.
0:04:55 How much capital is it going to take?
0:05:01 The initial version of the shoe site, for the sake of reference, was around $10,000 in development
0:05:02 costs.
0:05:07 Today, with the different website builders and AI tools, it would probably be less than
0:05:08 $500.
0:05:13 But that’s why we’re asking these 10 questions, because just because something has higher startup
0:05:18 costs doesn’t necessarily mean it should automatically be eliminated from the conversation.
0:05:23 Are you looking for a flexible income stream and one with real career potential?
0:05:27 I’m excited to partner with Intuit for this episode because they’re actively recruiting
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0:06:23 Okay, we’ve gone through four questions so far to help you objectively compare and evaluate
0:06:24 different side hustle options.
0:06:25 How excited are you?
0:06:28 Is there a clear path to your first customers or sales?
0:06:29 How much time is it going to take?
0:06:33 Is there going to be a long product development or audience building phase?
0:06:35 Or can you earn revenue right away?
0:06:37 And how much startup capital is it going to take?
0:06:41 Question five is, what’s the revenue potential?
0:06:44 Very important question is to consider the upside.
0:06:48 We tend to be very focused on the downside, which is also important, right?
0:06:51 To make sure a failure doesn’t bankrupt us.
0:06:55 But sometimes we skip the, well, what if it works question?
0:06:59 So if you project out three to five years, if everything goes well, if everything goes according
0:07:01 to plan, what does success look like?
0:07:04 Is it a $10,000 a month business?
0:07:06 Is it a $100,000 a month business?
0:07:07 What’s the ceiling here?
0:07:08 What’s the revenue potential?
0:07:14 And the reason you want to ask this is you want to make sure you’re pursuing an opportunity
0:07:16 that’s big enough.
0:07:20 And that’s going to be relative to everybody, but big enough to be worthwhile because it’s
0:07:22 going to take a lot of effort and energy.
0:07:28 And if the best case scenario or even the most likely case scenario outcome isn’t life changing
0:07:30 for you, why do it?
0:07:31 You’re probably going to run out of motivation.
0:07:36 If it’s not, I think Noah Kagan called this the million dollar rule, and you might adjust
0:07:38 that number higher or lower depending on your circumstances.
0:07:42 But it was something like, if I don’t see a path for this business to make a million dollars,
0:07:45 I’m not doing it because it’s going to be hard.
0:07:49 So one through four, what’s the revenue potential for each of your ideas?
0:07:52 Question six is how easy is it to operate?
0:07:56 And you might not know the answer to this having never done it before, but it’s kind of your
0:08:00 best guess, or you might talk to other people doing similar things to what you’re considering.
0:08:04 But is it operationally simple or complex?
0:08:06 What does the sales funnel look like?
0:08:09 What kind of delivery logistics are involved?
0:08:11 How many different software tools might you have to duct tape together here?
0:08:13 A simple solo freelance service?
0:08:14 Probably a four.
0:08:15 A newsletter?
0:08:20 Maybe two or three, only because you have to constantly recreate the product every day
0:08:21 or every week.
0:08:23 But how easy is it to operate?
0:08:25 One through four on that question.
0:08:29 Question seven is how easy is it to automate or delegate?
0:08:34 And it’s probably never as easy as you think, or as easy as the passive income gurus would
0:08:39 have you believe, but is the model you’re considering ripe for automation or delegation?
0:08:45 For example, kind of hard to automate a service business like pressure washing or mobile car
0:08:48 detailing, but it’s a service that could probably be delegated.
0:08:54 Digital product business, like selling printables, much more automated, probably scores a four on this
0:08:55 matrix.
0:08:58 But question seven, how easy is it to automate or delegate?
0:09:01 Question eight, how easy is it to scale?
0:09:07 And when I think about scale, I think about the ease of adding an additional customer.
0:09:14 For example, if I have a YouTube channel or a podcast or an email newsletter, extremely easy to scale.
0:09:20 It costs zero or almost zero to add that incremental viewer, listener, subscriber, and your production
0:09:21 costs are the same, right?
0:09:26 It costs the same to produce an episode that 10 people listen to or that 10,000 people listen
0:09:27 to or that 100,000 people listen to.
0:09:29 Very scalable.
0:09:34 So those kinds of businesses would earn a four, where a vending business might be a two, right?
0:09:39 You can use your existing systems and distribution network, but it’s still a new location to onboard
0:09:44 and lots of one-on-one sales calls to make that scale happen.
0:09:46 So how easy is it to scale?
0:09:49 Freelance service, maybe a one or a two, right?
0:09:53 You can sell additional clients, but then you got to find the time to fulfill the work.
0:09:55 Question nine is the shutdown question.
0:10:00 How easy is it to stop operations if you find out it’s not working?
0:10:01 This is the pull the plug question.
0:10:05 If it’s a website, I mean, you can just stop updating it.
0:10:05 You can stop paying the hosting.
0:10:07 Pretty easy.
0:10:10 If it’s a physical product business, do you have to liquidate the inventory?
0:10:14 Do you still have to honor any product warranty issues?
0:10:15 Got a few more moving parts.
0:10:19 If you sold a membership to something, do you have to issue refunds?
0:10:23 Do you have to continue providing access to a dashboard or a product?
0:10:26 One through four, how easy is it to shut down if you need to,
0:10:29 with four being the simplest and easiest in this case?
0:10:34 And question 10 is, is the business something I could sell down the road?
0:10:35 How sellable is it?
0:10:37 Solo freelance business?
0:10:39 Probably not very sellable.
0:10:41 Personally branded YouTube channel?
0:10:42 Probably not very sellable.
0:10:44 Library of digital products?
0:10:45 Maybe more so.
0:10:47 Profitable vending machine route?
0:10:48 Absolutely.
0:10:51 Online newsletter with a hands-off production system?
0:10:52 Absolutely.
0:10:56 My only experience in selling a business was my virtual assistant business.
0:11:00 And it was absolutely not a consideration when I started.
0:11:01 Probably should have been.
0:11:07 With that in mind, I probably would have put better bookkeeping and revenue tracking in place.
0:11:13 And you may never intend to sell your business, but operating it as if it were a sellable asset
0:11:16 is probably going to make you a better business owner anyway.
0:11:21 And that exit could be a pretty substantial wealth building event.
0:11:26 So don’t discount question 10, even if you’re not thinking, I’m just in the startup phase.
0:11:27 I’m trying to get something off the ground.
0:11:29 But don’t discount question 10.
0:11:32 Is the business something I could potentially sell down the road?
0:11:37 Again, you can download a blank version of this matrix with all these questions at the show
0:11:41 notes for this episode, and then you can just plug in the business ideas that you’re considering
0:11:41 across the top.
0:11:43 But here’s where it gets fun.
0:11:47 Now you can total up the score for each of these columns, for each of these side hustle
0:11:50 ideas, and objectively see which one won.
0:11:53 Because it’s going to give you a clear numerical winner.
0:11:59 And what else is cool is if the one you wanted to win didn’t, that’s a great gut reaction to
0:12:02 go do that one instead, the one you wanted to win.
0:12:06 You can even manipulate the weighting of the different criteria to massage the data, because
0:12:08 ultimately it’s your side hustle.
0:12:09 You get to choose.
0:12:12 I think this will be an eye-opening exercise for you.
0:12:18 If you’re an over-analyzer, if you’re debating between different options, it gives you, hopefully
0:12:23 it gives you mathematical permission to proceed if you’re the permission-seeking type.
0:12:24 And you can’t argue with math.
0:12:29 And once you’ve got that side hustle selected, you’re going to want to tune in next week as
0:12:34 I walk through 10 ways to shrink the internet, to do some marketing, to get your first customers.
0:12:38 I know it seems like a big, scary place, but with these 10 strategies, you can find your
0:12:39 people and you can start to make some more money.
0:12:43 So be sure to hit that subscribe or follow button in your podcast app so you don’t miss
0:12:49 that or any of our other awesome upcoming episodes to help you add more profit to your pocket.
0:12:52 Big thanks to our sponsor, Intuit, for helping make this content free for everyone.
0:12:57 Intuit, the maker of TurboTax and QuickBooks, is inviting Side Hustle Show listeners to join
0:13:00 its world-class network of tax and bookkeeping experts.
0:13:05 To learn more or apply now, head on over to intuit.com slash expert.
0:13:08 Once again, that’s intuit.com slash expert.
0:13:09 That is it for me.
0:13:11 Thank you so much for tuning in.
0:13:14 Until next time, let’s go out there and make something happen.
0:13:16 And I’ll catch you in the next edition of the Side Hustle Show.

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0:00:50 There’s a lot nobody tells you about running a small business, like the pricing.
0:00:52 The marketing.
0:00:53 The budgeting.
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0:01:22 What makes for the perfect summer read?
0:01:28 Maybe it’s a romance, or that non-fiction book you’ve been meaning to get around to, or maybe it’s something else.
0:01:32 The summer vibe is like easy, breezy, lesbian vampires.
0:01:33 That’s the vibe.
0:01:36 No, no, like summer.
0:01:40 What we read and why we read during the summer.
0:01:42 That’s this week on Explain It To Me.
0:01:46 New episodes every Sunday, wherever you get your podcasts.
0:01:52 Welcome to Office Hours with Prop G.
0:01:57 This is the part of the show where we answer your questions about business, big tech, entrepreneurship, and whatever else is on your mind.
0:02:02 If you’d like to submit a question for next time, you can send a voice recording to officehours at propgmedia.com.
0:02:04 Again, that’s officehours at propgmedia.com.
0:02:10 Or post your question on the Scott Galloway subreddit, and we just might feature it in our next episode.
0:02:14 First question.
0:02:19 Our first question comes from AmatterOfFap on Reddit.
0:02:19 They ask,
0:02:23 Prop G, what are your thoughts on sugar relationships?
0:02:26 Aren’t all healthy relationships mutually beneficial?
0:02:31 What are your thoughts on its social acceptability and portrayals like in the latest White Lotus season?
0:02:38 Please pardon my username, but had to ask the question on my alt, but feel free to identify me as such.
0:02:39 Ha ha.
0:02:43 Look, I think every relationship is a transaction to a certain extent.
0:02:48 And I don’t, the bottom line is I don’t have a problem with it.
0:02:50 I think as long as there’s consenting adults,
0:02:55 I think there’s a real problem with trafficking young women around the world where they’re forced into relationships
0:02:59 where they are preyed upon because of their economic desperation.
0:03:01 I think that should be illegal.
0:03:06 And, you know, when certain members of the manosphere are accused of trafficking young women,
0:03:12 I think that should basically convince everyone that we just don’t need to listen to these people around trying to help young men.
0:03:21 But if you’re a young person and you enter into a relationship with someone and you’re giving up your time and you have more time than money and they have more money than time,
0:03:25 yeah, you’re consenting adults.
0:03:26 I don’t see anything wrong with that.
0:03:36 I think that traditionally the male-female dynamic in the United States was I get emotional support and nurturing from the woman and the man provides financial support.
0:03:41 And over the course of the last 30 or 40 years, women have been able to step up and provide more financial support.
0:03:50 And there’s a decent argument that men haven’t stepped up in terms of emotional or domestic or logistical support, creating an imbalance where a lot more men are a lot less attractive to women.
0:03:52 Now, I think there’s other things involved there.
0:03:55 I think online dating creates unreasonable expectations on both sides.
0:04:00 I don’t think young men have venues to demonstrate excellence.
0:04:01 Young people aren’t getting together.
0:04:07 There’s a zeitgeist of the moment you see not even a red flag, but a magenta flag, you should exit the relationship immediately.
0:04:08 Like, oh, he didn’t open your door.
0:04:09 You’re out of there.
0:04:11 Well, okay, folks, not all of us are perfect.
0:04:15 Anyways, I have no problem with it is the bottom line.
0:04:17 I have absolutely no problem with it.
0:04:20 I think at some point, relationships are a transaction.
0:04:23 It’s just a matter of cadence and currency.
0:04:29 And as long as you’re both consenting adults, also, let’s be honest, the relationship is usually an older man giving a younger woman money.
0:04:42 And if a younger woman whose fertility window is much shorter, who’s in a city that values women of a certain age and devalues women of a certain age, if she’s giving up her time, she should at least ensure she’s going to get something out of it.
0:04:46 And if the man has more money, I don’t see any reason.
0:04:55 So I have absolutely no problem with sugar relationships if, in fact, they’re both consenting adults and it works for both of them.
0:04:58 I think every relationship involves some sort of transaction.
0:05:06 And as long as you’re both sides are transparent, as long as both sides are honest with each other, yeah, have at it.
0:05:09 I think there’s absolutely, yeah, no problem with it.
0:05:11 So sugar away.
0:05:14 Our second question comes from Paul.
0:05:15 Not from Reddit.
0:05:16 Paul asks.
0:05:18 Hey, Scott.
0:05:20 This is Paul, longtime fan of the pot.
0:05:25 I actually got to shake your hand this past January in Houston after one of your speeches.
0:05:32 We shared a brief memory flashback to Petrero Hill in the 90s and Goat Hill Pizza.
0:05:39 Following up to a recent comment about second language learning being less valuable in today’s AI era.
0:05:48 One of my sons studied Mandarin through college and a formal language training program, including some immersion in Taipei and Beijing.
0:05:50 I get your point.
0:05:57 AI tools like real-time translation make the transactional need for another language less critical.
0:06:14 But do you think that overlooks the relational side, trust, nuance, mutual respect, that can only be built through two people communicating directly, especially in something as geopolitically important as the U.S.-China relationship?
0:06:19 Thanks to you, your team, for the content and the occasional good jokes.
0:06:21 Occasional?
0:06:22 Come on, Paul.
0:06:25 Thought it was good to see you in Houston.
0:06:29 Look, I agree with everything you said.
0:06:36 I think I’ve just finished writing a book on masculinity called Notes on Being a Man.
0:06:47 And the thing about when you write a book, you can get on almost any media outlet, or at least I’ve been blessed enough that if I write a book, I can get on almost a media outlet.
0:06:52 And I think a lot of it is because people in media realize how hard it is to write a book.
0:06:54 And they’re like, okay, you did the work, and they have some goodwill towards you.
0:07:08 I would imagine that I remember going to China with my friend Doug Guthrie, who was the head of Apple University in China and was the dean of the George Washington Business School and a colleague of mine at NYU and a big China scholar.
0:07:11 And he got up on stage and started speaking perfect Mandarin.
0:07:20 And the whole audience just kind of stopped and listened very attentively, because here was a white dude from the U.S. speaking perfect Mandarin.
0:07:23 And there’s just no doubt about it.
0:07:25 That’s like people go, that’s hard.
0:07:26 So we have more goodwill for you.
0:07:30 Also, I think my understanding is learning a language is like learning an instrument.
0:07:48 And that is, even if you never end up making a dollar from playing the tuba or get any additional advantage from understanding Mandarin or French, it opens a part of your brain when you’re young that helps you absorb other knowledge more easily.
0:07:49 That it’s a great training.
0:07:52 It’s like when you damage a muscle and it grows back stronger.
0:07:59 Essentially, I think learning the languages and music damages that muscle, your brain, and it grows back stronger across a variety of activities.
0:08:03 So I’m not saying that we should get rid of language classes.
0:08:12 I learned Spanish, and it introduced me to Gabriela Garcia Marquez, 100 years, un ciento años de soledad, and 100 years of solitude.
0:08:22 And I remember reading it in Spanish, and there’s the most beautiful scene in this book where this young woman is so beautiful that she literally floats away.
0:08:41 And I remember telling my mother of my children at one point, I was like a little drunk and feeling pretty good, that she was so beautiful that I thought at some point that she might, you know, that it was a realistic or there was a non-zero probability that the winds were going to kick up and she was literally going to just fly away or float away.
0:08:47 And that romance and understanding it through the lens of Spanish, and I think Spanish is such a beautiful language.
0:08:49 I took five years of Spanish.
0:08:51 I’m a lot of fun in Mexican restaurant.
0:08:53 I actually still can’t speak it.
0:09:01 Mrs. Witten at Emerson Junior High School, no, University High School, always gave me a B, even though I probably should have got a C.
0:09:07 I was terrible, terrible in languages, but I liked her, and she liked me, and she always gave me a B, which was comforting to get a B in Spanish.
0:09:09 Anyways, I’m a fan.
0:09:21 I just, what I don’t like, or I think is stupid, is all of these, you know, tiger moms trying to get their kids to learn Mandarin by the time they’re, you know, in 11th grade so they can go to China, which is going to economically conquer the U.S.
0:09:33 For the most part, when I started going to Europe in the 90s with my consulting firm Profit, you’d walk into a meeting in France and they would speak French and be pissed off that they needed to translate for you.
0:09:40 And now what I find is that lingua franca, even in Germany, when I go to meetings in Audi, they conduct the meetings in English.
0:09:46 And I find, generally speaking, the corporate world in Europe now is now conducting meetings in English.
0:09:51 And with AirPods and iPhone and AI, you’re going to basically be able to speak any language or at least understand it.
0:09:58 Having said that, you don’t take language or music for economic prosperity or utility.
0:10:02 I think you take it to learn, to appreciate the art, everything you’ve said.
0:10:04 I think it’s wonderful.
0:10:06 So I think we’re pretty much in agreement here.
0:10:12 But the notion that you need to learn Mandarin to be economically viable, I, you know, I just don’t buy it.
0:10:14 But yeah, it’s something I wish I was better at.
0:10:17 I took Spanish for a long time and I was just never very good at it.
0:10:18 And I clearly don’t have any earful languages.
0:10:20 But anyways, muchas gracias.
0:10:24 Si, me llamo Scott.
0:10:26 ¿Dónde está la biblioteca?
0:10:29 We’ll be right back after a quick break.
0:10:38 Support for the show comes from Grunz.
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0:10:58 And just in time for summer, Grunz has a limited edition raspberry lemonade flavor.
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0:11:38 It’s Today Explained.
0:11:40 What’s going on, my boys and in some cases, gals?
0:11:43 Recently, one of you emailed us with this request.
0:11:44 You’ve got mail.
0:12:05 Curtis Yarvin is a very online far-right philosopher whose ideas include the fascinating, the esoteric, the absurd, the racist, and so on.
0:12:11 Six months into the Trump administration, there’s evidence that he is influencing the MAGA movement, and even President Trump.
0:12:13 J.D. Vance knows him and likes him.
0:12:16 Elon consulted him about this third-party idea.
0:12:19 Yarvin can take some credit for inspiring Doge.
0:12:29 And, as you’ll hear ahead, one of Trump’s most controversial, doesn’t even begin to cover it, ideas may have come from Yarvin or someone who reads his substack.
0:12:32 I can almost guarantee you that Trump does not.
0:12:33 Everything’s computer.
0:12:35 Today Explained, weekday afternoons.
0:12:45 This week on Net Worth and Chill, we’re diving deep into Trump’s one big, beautiful bill, the sweeping legislation that promises to reshape America’s economic landscape.
0:12:54 From tax cuts to student loans, I’m breaking down what this massive piece of legislation actually means for your wallet, your investments, and your financial future.
0:13:05 We’re going to find out who wins and loses in this economic overhaul, analyze the market reactions that have investors buzzing, and discuss whether this bill will deliver on its promises or create unexpected consequences.
0:13:09 Just because you’re not on Medicaid doesn’t mean this doesn’t impact you.
0:13:12 Poor people don’t stop having medical emergencies.
0:13:14 They just stop being able to afford them.
0:13:19 Listen wherever you get your podcasts or watch on youtube.com slash yourrichbff.
0:13:23 Welcome back.
0:13:24 Our final question comes from Reddit.
0:13:28 Mother Ratio 9806 asks,
0:13:31 Hey Scott, I’m at a crossroads with my wealth creation.
0:13:32 I’m about to have an exit.
0:13:37 I don’t have much family, but I’d love to financially help out those I care deeply about post-exit.
0:13:41 Is there a rule of thumb for family donations, and is it ongoing or a one-off?
0:13:47 So, I never really gave away a dollar to anyone or anything until I was 40.
0:13:51 And now that I have some economic security, I like to give money away.
0:13:52 It makes me feel masculine.
0:13:53 It makes me feel civic.
0:13:57 And I pay, or I give some money away to my family.
0:14:04 I pay for education for some of my nieces and nephews.
0:14:06 And I like it.
0:14:07 I think it’s a great investment.
0:14:08 It’s easy for me.
0:14:13 And it’s a big source of relief for their parents because education can be so expensive.
0:14:16 So, it’s sort of a win-win-win all around.
0:14:20 In terms of best practices, one, A, do it.
0:14:21 If you have the money, do it.
0:14:22 I don’t believe in hoarding wealth.
0:14:26 I got to my number in 2017, and I’m giving everything above it now.
0:14:27 I either spend it or give it away.
0:14:33 And what I would say is the best practice is don’t expect anything in return.
0:14:35 Decide if you’re giving it.
0:14:39 If you’re giving it, you don’t expect anything in return.
0:14:42 You don’t expect your brother to be nicer to you.
0:14:48 You don’t expect your nephew to send you pictures of his or her graduation.
0:14:51 I mean, if they do that, great.
0:14:56 But if you’re expecting anything, one, I think you’re setting yourself up to be disappointed.
0:15:00 Two, they’re going to feel some sort of pressure that you’re sort of controlling them through money.
0:15:07 What I try and do when I give money to family members is I try to make it as seamless as possible.
0:15:11 Hey, I was thinking about paying tuition for Jimmy.
0:15:12 And I’d really like to do that.
0:15:13 I have a fund that does that, da, da, da.
0:15:15 How much is he paying?
0:15:16 And then there’s some back and forth.
0:15:17 How much is it?
0:15:18 Are you down with it?
0:15:21 Get the wiring information, send it, and don’t bring it up again.
0:15:22 Don’t bring it up again.
0:15:24 Giving money is a weird thing.
0:15:29 It can make them feel less, I don’t know, less adult or less successful.
0:15:30 You don’t want them to feel bad.
0:15:33 You don’t want them to feel like there’s any reciprocal expectation.
0:15:35 You don’t want to feel like you’re exerting control.
0:15:38 You’re not trying to flex and make them feel bad.
0:15:41 So just, one, don’t expect anything back.
0:15:43 Make it as seamless, easy.
0:15:44 Don’t bring it up again.
0:15:45 If they say, thank you, great.
0:15:46 Oh, it’s no problem.
0:15:48 Don’t dwell on it.
0:15:48 Don’t bring it up.
0:15:52 That you want this to be giving, right?
0:15:54 You don’t expect anything in return.
0:15:56 You don’t even need them to acknowledge it.
0:15:57 You’re giving it to them.
0:15:59 It’s out of your mind.
0:15:59 You’ve given it to them.
0:16:00 It’s done.
0:16:01 It’s over.
0:16:05 So, one, do it, especially if you’re in a position to do it.
0:16:09 And you’re going to find, as you scratch the surface, even if you have cousins who look
0:16:12 economically prosperous, they’re stressed out about money.
0:16:15 So it’s an easy way to relieve stress.
0:16:18 Money is nothing but the transfer of time and work to other people.
0:16:23 So if you can give someone back a Sunday because they don’t have to spend as much time working
0:16:28 or they’re not as stressed, you take tension out of the relationship, it’s a wonderful thing
0:16:29 to do.
0:16:30 So, yes, do it.
0:16:33 Two, don’t expect anything back.
0:16:39 And three, make it as clean and easy and covert and ninja-like as possible.
0:16:41 Don’t turn it into a big thing.
0:16:41 Just do it.
0:16:42 It’s done.
0:16:43 Never think about it again.
0:16:50 And also just be really grateful and enjoy time thinking about how fortunate you are
0:16:51 that you get to do that for other people.
0:16:53 It feels, it really does feel wonderful.
0:16:56 That’s all for this episode.
0:17:00 If you’d like to submit a question, please email a voice recording to officehoursofpropturedmedia.com.
0:17:02 That’s officehoursofpropturedmedia.com.
0:17:07 Or if you prefer to ask on Reddit, just post your question on the Scott Galloway subreddit,
0:17:09 and we just might feature it in an upcoming episode.
0:17:16 This episode was produced by Jennifer Sanchez.
0:17:18 Drew Burrows is our technical director.
0:17:21 Thanks for listening to the Prop G Pod from the Box Media Podcast Network.

0:00:05 Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life.
0:00:14 I’m Andrew Huberman, and I’m a professor of neurobiology and ophthalmology at Stanford School of Medicine.
0:00:17 My guest today is Dr. Chris McCurdy.
0:00:21 Dr. Chris McCurdy is a professor of medicinal chemistry at the University of Florida,
0:00:25 where he directs research on natural products and their pharmacologic effects,
0:00:30 most recently the plant-derived compound kratom, which is readily sold in the U.S. and around the world
0:00:35 and is now used by tens of millions of people daily, and those numbers are increasing fast.
0:00:39 Dr. McCurdy’s research focuses on understanding how kratom interacts with our nervous system
0:00:44 and affects our physiology and behavior. He also studies its potential for addiction.
0:00:49 During today’s episode, we discuss the complex effects of kratom and its relationship to the opioid system.
0:00:53 Dr. McCurdy explains how kratom’s active compounds work in the brain,
0:00:59 why it shares certain similarities to opioid drugs, and critically, how kratom products available in the U.S.
0:01:03 and elsewhere are largely derivatives and isolates of the kratom leaf,
0:01:08 which is very different in terms of the effects it produces when compared to the traditional leaf products.
0:01:12 And unfortunately, that has confused and in many cases harmed consumers.
0:01:17 So today, you’ll learn about kratom’s effects at different doses and when it’s sourced in different ways.
0:01:21 You’ll learn about how it can be a stimulant, how it can increase focus, how it can be a painkiller,
0:01:25 how it can increase euphoria, but also its strong potential for addiction.
0:01:32 You’ll also learn what is known about kratom in terms of its ability to help people transition off traditional opioid drugs.
0:01:34 It has been shown to be effective for that.
0:01:37 However, we are also going to explain the potential harms of kratom,
0:01:40 in particular in young people whose brains are still developing,
0:01:44 and in people that don’t have a prior opioid addiction.
0:01:49 Our discussion about kratom also opens up a broader discussion about other plant alkaloids that have medicinal properties,
0:01:53 including those found in things like cocoa and 100% chocolate.
0:01:59 And we discuss the incredible history of soft drinks like Coca-Cola, Pepsi, 7-Up, and Dr. Pepper,
0:02:02 which, believe it or not, were originally developed as pharmacologic tools
0:02:06 before becoming the ultra-popular beverages that we’re familiar with today.
0:02:10 So I realize many people have heard about kratom, but also many of you perhaps have not.
0:02:15 What everyone should know, however, is that kratom products are pretty much everywhere now.
0:02:17 You can find them in supermarkets, convenience stores, online,
0:02:23 and they’re sold under the pretense of having very specific effects related to energy, pain management, or mood.
0:02:28 But by the end of today’s episode, you’ll have a thorough understanding of how this plant compound actually works.
0:02:32 Yes, its potential effects, but also its serious risks.
0:02:37 Before we begin, I’d like to emphasize that this podcast is separate from my teaching and research roles at Stanford.
0:02:42 It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science
0:02:44 and science-related tools to the general public.
0:02:47 In keeping with that theme, today’s episode does include sponsors.
0:02:50 And now for my discussion with Dr. Chris McCurdy.
0:02:53 Dr. Chris McCurdy, welcome.
0:02:54 Thank you.
0:02:55 It’s really a pleasure to be here.
0:03:00 I’m excited to have you here because you work on some incredibly interesting compounds,
0:03:02 several of which are very controversial,
0:03:08 and all of which are impacting health and society in a major way right now,
0:03:09 especially in the United States.
0:03:12 The most notable of those is kratom.
0:03:14 I’m guessing some people have heard of kratom.
0:03:16 I’m guessing some people perhaps have not.
0:03:21 I’m pretty certain everyone has seen a kratom product because they are everywhere.
0:03:24 But it’s often in the fine print.
0:03:33 So could you just tell us what kratom is, where it’s found in nature and in the United States,
0:03:39 and some of its properties that people take it in order to achieve certain effects,
0:03:41 maybe some of its lesser-known properties.
0:03:42 So that’s a lot of questions.
0:03:46 So maybe just a general description of kratom, where it’s found, and what it does.
0:03:48 Let’s just start from the beginning and make it easy.
0:03:53 It’s a tree that’s called Mitragana speciosa by its botanical name.
0:03:58 It’s called kratom in Southeast Asia, which is where it’s native to.
0:04:04 It’s actually native to where Peninsular Malaysia and Thailand connect.
0:04:06 So at the border of those two countries,
0:04:10 it’s thought to be ground zero for where this tree species came from.
0:04:14 And in that region, it’s very rural.
0:04:17 It’s lots of farmers and lots of outdoor laborers.
0:04:23 And those outdoor laborers chew the leaves in Thailand, or they make a tea,
0:04:29 more technically what we call a decoction, because they boil the leaves for hours.
0:04:33 But they’ll harvest fresh leaves and boil those leaves and then drink that,
0:04:38 just like we would drink a coffee drink in the morning to give them energy,
0:04:43 to give them sort of sustainability throughout the day to tolerate that heat,
0:04:45 humidity, and very harsh tropical environment.
0:04:50 And it gives them the stamina to make it through the day.
0:04:55 And that’s really what the traditional use has always been,
0:04:58 more or less for energy and to get through that day.
0:05:02 But it also has been used to treat pain.
0:05:08 It’s been used to treat, of all things, erectile dysfunction.
0:05:11 It’s been said to be nature’s sort of Viagra.
0:05:16 It’s used for mood elevation primarily.
0:05:22 And so these individuals will utilize it, like I said, throughout the day.
0:05:28 It’s a Muslim population in that area, so there’s no alcohol really and no consumption of alcohol.
0:05:32 And this is sort of a socially lubricating product.
0:05:36 And so in the evenings, on Friday, Saturday evenings,
0:05:44 the men would generally gather and then increase their consumption of the tea just socially.
0:05:48 And they could get them into a more sedative-like effect.
0:05:59 And so there’s this always this sort of paradoxical description of Kratom or, as we say in the United States, Kratom,
0:06:07 where you get this stimulant effect at lower doses or smaller amounts.
0:06:13 And you get this more euphoric or sedative-like, opioid-like effect, if you will, at higher doses.
0:06:16 And so they tend to use that traditionally.
0:06:25 So they’ll take the benefits of it, just like we would use coffee, I think, to sort of get us moving in the mornings.
0:06:27 That’s what they sort of use in those regions.
0:06:33 And they move into, you know, on the weekend evenings, they’ll use it as more of a social beverage.
0:06:36 And so that’s where that’s been.
0:06:46 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
0:06:48 so that they wouldn’t go into withdrawals.
0:06:51 And so essentially they’re already using it.
0:06:56 They would increase the consumption when they ran out of heroin or opium.
0:06:59 And that would stave off withdrawals for them.
0:07:04 And that became really interesting to me as an opioid researcher, a pain researcher.
0:07:14 Could this be something that has potential and obviously would have potential in helping with the opioid crisis that we’re in?
0:07:18 And that’s kind of what drove us into starting to look at this.
0:07:22 I’d like to take a quick break and acknowledge one of our sponsors, David.
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0:07:56 In fact, the toughest challenge is knowing which ones to eat on which days and how many times per day.
0:07:59 I limit myself to two per day, but I absolutely love them.
0:08:03 With David, I’m able to get 28 grams of protein in the calories of a snack,
0:08:08 which makes it easy to hit my protein goals of one gram of protein per pound of body weight per day.
0:08:12 And it allows me to do so without ingesting too many calories.
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0:08:29 If you’d like to try David, you can go to davidprotein.com slash Huberman.
0:08:33 Again, that’s davidprotein.com slash Huberman.
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0:10:11 When we see a Kratom product in the United States,
0:10:13 and I realize there are a variety of those,
0:10:16 but let’s just take, for example,
0:10:20 I’m aware of a product that’s very popular nowadays.
0:10:22 It’s a small blue bottle.
0:10:27 It includes kava and Kratom as its primary ingredients.
0:10:30 I have zero financial relationship to this company.
0:10:32 I actually had the opportunity to be an early investor.
0:10:33 I turned it down.
0:10:39 When somebody takes a bottle of that,
0:10:40 when they drink a bottle of that,
0:10:45 how concentrated and how much Kratom are they getting
0:10:50 compared to, say, the typical adult user in Malaysia
0:10:54 who drinks, I don’t know, a mug of this concoction?
0:10:57 Are they comparable?
0:11:00 Are they even the same compound?
0:11:02 Can we think about them the same way?
0:11:05 Because this is very much, in my mind,
0:11:09 like comparing smoked cannabis.
0:11:13 Let’s just say there is no typical variety,
0:11:18 but compared to a highly concentrated THC tincture, for instance.
0:11:20 I mean, the same chemical structure,
0:11:22 but at some point the pharmacokinetics changes,
0:11:24 and you’re basically looking at different brain circuits,
0:11:26 different bodily organs engaged,
0:11:28 is like kind of different experience altogether.
0:11:28 Correct.
0:11:32 And I think it’s an important distinction to make at the outset of this
0:11:33 is that, you know,
0:11:39 what I described as the traditional use is freshly picked leaves that day.
0:11:41 They’re either chewing them directly when they pull it off the tree
0:11:44 or they’re brewing this decoction right away.
0:11:48 In the United States and in the Western world,
0:11:50 it’s a very different product from day one
0:11:55 because it’s a dried leaf material that’s been exposed to the air,
0:11:58 the sun, whatever environmental factors are there,
0:12:02 plus shipping it all the way across the world from Indonesia,
0:12:05 which is the primary country where most of this is grown.
0:12:14 The last I heard a year ago was there’s about 250,000 kratom farmers in Indonesia
0:12:20 that are producing and exporting raw materials around the globe,
0:12:22 but primarily to the United States.
0:12:25 So that leaf material comes in,
0:12:30 and then leaf material has been ground and put into capsules,
0:12:33 put into various products,
0:12:37 even just powdered product where people will use tablespoons of powder
0:12:39 and, you know,
0:12:44 a couple grams of powder in their warm water or however they’d like to do.
0:12:52 So it’s an interesting product because that’s as close to the traditional use
0:12:55 that you can get in the Western world, right?
0:12:57 Because you’re still using leaf,
0:12:59 you’re ingesting it,
0:13:01 or you’re making a tea from it.
0:13:03 Water is the worst,
0:13:09 least efficient extractor of chemicals out of a plant material.
0:13:12 And even if we don’t make a tea out of it,
0:13:14 if we just take the leaf material internally,
0:13:17 our body has to work incredibly hard
0:13:21 to pull those active ingredients out of the plant material.
0:13:27 So it’s an active process for us as humans or as animals,
0:13:31 if we want to talk about the animal research too and where we’ve learned most all of this from,
0:13:35 that our body has to work hard to get that into our system.
0:13:40 Now, you take that leaf material and then you do something like you mentioned,
0:13:47 put it into a tonic or you put it into a concentrate form or an extract.
0:13:56 And now the compounds have been already pulled out of the leaf material by the solvent or the liquid that’s being utilized,
0:14:04 whether it’s ethanol or it’s oil or some other type of vehicle.
0:14:06 I think in the product you mentioned is pineapple juice,
0:14:12 which again is not as efficient as something like oil or a solvent would be.
0:14:20 But you start to pull these compounds into that liquid instead of our body having to pull it out of the leaf.
0:14:22 It’s already out of the leaf.
0:14:29 Now we can ingest that and those compounds are absorbed much faster into our body, into our system.
0:14:39 And it totally changes the dynamics of what our body is exposed to from that sort of more traditional based product.
0:14:43 And this is also where we feel that things have become problematic.
0:14:52 And so if we go back to Paracelsus, you know, hundreds of years ago, talking about the poison is in the dose,
0:15:00 where we’ve seen somewhat non-problematic use, I would say.
0:15:06 The majority of non-problematic use is with that leaf material, more of that closer to traditional use.
0:15:12 But as you start to make these concentrates and extracts and now isolates,
0:15:17 which are even a whole other discussion because they’re no longer even Kratom products,
0:15:23 you start to move ever so far across that spectrum.
0:15:34 And I like to equate it to the alcohol world where we talk about seltzers or light beers being more comparable in an alcohol beverage
0:15:45 to that traditional use of Kratom, whereas we get to things like almost pure alcohol, ever clear, 190 proof, 95% alcohol.
0:15:48 Now you’re talking about these isolate products.
0:15:52 And we have products in the alcohol industry through that whole span.
0:15:54 But we’ve classified all of them.
0:15:57 We don’t call them alcohol in general.
0:15:59 We’ll define them.
0:16:00 Beer, wine.
0:16:01 Beer, wine.
0:16:01 Cider.
0:16:02 Yeah.
0:16:08 And into spirits and then into very fortified beverages.
0:16:13 And so we don’t have that delineation in the Kratom space.
0:16:17 And so all Kratom products get dumped into a single bucket.
0:16:24 And so whether or not it’s a benign product or something that’s highly, highly concentrated, and I shouldn’t say benign,
0:16:33 but something that is much more close to that traditional use that you’re not going to have a risk of getting a great exposure
0:16:40 exposure when you take some of it versus a shot that might be 15 milliliters.
0:16:46 And it tells you on the bottle, it’s nine servings, but nobody reads that part and just downs the entire bottle.
0:16:49 Is that what we’re talking about when we talk about this little blue, little blue bottle?
0:16:58 No, the little blue bottle is more, actually is more similar in terms of what is dosed in there to a traditional exposure of a beverage.
0:16:58 One bottle.
0:17:00 One bottle.
0:17:00 One bottle.
0:17:10 I say one bottle and forgive me for interrupting because about a year and a half ago, I ran into a friend and his assistant.
0:17:17 She came running out and knowing what I do, she said, hey, do you know about this like blue bottle product?
0:17:19 And I said, yeah, I’ve seen it, not tried it.
0:17:21 And why?
0:17:22 What do you think?
0:17:27 And she said, well, I liked it because I drank one, but now I’m drinking six a day.
0:17:30 And I can’t seem to whittle it back.
0:17:33 Like when I went to three, I did not feel well.
0:17:37 Headaches, anxiety, not well.
0:17:38 It was basically how she described it.
0:17:45 And I said, well, sounds like either addictive or habit forming.
0:17:48 And I don’t know where she’s at with that, but this seems very common.
0:17:53 People start with one, not unlike nicotine pouches, start with three milligrams and they’re up to six milligrams.
0:17:57 And then pretty soon it’s a tin a day or a canister a day.
0:18:05 So one bottle of that, of Kratom Kava, that’s comparable to the plant use?
0:18:08 I think if I remember right, a bottle is two servings.
0:18:19 So we’ve tested almost every single product in the marketplace and we’ve analyzed it for the content of alkaloids to see what’s there and what they consider a serving.
0:18:25 But if we only look at a serving, they’re pretty much all equivalent.
0:18:29 Again, it’s what’s in that bottle, right?
0:18:34 Is it one serving, two servings, nine servings, 15 servings in a single bottle?
0:18:48 So most people aren’t going to look at it from the standpoint of, hey, I’ve got this bottle here, which is actually smaller than the blue bottle, but it’s 10 times more servings, right?
0:19:00 And so if you’re used to consuming that blue bottle all at once, which is two servings, I think, then if you pick up one of those bottles, that’s 15 servings and you can serve the whole thing at once.
0:19:13 You’re getting a much greater exposure immediately and it’s in a much easier vehicle for our body to welcome those compounds in, if you will.
0:19:24 So it becomes a very, very slippery slope, in my opinion, with these different products that are out there in the marketplace.
0:19:34 And so if someone is not paying attention to what the actual serving is supposed to be, then this is where problems become.
0:19:39 And the other thing I would add to that is that a lot of times – and I’ve seen this.
0:19:53 I’ve stopped in – of all places, I stopped at a Murphy USA gas station, Walmart’s gas station, and they had Kratom energy shots right next to the five-hour energy shots.
0:20:01 And so if you’re in a hurry and you weren’t even paying attention, you might accidentally grab something that you thought was a five-hour energy shot, right?
0:20:09 And suddenly – and I took – you normally take two of those and I do it right back, back and throw them right back.
0:20:23 And so if you get these – and generally what we worry about is kids getting these, right, and getting these and then taking a shot, a whole bottle, which may be multiple servings.
0:20:28 And they don’t feel anything right away and somebody told them you’re going to get high from this.
0:20:32 You can’t believe it, but you’ll get high from this thing you can buy in the gas station.
0:20:38 And then they don’t feel anything and then suddenly they have another one, right?
0:20:45 And then all of it gets absorbed and hits them harder almost all at once.
0:20:54 You can think of it like if you sat down and you drank a light beer and you drank that 12-ounce beer in a short period of time.
0:20:57 Just – you could really drink it fast.
0:21:02 You’re not going to get very much alcohol exposure because there’s only 3.5% in that 12 ounces.
0:21:13 But if you sit down and you do three shots of tequila in a row in that same time frame, your body is getting exposed to significantly more alcohol in that time frame.
0:21:16 And that’s what our concerns are around some of these products.
0:21:28 And so when you look at the specific serving, yeah, they dial it in to say, yep, this is what is comparable to a traditional full glass of tea.
0:21:32 But they’re very, very concentrated.
0:21:46 And now as I mentioned, you know, 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.
0:21:49 They’re actually semi-synthetically produced.
0:21:56 That means they’re chemically modified into other things that they’re calling in some cases kratom product.
0:22:04 Again, this is that trash can or they’re actually calling them kratom-derived products.
0:22:17 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.
0:22:23 And it’s interesting that those small bottles and frankly the packaging of most things is pretty small.
0:22:25 And I don’t think it’s just my age.
0:22:30 You need a compound microscope to read some of the print.
0:22:42 Like literally fine print has become so fine that I think it’s below the threshold of a, you know, a Air Force fighter pilot’s high-acuity vision.
0:22:42 2015.
0:22:46 So in all seriousness, you need to look at the serving size and know how many servings are in there.
0:22:47 Absolutely.
0:22:48 So check serving size.
0:22:57 And the other thing is to look for kratom-derived or kratom-extracted versus actual kratom plant product.
0:23:03 Because while we’re not recommending usage here, there are a number of people using these products.
0:23:05 There are a number of people that are going to use these products.
0:23:07 We just have to be honest about that.
0:23:14 And I think it’s very important to understand how to navigate this space because as you’ve pointed out, it’s not one thing.
0:23:15 It’s just not.
0:23:19 And maybe just for the moment, let’s step back in light of that.
0:23:25 And let me just ask, you said earlier that when people use the plant at lower dosages, it’s a bit of a stimulant.
0:23:43 It might even have some aphrodisiac qualities to it, which suggests to me, I’m not a medicinal chemist as you are, but suggests that there might be some dopaminergic, maybe some cholinergic, maybe some vasodilation activity given the aphrodisiac part, et cetera.
0:23:48 Okay, but then at higher doses, it starts to become more of a sedative.
0:24:09 When people take kratom derivatives or these more manufactured or processed kratom products in the United States, the small blue bottle, let’s say one or two servings, or the ones that are in the energy shot, let’s say they take one or two servings, which would be basically a quarter of a sip of one of those little thimble-sized things.
0:24:21 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 U.S. are really going for that kind of sedative numbing out effect?
0:24:23 Because those are two very different things.
0:24:23 Very, very different.
0:24:27 And I don’t think we have good, strong, definitive data.
0:24:41 So I will say that with my colleague, Dr. Kirsten Smith at Johns Hopkins and others on our team, we’ve done pretty extensive surveying of users.
0:24:46 These users, you know, volunteer themselves into the studies.
0:24:56 So I think we have to look at that from a standpoint of, you know, we’re not just putting out random people on the street and asking them questions.
0:24:59 These are people that choose to answer.
0:25:16 But what we found in the largest study that we’ve done to date is most users are using it in a very responsible and directed way, where they’re not using it to get this high or euphoria or sedative feel.
0:25:17 Really?
0:25:18 Really.
0:25:18 Okay.
0:25:20 Could you repeat that?
0:25:22 You said it very clearly, but I think the world needs to hear this.
0:25:30 The estimated number of users right now, we don’t really have a good thumb on this, right?
0:25:35 So the most recent literature report was around 2 million, 2.5 million users.
0:25:44 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.
0:25:50 And if you look at the availability of product, it’s got to be closer to those numbers.
0:25:51 On a daily basis?
0:25:52 On a daily basis.
0:25:53 On a daily basis.
0:25:59 So this isn’t, you know, 2 to 20 million people per year ingest a Kratom product.
0:26:01 This is 20 million people a day.
0:26:03 This is what is the estimate right now.
0:26:04 Wow.
0:26:14 Based on the amount of material that’s been imported or, if you will, exported to the U.S. and then manufactured.
0:26:22 And so in 2019, when we actually had solid data, it is 1,950 metric tons per month coming in.
0:26:32 Do you think there are many people in the U.S. that are ingesting Kratom products like them for the effect it produces and are not aware that they’re actually taking Kratom?
0:26:34 It’s a very interesting question.
0:26:41 So I work with a whole plethora of different people, right?
0:26:49 So from emergency room physicians to medical toxicologists to basic scientists like myself and everything in between.
0:26:53 And if people have heard of Kratom, they know what it is.
0:27:03 And if they’ve heard of it and they are experienced in trying things, they’ve probably tried it.
0:27:14 And then there’s a whole group of people that have no idea what it is, never heard of it, just completely something that they drive by.
0:27:14 They see it.
0:27:20 Like you said, you see it everywhere, but you don’t have any idea what it is.
0:27:27 So I think most people that are ingesting it or utilizing it know that they’re utilizing it.
0:27:29 I think they know they’re specifically going after it.
0:27:35 But again, what I’ll say is what we did, it was an ecological momentary assessment.
0:27:48 And so this is an EMA study where you’re actually monitoring people with smartphone apps and every single dose they’re taking, they’re reporting what they’re feeling, they’re reporting why they’re taking it, when they’re taking it, right?
0:27:57 And the majority of those people that were involved in those studies were using it in an appropriate sort of not-to-get-high way.
0:27:58 What are they using it for?
0:28:02 Mostly for energy, mood elevation, and pain treatment.
0:28:09 So people like to use it as an alternative, particularly to opioids.
0:28:15 So what we were surprised at, we thought we would see a lot of people using it to get off of opioids, right?
0:28:20 Because that’s sort of the general theme that it’s had.
0:28:22 Indeed, people are doing that.
0:28:32 And I get emails almost weekly of people writing to me saying that this got them off the couch, you know, they’re getting their families back, they’re getting their lives back,
0:28:36 because this really helped give them that energy that they didn’t have when they had opioids.
0:28:37 Really?
0:28:39 Okay, we’ll definitely double click on that in a few minutes.
0:28:40 Yeah.
0:28:40 Yeah.
0:28:47 And so that’s an interesting group of people, but I’m not sure that that’s the largest group that are out there.
0:28:49 It’s really these mood elevations.
0:28:52 You touched on it a little bit, too, with the exercise.
0:29:03 People are using this as a pre-workout stimulant to give you more endurance, very similar to that traditional use, right?
0:29:08 These people in the outdoor hot environment being able to work better, harder, faster.
0:29:20 And people are using it as a post-workout pain treatment, right, to help kind of soothe them through all that lactic acid buildup and that pain feeling.
0:29:27 So there’s a variety of groups or reported groups of users.
0:29:38 But the biggest one is really that mood elevation, that sort of kind of energy boost, just overall general good feeling, not a high feeling.
0:29:44 And we specifically ask for those questions, you know, are you using this to get high?
0:29:49 And yet there is a population of people that are purely out there to say, this is my thing.
0:29:51 This is what I use it for.
0:29:52 I get high.
0:29:59 I know people that on Friday nights, they’re like, this is my Friday night jam and this is what I do.
0:30:04 And it makes me feel, you know, euphoric and relaxed and that’s it.
0:30:24 And so I think there’s just various user populations and 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?
0:30:27 More than likely, that would be the assumption.
0:30:37 And are the people that are using it more on a daily basis, are they doing it with more of the powdered leaf material and those types of products?
0:30:39 And that’s generally what we’ve seen.
0:30:44 And interestingly enough, I mean, we looked at the time of day.
0:30:46 When are people using these products, right?
0:30:49 They wake up and within the first half hour, they have it.
0:30:51 Would you say they have it or they need it?
0:30:52 It could be they need it.
0:30:53 It does.
0:30:55 It absolutely causes a physical dependence.
0:30:58 You said it absolutely causes a physical dependence.
0:31:05 Do you mean it absolutely causes a physical dependence at every dose and every desired effect?
0:31:07 I would say not.
0:31:11 So if you take it one time, you’re not going to be physically dependent on it.
0:31:19 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.
0:31:27 And sadly, we don’t even have chronic studies in animals, although animals aren’t going to be able to tell us, I need this, right?
0:31:34 So the physical dependence feeling that most people will report is very similar to that.
0:31:51 And 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.
0:32:02 They’re drinking kratom or kratom, and they have a headache or they feel miserable if they don’t get that into them.
0:32:08 Very similar to what we would get with a caffeine withdrawal or physical dependence on caffeine.
0:32:18 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.
0:32:25 But I can tell you that anecdotally, people have said they get more restless leg syndrome.
0:32:40 They get more severe type physical dependence signs, which restless leg is much more related to an opioid withdrawal type issue than it is to a coffee withdrawal issue.
0:32:53 So there’s – not only is there a spectrum of physical dependence symptoms, you know, you have this spectrum of products and which ones are causing which we don’t have a handle on yet.
0:32:59 So I’m gathering at this point that there are basically three paths of kratom usage in the United States.
0:33:11 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.
0:33:11 Right.
0:33:15 It sounds like they’re using kratom products pretty regularly to achieve that.
0:33:26 And if they don’t use their kratom product, they feel a little bit more lethargic, maybe a little bit of minor headache, not as energized and clear as they would otherwise.
0:33:28 Sounds a lot like caffeine to me.
0:33:28 Right.
0:33:41 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.
0:33:46 The effect of caffeine doesn’t shift from a stimulant to a more opioid-like effect the more you take.
0:33:50 It tends to just make you less sensitive to caffeine over time.
0:33:55 It’s more of an inverted U-shaped function as opposed to two different curves, right?
0:33:55 Right.
0:34:04 But you will become – you know, you’ll get jittery with caffeine and you get – it actually causes anxiety when you get into higher amounts of it.
0:34:06 And so, yeah, I mean, point well taken.
0:34:11 It’s just a matter of where you are in that sort of U-shaped curve, right?
0:34:19 You got to get over that sort of jittery anxiety point before it really starts to – it doesn’t bother you, right?
0:34:33 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, right?
0:34:35 And I go to bed, no problem.
0:34:35 Yeah.
0:34:37 I can’t do that today.
0:34:41 Recently on a podcast I was a guest on, I shared that I drink – and I do not suggest people do this –
0:34:49 But I legitimately drink somewhere between 600 and probably 900 milligrams of caffeine per day.
0:34:49 Wow.
0:34:59 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.
0:35:03 I’d limit it to the early part of the day or up to about 2 p.m., but no problem.
0:35:17 But most people who get their commercial vendor coffee, let’s say 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.
0:35:18 Okay.
0:35:21 So we got this first case caffeine-like usage.
0:35:21 Right, right, right.
0:35:22 Let’s just rub in that.
0:35:36 Second path of Kratom usage seems to be people who use fairly high doses or concentrates to achieve an opioid-like effect, a mild sedative effect, euphoric effect.
0:35:42 This sounds a lot like opioid use or higher dosage alcohol use, for instance.
0:35:42 Right.
0:35:51 And then we’ve got this third category that you mentioned that are using Kratom to get off opiates or to stay away from opiates.
0:35:51 Yeah.
0:36:02 And for whom you told us Kratom is a real benefit for them because otherwise they would be strongly addicted to opiates.
0:36:14 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 Kratom.
0:36:21 I just put out a then tweet, now post, which alluded to the darker sides of Kratom.
0:36:21 Right.
0:36:29 And I got attacked, actually, by this community that said, hey, were it not for Kratom, we’d see a lot more opioid dependence.
0:36:31 We’d see a lot more fatalities.
0:36:37 And actually, I learned about you in large part through the dialogue that emerged from that response.
0:36:51 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.
0:36:54 So we can’t just say Kratom bad, Kratom good.
0:36:55 Right.
0:36:58 We really have to explore how it’s delivered and what people are using it for.
0:37:03 And again, we can’t just say Kratom because it’s – that’s just like just saying alcohol, right?
0:37:10 So there’s a variety of different forms of product that are out there and that are being utilized.
0:37:15 And it could be that those are being utilized in very different ways.
0:37:24 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?
0:37:30 So I think two things that will really kind of probably blow this open a little bit more.
0:37:40 One is, is that Kratom itself contains multiple compounds, multiple chemical compounds.
0:37:43 So it’s not just one thing.
0:37:44 It’s an alkaloid.
0:37:48 It has at least 20 to 40 alkaloids in it.
0:37:53 Can you explain to people what an alkaloid is and some other examples of alkaloids they might be familiar with?
0:37:59 Sure. So alkaloid is a organic molecule that has at least a nitrogen in its structure.
0:38:03 So it has to be nitrogen, carbon, hydrogen.
0:38:05 It can or cannot have oxygen.
0:38:11 But those are essentially the template for what we would define as an alkaloid.
0:38:14 And then there’s various classes of alkaloids.
0:38:20 Many things that people are familiar with, dopamine, serotonin, these are alkaloids.
0:38:22 But we could go further.
0:38:24 We’ve just talked about caffeine.
0:38:25 Caffeine is an alkaloid.
0:38:27 Cocaine is an alkaloid.
0:38:28 Morphine is an alkaloid.
0:38:37 So all of these molecules contain a nitrogen that is core to part of their activity.
0:38:42 What we believe is essential for them to interact with the proteins in the body.
0:38:44 Can I ask a question about nitrogen and protein interactions?
0:38:44 Sure.
0:38:47 Given this is a science slash health podcast.
0:38:58 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.
0:39:11 But the fact that you have this N, this nitrogen, and you have cells that have proteins, for the non-chemist, could you explain how the nitrogen allows that molecule to do something?
0:39:13 Does it bind with more affinity?
0:39:16 Does it change the gene expression?
0:39:21 What is it about having a nitrogen that really changes the properties of a molecule?
0:39:24 Yeah, so there’s a couple of important pieces here.
0:39:29 Nitrogen is an element that can act as a base.
0:39:33 So it can, in a technical term, can accept a proton.
0:39:37 So it can also develop a charge.
0:39:47 Charges are important because if you think about magnets, right, we have a positive charge magnet face and a negative charge magnet face.
0:39:49 And those two things will attract each other.
0:39:55 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.
0:40:11 That’s a very similar thing that happens between nitrogen that can gain a positive charge in our body and, say, a carboxylic acid or a negative charge that will be present on a protein.
0:40:18 And so that nitrogen being charged, I always call it, when I teach my pharmacy students, it’s almost like a tractor beam.
0:40:26 That molecule is floating around and it’s trying to find that negative charge to interact with.
0:40:39 And when it finds the right one in the right space in 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.
0:40:47 It’s going to be a positive charge.
0:40:55 It’s going to be a positive one in the right fit, but it’s going to be a positive charge.
0:41:06 And so the proteins can have positive charges from the nitrogens and they can have negative charges from the acids.
0:41:13 And what we generally see with plant materials is they have alkaloids within those plants.
0:41:20 And those alkaloids have helped define, really, our chemical neurotransmitter systems.
0:41:22 Nicotine, perfect example.
0:41:23 It’s an alkaloid.
0:41:30 We have an entire acetylcholinergic nervous system, which is the exclusive nervous system in insects.
0:41:36 But nicotine binds to nicotinic acetylcholinergic receptors.
0:41:39 That whole system was defined by nicotine.
0:41:39 Right.
0:41:58 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 acetylcholine receptors.
0:42:05 They didn’t evolve because we thought that people would take nicotine.
0:42:16 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.
0:42:22 So this reflects the fact that humans have been nibbling on plants and seeing what happens for a long time.
0:42:29 There’s an explicative version of this, which is F around and find out kind of experimentation.
0:42:33 But this is really what old world primates, including humans, have been doing for a long time.
0:42:45 And then just seeing whether or not your buddy that ate the plant died, got energized, mated, fought, slept.
0:42:46 Right.
0:42:48 And I mean, this is kind of still what we’re doing.
0:42:50 It’s just that we do this now with lab coats on.
0:42:51 Right.
0:42:52 In many ways.
0:42:54 And you’re 100% right, right?
0:42:55 There’s the old joke.
0:42:59 There’s two types of mushroom hunters, the good ones and dead ones, right?
0:43:01 Good joke, because it’s going to keep a lot of people safe.
0:43:01 Yeah.
0:43:02 Yeah.
0:43:04 And I mean, that’s the point.
0:43:23 And in fact, I’ve done a lot of work with ethnobotanists and ethnopharmacologists and somewhat am one myself, being in that work we’ve been doing and actually going into the native places to learn more about it, which is what ethnobotanists or ethnopharmacologists would be doing.
0:43:33 And, you know, we have a lot to learn from the things that have existed on this earth for a long time.
0:43:35 Many of those are animals.
0:43:43 Animals were probably the first pharmacists and the first physicians because they learned which plants to utilize when they were ill or sick.
0:43:47 And they use which plants to avoid to stay alive.
0:43:57 So 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?
0:44:06 And then this is sort of how modern medicine started to develop was all by observational, all by anecdotal.
0:44:09 Hey, that looks interesting, right?
0:44:11 This is happening.
0:44:13 And you still do this now in your laboratory.
0:44:14 Yeah.
0:44:16 We study animals and we advance to human clinical trials.
0:44:16 That’s right.
0:44:24 Animals have a certain advantage in this regard because they don’t subject themselves to the placebo effect as far as we know.
0:44:24 Correct.
0:44:36 And in addition to that, animals, most animals, including insects, but many non-human mammals, have a much more powerful sense of smell than we do.
0:44:50 And 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.
0:44:59 They literally have an aroma that chemists in the lab know, or you could smell if something has a steroid-like chemical structure by virtue of the way it smells.
0:45:10 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 sensitively.
0:45:14 And you take it a little step further, it’s also the taste part that’s involved.
0:45:28 I 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.
0:45:37 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 this.
0:45:37 These guys did it.
0:45:41 He’s dead now by way of age, but he was a member of the National Academy and everything.
0:45:50 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.
0:45:51 Friends of mine will know who this is.
0:46:03 And he opened up the jar that it was shipped in, it was in liquid, and he took off his glove, which itself is crazy, dipped two fingers in it, and he goes, 30% sucrose.
0:46:06 But this could have prions in it.
0:46:08 Now it was fixed, also being a paraformaldehyde.
0:46:09 Yeah, exactly.
0:46:11 No regard whatsoever.
0:46:13 Re-screwed it, put it on the shelf, and then people got to work.
0:46:20 And it was obviously a demonstration, this was kind of bravado in laboratories too, self-experimentation, terrible habits.
0:46:24 But it was not uncommon.
0:46:26 I mean, this is the way chemistry was done.
0:46:36 One of my great mentors, and I’ll spare him sharing his name, but his master’s thesis was making analogs of methylphenidate, which is Ritalin.
0:46:41 And so he – Ritalin is a methyl ester.
0:46:46 So it’s a carboxylic acid that has one carbon attached to where the acid part is.
0:46:48 So this makes what we call an ester.
0:47:03 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.
0:47:15 And so his whole project was making from the methyl, now we take two carbons, which is ethyl, and we take three carbons, which is propyl, and we branch those carbons to make isopropyl or whatnot.
0:47:26 And he would try each one of the compounds that he made himself to see if pharmacokinetically and pharmacodynamically, it’s improved on methylphenidate.
0:47:29 Well, guess what’s still on the market today, methylphenidate.
0:47:32 So that ought to tell you the result of his work.
0:47:42 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.
0:47:45 Good. You can blow out your olfactory epithelium.
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0:51:23 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,
0:51:32 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.
0:51:45 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 kratom at this point in time,
0:51:49 which is historically or what you call the traditional use.
0:51:51 People would harvest the plant.
0:51:57 They have knowledge of kind of the coloration of the plant, the texture, the feel, a lot of unconscious knowledge too.
0:51:59 Maybe it’s passed down through generations.
0:52:02 Maybe they just learn it, you know, in a couple of years.
0:52:05 And next thing you know, they’re brewing it, they’re drinking it.
0:52:06 As they’re brewing it, they’re smelling it.
0:52:12 There are many more avenues of information coming in about the concentration.
0:52:17 You’re not just going from product purchase, ingestion, effect.
0:52:17 Right.
0:52:29 And I think that perhaps this explains a lot of how we end up with the highly processed food industry where, you know, much of what we’re talking about today is paralleled.
0:52:32 So, you know, sugar is, we have an innate desire for sugar.
0:52:34 Who doesn’t like sugar?
0:52:36 We have an innate desire for protein and amino acids.
0:52:44 But the highly processed food industry has figured out how to put all this into a package where there’s two servings worth, right?
0:52:49 So you’re ingesting far more calories, far more preservatives, et cetera, in trying to get some effect.
0:52:51 But what happens is your threshold changes.
0:52:51 Right.
0:52:54 And the next thing you know, you’re going to the highly concentrated version.
0:53:02 In other words, we don’t go through this process of stepping through and getting familiar with a molecule.
0:53:06 And I think that could explain why people, you know, you’re prescribed an opioid.
0:53:08 Next thing you know, you need that opioid.
0:53:08 Right.
0:53:20 I mean, 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.
0:53:20 Right.
0:53:23 And often the person they’re harming the most is themselves.
0:53:36 I think what you hit on is a really deep philosophical conversation on a whole other level because I just had this conversation with a colleague.
0:53:42 We’ve lost totally in our culture where it is that medicines have come from.
0:54:05 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 drugstores and our hospitals.
0:54:06 Aspirin.
0:54:08 Aspirin is one perfect example.
0:54:09 Salicylic acid.
0:54:10 Salicylic acid.
0:54:14 It comes from salicylic acid, which is in the bark of the willow tree.
0:54:18 And people used to chew on the bark of willow tree and that salicylic acid is the active form.
0:54:22 You know, you get salicylic acid, makes it more stable.
0:54:23 And there’s a long story there.
0:54:36 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?
0:54:39 That watching the animals do things and learning from the animals.
0:54:50 Metformin, berberine, a tree bark that lowers blood glucose and works for all the world as well as metformin.
0:54:54 Well, look at the biggest selling weight loss drugs right now, the GLP-1s.
0:54:56 You know that story.
0:55:01 They actually came from the saliva of the Gila monster.
0:55:05 So this is a lizard that eats only a few times a year.
0:55:14 But in its saliva, it has GLP-1 peptides.
0:55:20 And this was learned to help control glucose and help do all these things.
0:55:21 And that was modified.
0:55:43 And now we have Wigovian, whatever, Ozempic out there as blockbuster drugs that are really changing, you know, the shape of our society for hopefully for a good benefit and getting people away from some of these sugary things you mentioned earlier too.
0:55:49 But, yeah, there’s just this history, rich history of how drugs have gotten to where they are.
0:55:59 And most of us, including myself, 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.
0:56:02 We know it’s going to give us this effect and boom.
0:56:05 And so you’re 100 percent right.
0:56:11 And like I say, it’s a very long, deep philosophical discussion to get this whole thing circular.
0:56:18 But we’ve lost that whole understanding of where things are coming from.
0:56:23 And that’s one of the things that I’ve always loved in my training originally as a pharmacist.
0:56:30 I’ve always felt like for every disease that presents itself in this planet, there’s got to be a solution.
0:56:32 There’s got to be this balance in nature.
0:56:37 And natural products has always attracted me because of that.
0:56:53 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 out in nature to through experimentation.
0:57:06 And observation to medicine and then how those same medicines are extracted and concentrated and, in some cases, diabolically hidden in other things like food.
0:57:12 Because I don’t think sugar is poison in the same way that heroin is poison.
0:57:17 But sugar clearly can be destructive in a way that makes it poisonous.
0:57:22 And the way it’s used and packaged and marketed, et cetera, and kid cereals and things like that, I think is absolutely clear.
0:57:34 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.
0:57:36 And it is that the dose makes the poison.
0:57:39 It’s also whether or not people are aware of what they’re doing.
0:57:49 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.
0:58:01 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.
0:58:22 I think that’s an exciting thing to hear from a medicinal chemist who runs a laboratory, which by the way, folks, looking over Chris McCurdy’s CV, they publish at an absolutely staggering rate and all high-quality papers.
0:58:24 I mean there’s never been a single retracted paper.
0:58:33 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.
0:58:36 So I just want to point that out.
0:58:38 It’s clear that you’re very passionate about this.
0:58:49 I have heard the concept of slow food, this idea that instead of just consuming prepackaged food and we’re going to slow down, we’re going to cook our food, we’re going to get in touch with the food,
0:58:52 and that will give us a better understanding and health relationship with the food.
0:58:55 I almost feel like we need a slow medicine movement.
0:58:56 Yeah, almost.
0:58:57 Might as well.
0:58:58 I like that idea.
0:59:07 As somebody who has been using supplements since I was in my teens, and I know it’s a less well-regulated industry,
0:59:18 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 Fadojia.
0:59:24 I continue to use these and my blood work says it’s fine and I enjoy them and it works well for me.
0:59:40 But if those were put into a pharmacologic agent at very high concentration, I can bet that it’s an entirely different molecule and experience and might cause shutdown of the – of certain hormone pathways and things like that.
0:59:56 There seems to be something kind of unregulated and yet more nuanced and stayed about the use of medicinals in their more natural form.
0:59:58 And this is kind of the yin-yan of it.
1:00:05 It’s like, yeah, you can’t get an exact milligram dosage and concentration, but you’re also not playing at very high concentrations.
1:00:06 Right, right.
1:00:16 I look at it like a – natural products, they have evolved in Mother Nature’s kitchen for millennials.
1:00:20 I mean they’ve been there for thousands of years.
1:00:29 It only took humans coming along to figure out how to manipulate all that, right, and mess it up.
1:00:33 So Mother Nature’s kind of got it right in many cases.
1:00:42 A couple of examples just to bring this back to more of a discussion around alkaloids.
1:00:50 Opium poppy has long been used – and yes, it’s problematic, addictive and all these things.
1:01:01 But it’s nowhere as bad as once – morphine, which by the way, was the very first alkaloid ever isolated, characterized, identified.
1:01:10 Morphine, when that happened, the poppy became sort of not that important anymore because we found the magic piece.
1:01:16 The same thing happened with the second alkaloid ever isolated, cocaine.
1:01:26 Cocaine comes from coca leaf, which has been used for thousands of years in South America and in indigenous tribes and cultures there.
1:01:27 It’s still used today.
1:01:30 It’s one of the only places on the face of the earth that it’s legal.
1:01:40 When cocaine was isolated and discovered, the rest of the leaf was criminalized and thrown out like the baby’s bathwater.
1:01:53 Yet, there seems to be great medical potential with coca leaf and this is something that my lab is getting ready to embark on next as kind of like our new challenge.
1:01:59 We still have a lot of work to do with Kratom and understanding that.
1:02:07 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.
1:02:15 But we want to come back to some of that initial excitement project type work again and that’s why we’re embarking on that.
1:02:34 The 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.
1:02:43 It’s utilized by tribes in the high mountains, high elevations in South America where they don’t have much dairy in their diet.
1:02:49 There’s tons of calcium in this, in the coca leaf.
1:02:50 There’s tons of vitamins.
1:02:57 It’s so nutrient rich and just a remarkable plant in and of itself.
1:03:09 But, again, we’ve forgotten about this because we found this, you know, smoking bullet cocaine and we don’t want people to mess with that plant because there’s a chance they’re going to get that out of it.
1:03:27 And this has been 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.
1:03:32 And they’re manipulating these into very potent opioids.
1:03:35 They’re chemically changing these molecules.
1:03:42 And these are now products that are out in the market that are available, easily purchasable.
1:03:50 And, unfortunately, in the same places you can buy the more, you know, benign leaf, if you will.
1:03:51 And it’s not benign.
1:03:58 And please don’t think that I’m saying Kratom is benign at all because the leaf material can be dangerous.
1:04:03 And we know that people have problems with even just the leaf material over time.
1:04:06 And so we don’t understand where those things come from.
1:04:11 We don’t have a good scientific history of how that evolves.
1:04:29 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, Kratom.
1:04:36 And now we’re whittling down and figuring out actually it’s a metabolite in our bodies.
1:04:43 It’s a metabolite controversially that may or may not exist in the plant.
1:04:51 We’ve never found with all the work that we’ve done with expert biosynthetic plant folks.
1:04:57 We’ve never found enzymes that will produce this compound, 7-hydroxymitrogynin.
1:05:05 And that’s a metabolite of mitrogynin, which mitrogynin is the major alkaloid within the plant, Kratom.
1:05:10 And as I mentioned, there’s more than 20 alkaloids within this plant.
1:05:19 And I really want to come back to this discussion about the differences in some of these alkaloids because they’re very, very different.
1:05:23 I look at this plant as almost a pharmaceutical shotgun.
1:05:29 It’s got different alkaloids that are targeting different systems in our body.
1:05:32 And this is what makes Kratom different.
1:05:38 You referred to it in the past as it’s opioid, but it’s different opioid, right?
1:05:43 It’s different because it’s interacting with multiple other systems in our brains.
1:05:47 And so we need to come back and revisit that.
1:06:03 But before we do that, what we know is that this 7-hydroxymitrogynin, this metabolite that our bodies produce naturally from the major alkaloid is being chemically produced now and sold in commerce.
1:06:10 And these are now Kratom-derived products or isolates or synthetically derived products.
1:06:16 We know that that molecule is pure opioid in its activity.
1:06:20 It only interacts with opioid receptors.
1:06:24 You said these are Kratom-derived or Kratom isolates.
1:06:43 If they’re going to experiment with or use Kratom products, they need to pay attention to serving size and also pay attention to whether or not the product contains Kratom-derived products within it or Kratom isolates because those more closely mimic powerful opioids.
1:06:44 It’s a pure drug, right?
1:06:44 A pure drug.
1:06:52 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.
1:06:53 Correct.
1:06:55 Even if they’re drinking it, it’s because we just call it one thing.
1:06:56 I agree.
1:07:05 We’ve published commentaries on this because we feel it’s just really important to get this message out.
1:07:17 And it’s important to get this message out to the medical community because the medical community that are dealing with patients, humans, firsthand, they show up in an emergency department.
1:07:22 They don’t know to ask, did you take leaf?
1:07:25 Did you take extract?
1:07:26 Did you take a concentrate?
1:07:29 What product is it that you actually take?
1:07:40 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 Kratom.
1:07:44 They’re not going to specify what it was.
1:07:55 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?
1:08:13 Well, fortunately, we have the ear on this podcast from some of the folks like Jay Bhattacharya, NIH, and others who are thinking seriously about revising laws around packaging of food and drugs.
1:08:17 I don’t have any direct relationship to them, but we have their ear.
1:08:31 So 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.
1:08:51 In the same way that 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 cannabis science, people who smoke cannabis are pretty good at regulating the dose based on number and duration of inhales.
1:09:04 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.
1:09:05 There’s this delay.
1:09:15 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.
1:09:21 And I know it might be hard to answer these with a yes or no, so feel free to say maybe or it depends.
1:09:27 Kids 18 or younger, avoid, don’t avoid, or it depends when it comes to Kratom.
1:09:34 And here we’re talking about leaf Kratom or Kratom products, and we’re talking about kids in the U.S. and in Europe.
1:09:39 We’re talking about outside of Malaysia where they have a more innate historical understanding of the plant.
1:09:48 I’ll preface it by saying I am not familiar with anybody young using this in Southeast Asia in a traditional sense.
1:09:49 Well, that’s good to know.
1:09:56 So it’s mostly used by people that are laborers that are out doing this, you know, more adult, if you will.
1:10:09 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.
1:10:11 Do you agree with that, Charlie?
1:10:16 I agree with that from the standpoint that the brain is still developing until we’re 24, 25.
1:10:31 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.
1:10:38 So we have no idea what the impact is of Kratom on developing brain.
1:10:48 A lot of people will hate me for saying this, but my feeling is, you know, the drinking age should be 24, 25, just like when your insurance rates go down for your car.
1:10:49 It’s 25.
1:10:52 It’s because you have a prefrontal cortex, right?
1:10:59 And I think when you hijack that system with any substance that can be psychoactive, you run into problems.
1:11:06 And so the best recommendations are, in my opinion, getting all the way up to that 24, 25.
1:11:19 But I would be OK with people saying 18 or 21 because that seems to be more acceptable in society as to where we’ve set barriers in, you know, historical precedent.
1:11:35 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 them,
1:11:42 hey, this is cool, try it, you know, and consume it and something happens.
1:11:56 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.
1:12:08 And so young people are, again, because there’s not that executive control of the prefrontal cortex, are much more likely to take those risks.
1:12:11 But not because they’re being dumb.
1:12:13 They just don’t—they don’t understand.
1:12:15 Well, they’re not getting the information.
1:12:15 Correct.
1:12:18 And thanks to you, they’re getting the information now.
1:12:25 The second cohort that I’ll ask about would be, you know, people, let’s just say, you know, 18 to 25 and older,
1:12:35 who are seeking a caffeine stimulant-like effect, assuming they can get a hold of the more plant-like products.
1:12:41 So the, you know, where it’s not a kratom-derived product or isolate,
1:12:47 are most people able to use a kratom product in the same way that they use caffeine?
1:12:56 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.
1:12:59 They could drink caffeine instead and get over the hump, so to speak.
1:12:59 Yeah.
1:13:02 So it’s a—that’s a definite maybe question.
1:13:03 So it depends on the person.
1:13:04 It depends on the person.
1:13:10 As you know, that we’re all so different and we all respond differently to different—or the same thing.
1:13:22 But I think that—let’s just say the most frequent thing I hear from people that are using kratom,
1:13:27 and particularly kratom leaf products on a regular basis, they always say less is more.
1:13:34 They always say that the lower amounts they take, they seem to derive more benefit from it.
1:13:41 And I’ve struggled with that from the standpoint of just understanding pharmacology and understanding tolerance
1:13:45 and understanding, you know, after you’ve been taking something for so long,
1:13:50 you naturally think you’ve got to take more to benefit from it.
1:13:55 And I think it comes, again, back to the group of users that we talked about.
1:13:57 What is their goal at the end of the day?
1:14:08 But if they’re just taking it as this sort of mood-lifting, elevating, energy-derived thing,
1:14:15 then the recommendation that—and I would say this for anything—is stay low and stay slow
1:14:19 and, you know, never increase things.
1:14:24 What I’ve been told, because, again, this is not something that I use,
1:14:31 is that people benefit from this on a consistent basis,
1:14:35 just like most people benefit from a cup of coffee or two a day.
1:14:39 And, yeah, if you go a couple of days without it, you’re going to have a headache.
1:14:48 Where people start to develop problems is if they are using this for pain treatment
1:14:54 or something else like that, and they initially start out, and this is great, everything’s good.
1:15:00 It does seem that a tolerance develops to the pain-relieving properties of this.
1:15:05 We don’t know what that timescale looks like, so we have no idea.
1:15:07 And it’ll differ for everyone.
1:15:12 We’ve not done these studies in animals to tell you that, you know,
1:15:17 a mouse or a rat is going to take this much time,
1:15:21 and therefore we can, you know, scale this to what it would be on a human.
1:15:24 We’ve not even done those types of studies to understand.
1:15:28 But I can tell you anecdotally from talking to people, that’s what happens.
1:15:35 They’ll develop these tolerance, and they’ll suddenly have to take more to get that relief.
1:15:39 And as we take more of anything, we get closer and closer to a problem,
1:15:44 because it’s not the benefit that we’re getting that generally gives us the problem.
1:15:53 It’s something off target or off of that original frame that we’re focused on that gives us into the problems.
1:16:02 You know, opioids, for just a clear example, opioids are fantastic pain relievers.
1:16:08 But humans develop tolerance to the pain relief properties of opioids quickly.
1:16:16 Unfortunately, we don’t develop tolerance to the constipating effects and the respiratory depressive effects of these as well.
1:16:22 And those are the two things that limit clinical utilization of opioids.
1:16:29 If you’re getting constipated, then we have to stop using opioids from a clinical standpoint to treat your pain,
1:16:34 because it’s – you can get too stopped up, and this could be worse.
1:16:37 Same thing with respirations.
1:16:42 Of course, the main reason that individuals die from opioid overdose is because they stop breathing.
1:16:47 And that respiratory depression is nothing to do with the analgesia.
1:16:49 It has nothing to do with the pain relief.
1:16:52 It’s just this offside target.
1:16:55 It has these receptors in the brainstem.
1:17:02 I mean, I think it raises the question whether or not kratom can cause respiratory suppression.
1:17:07 It’s a good segue to a paper that should be coming out in the next week or two.
1:17:07 Oh, great.
1:17:11 Well, since it’s already accepted, yes or no?
1:17:12 It’s complicated.
1:17:13 Is it dose-dependent?
1:17:15 So I will say this.
1:17:21 In kratom as a whole, we’ve not studied in respiratory depression.
1:17:24 So the products that are in the marketplace, we don’t know.
1:17:25 I don’t know an answer to this.
1:17:36 It’s long been said that there’s much less respiratory depression from kratom than there is from clinically or illicit opioids.
1:17:41 I think that’s pretty well accepted in an anecdotal way.
1:17:45 Scientifically, we can’t say definitively what that is.
1:17:52 The paper that we have that’s coming out, it should be in the Journal of Pharmacology and Experimental Therapeutics.
1:17:58 It’s already on BioArchive right now, but BioArchive is not a peer-reviewed site.
1:18:04 We just wanted to get this information out as soon as possible because we think it is vitally important for public safety.
1:18:21 These seven hydroxymitrygine products that are now being sold, as I mentioned, as semi-synthetics or isolates are actually causing respiratory depression equivalent to opioids.
1:18:21 Wow.
1:18:22 Okay.
1:18:27 So these are the specific alkaloid metabolites.
1:18:33 So to back up again, folks, the kratom contains somewhere between 20 and 40 alkaloids.
1:18:37 One of them is most abundant.
1:18:40 The metabolite of that is what’s active in the body.
1:18:45 Chemists have figured out how to manufacture that metabolite.
1:18:54 People are taking products of the pure metabolite mixed in with some other things, and that can cause respiratory depression on par with opioids.
1:18:55 In a rat.
1:19:02 So I will caveat that, but, you know, it’s one of these things that we talk about all the time.
1:19:08 If it walks like a duck, if it quacks like a duck, if it looks like a duck, it’s a duck.
1:19:08 Yeah.
1:19:18 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 metabolism is different, et cetera.
1:19:39 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-Botzinger and parafacial nucleus, which have abundant receptors for these things that control breathing, that machinery is so highly conserved from mice to rats to non-human primates.
1:19:51 That’s why we say rat, cat, monkey, bat, and human, that it would be remarkable and extraordinary for the system to work much differently than human.
1:19:55 And I think in humans, it’s going to have exactly the same effect.
1:20:00 You know, but I can’t say that definitively, and it’s not an ethical thing to really do, right?
1:20:08 But we know that that effect, even in the animals, is completely reversible with Narcan or Naloxone.
1:20:15 So it’s also highly opioid receptor involved.
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1:22:05 So let me ask you this.
1:22:08 If I were in charge of the FDA, and I’m not.
1:22:10 That makes two of us.
1:22:23 But if I were, I would say, okay, based on everything I’ve learned thus far, the plant-based Kratom products that were still close to the plant products seem like it’s a maybe scenario.
1:22:29 So kids and people up to 18, maybe 21 or even 25, it’s a hard no.
1:22:30 Stay away from it.
1:22:33 People older than that are going to have a varied response.
1:22:41 It could be like a cup of strong coffee or two or an energy drink or two.
1:22:44 I mean, some of these energy drinks now, I mean, they pack a serious punch.
1:22:55 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 effect, like increased dopamine, epinephrine.
1:22:58 I mean, they’ve got Hooperzine, alpha-GPC.
1:23:02 They’ve got things to enhance the serotonin pathway.
1:23:06 They’ve got things to take away the jitters, like L-theanine, plus the caffeine, plus some additional stimulants.
1:23:12 And pretty soon you go, yeah, the caffeine count isn’t that high, but what you’ve got is a neuromodulator cocktail in there.
1:23:23 So, 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.
1:23:25 Something like that.
1:23:34 But then I would probably also create a third category, which is, and I’m going to get the pronunciation wrong, but the 7-hydroxymetabolite of mitraginine.
1:23:35 Mitraginine.
1:23:36 Mitraginine.
1:23:38 Or mitraginine, some people call it.
1:23:48 Mitraginine, 7-hydroxymetraginine, tragedy, okay, should be, if I were FDA commissioner, I’d say, this just sounds all bad.
1:23:50 Just flat out make it illegal.
1:23:51 Yeah, I mean.
1:24:03 So you’re not making kratom illegal, you’re making the opioid-like derivative illegal, or extremely hard to get, or maybe you need some additional barriers there.
1:24:05 Why isn’t it that way?
1:24:20 I mean, why did we sit down here today, me, ready to ask you, should kratom be 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?
1:24:25 Yeah, well, even very different products, period, right?
1:24:39 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.
1:24:40 I see.
1:24:46 So this is kind of the loophole, if you will, that’s allowing this to be in the marketplace.
1:24:53 But there’s several group of advocacy, nonprofit organizations out there.
1:25:03 There’s American Kratom Association, there’s a Global Kratom Coalition, there’s a Holistic Alternative Recovery group.
1:25:08 What’s the role, are these people who are looking at this as a good alternative to opioid abuse?
1:25:13 So in many of the cases, yes, all of the cases, yes.
1:25:14 So I should say that.
1:25:45 The American Kratom Association and Global Kratom Coalition are much more 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 that they claim the FDA is not doing right now.
1:25:52 The FDA is just letting it exist in the marketplace in whatever form, shape, size it wants to.
1:26:02 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.
1:26:13 There’s this other group, the heart group, which is really a proponent for this 7-hydroxy product and saying that it’s out there to reduce harm.
1:26:20 It’s out there to help people benefit from a product that is not an opioid, right?
1:26:25 But it is purely an opioid, but it’s not a prescription opioid, and they’re saying it’s reducing harm.
1:26:26 Wait.
1:26:29 I don’t know that anybody has evidence to demonstrate that yet.
1:26:31 There’s no solid evidence.
1:26:34 There’s some, again, anecdotal evidence.
1:26:44 They released a statement recently suggesting that there’s no mention of these in the FDA’s databases of adverse events, the FEARS database.
1:26:58 But 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 it can even be recognized?
1:27:11 If somebody were to take a Kratom product, either an isolate or the plant product, and then drink alcohol, are they at greater risk for dying from respiratory failure?
1:27:16 In the same way that if somebody takes an opioid and drinks, they can die.
1:27:33 Actually, sadly, I know a lot of cases of this, of people who even took a prescription opioid a day before an afternoon or night of drinking, and were pretty good drinkers, if I’m going to say it was not someone real close to me.
1:27:39 But from what I understand, were good drinkers, and then end up dying, typically in their sleep after the night of drinking.
1:27:40 This is not uncommon.
1:27:44 And this is independent of all the fentanyl issues, right?
1:27:47 Does Kratom have the same potential risk?
1:27:50 So Kratom as a whole, it’s hard to say.
1:27:54 Nobody’s done any studies combining this.
1:28:02 In fact, interestingly enough, the studies that have been done with alcohol are looking at reduction of alcohol intake.
1:28:09 So it has been reported anecdotally, again, that Kratom actually reduces alcohol consumption.
1:28:10 Interesting.
1:28:15 And this has been anecdotally mentioned by many people that use it.
1:28:23 You know, 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.
1:28:32 Now, 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.
1:28:35 There are groups that are funded now.
1:28:37 We’re not one of them.
1:28:50 From the National Institute of Alcohol, Alcoholism, Alcohol Abuse, NIAAA to study specifically Kratom as a harm reduction agent in alcohol use disorders.
1:28:53 Such an interesting molecule, right?
1:29:03 We’re 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.
1:29:08 And at the same time, can serve as a stimulant and maybe even an aphrodisiac.
1:29:18 Is there any – 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?
1:29:20 Not specifically.
1:29:30 So it – you know, I earlier said it’s kind of nature’s Viagra, but it’s not interacting with the phosphodiesterase pathways.
1:29:31 It’s not causing vasodilation.
1:29:33 That we are aware of.
1:29:33 However –
1:29:35 Which is what Viagra basically does.
1:29:35 Right, right.
1:29:41 Limits the enzyme that would lead to vasoconstriction.
1:29:42 Correct, correct.
1:29:46 So you have – we don’t really have clear evidence of that.
1:29:53 And what it may be is that it’s this increased sort of stimulant, stamina activity.
1:30:03 But 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,
1:30:13 the main question that was asked was, can you isolate as many of these 20 to 40 alkaloids as possible?
1:30:18 Purify them and tell us what each one does individually.
1:30:22 So the easy one to get was Mitragynin.
1:30:29 And if you look at the majority of the literature around Kratom – and there’s almost 1,000 papers in PubMed now.
1:30:32 I looked this morning just on Kratom.
1:30:35 We account for almost 10% of that from my lab, by the way.
1:30:44 And the vast majority of the studies that are in the literature now have been done with the major alkaloid Mitragynin.
1:30:51 And I always remind my lab and my team and my collaborators, Mitragynin does not equal Kratom.
1:30:57 Kratom is a complex natural product with all these other alkaloids in it.
1:31:06 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.
1:31:12 So Mitragynin, the major alkaloid, actually has affinity for opioid receptors but very weak affinity
1:31:20 and doesn’t do much from an analgesia or painkilling perspective, which you would think the major one, that’s what it’s there for.
1:31:21 That’s what’s going on.
1:31:25 It also interacts with a couple other important neurotransmitter systems.
1:31:35 And there are other alkaloids within the plant that are majorly exposed when you ingest the whole plant product into our bodies
1:31:39 that are heavily interacting with serotonergic system.
1:31:45 So our sort of satiety center, our mood-elevating center, if you will.
1:31:52 Most of our antidepressants are targeting increased levels of serotonin and increased levels of norepinephrine in our bodies.
1:32:00 And so we know that we’re engaging and activating the serotonin system, which, by the way, is also involved in pain processing.
1:32:10 And then some of these alkaloids are heavily hitting the adrenergic receptors, which is our stimulant sort of activity centers,
1:32:14 our fight-or-flight sort of system, if you will.
1:32:24 And it makes it into this very complex alphabet soup, what I like to call a complex symphony orchestra,
1:32:30 that’s playing multiple instruments in our brain at the same time.
1:32:35 And some people say that this is the best pain relief they’ve ever had.
1:32:44 And I come back to it as a science and now saying, okay, we’ve looked at all these different mechanisms that are involved.
1:32:55 We’ve never treated pain from those three prongs at once in a single drug or in a cocktail of drugs in a human.
1:32:56 Can you list those off?
1:32:57 Yeah.
1:33:01 So those three are opioid, which obviously we use to treat pain.
1:33:05 Serotonin, which we sometimes use now for chronic pain.
1:33:14 Drugs like amitriptyline, which is a serotonin reuptake inhibitor, old school tricyclic antidepressant,
1:33:21 used a lot for neuropathic pain before things like gabapentin, neurontin came along, or pregabalin.
1:33:30 And then the adrenergic system, which is actually one that we target in some of the side effects of opioid withdrawal
1:33:38 with drugs like clonidine, which are alpha-2 receptor agonists that help shut down neurotransmission in our brain.
1:33:47 This is really fascinating because all three of these neurotransmitter systems are intimately involved in pain processing.
1:33:54 And we’ve always looked at, and I’ll say this from a medicinal chemist standpoint,
1:34:00 medicinal chemist’s goal are to make the best compounds, the most selective compounds for one target.
1:34:03 So pharmacologists can figure out what that target is doing.
1:34:10 And here’s another example from nature that’s saying, look, if we hit all of these targets at once,
1:34:17 you don’t have to step on the gas quite as hard on each one, and you get some kind of relief.
1:34:21 And that’s why I’m saying what I hear from a lot of people is less is more.
1:34:28 So a lot of people that are reporting pain relief or mood elevation, they’re not reporting psychoactivity.
1:34:32 They’re getting the benefit without the psychoactivity.
1:34:40 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,
1:34:50 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?
1:35:02 So I want to say, first of all, thank you for that description of this tripartite effect of the kratom plant
1:35:09 and how pain relief in its ideal form, not too much sedative effect, pain gone,
1:35:14 but still the noradrenergic effect where people aren’t sedated to the point where they can’t do anything, is ideal.
1:35:19 And that what you said also really highlights, and you said it better than I ever could,
1:35:24 that what we do in science and medicine, reductionist science and medicine,
1:35:27 is we’re trying to isolate receptors and pathways and dose-response curves,
1:35:36 and we’re trying to come up with essentially pills of isolated compounds that hit one, maybe two of these different pathways.
1:35:44 In fact, it’s interesting that whenever a drug impacts multiple pathways, we call them off-target effects, right?
1:35:52 Just that language alone tells you everything you need to know, which is that you’re trying to target specific receptors and pathways,
1:35:54 but the way that the brain works isn’t like that, right?
1:35:57 Earlier, we were talking about breathing.
1:36:03 I mean, the cardiorespiratory system are intimately involved, and it’s no surprise, therefore,
1:36:06 that you have some of the same receptors and systems involved.
1:36:11 You mentioned increasing serotonin for the treatment of depression, SSRIs.
1:36:18 These days, a lot of people are down on SSRIs because of the negative side effects, reduced libido, appetite, or increased appetite.
1:36:27 I will say, in fairness to SSRIs, SSRIs have helped a great many people, especially with people with true clinical OCD.
1:36:30 These are not people that are obsessive of nature.
1:36:32 These are people who are really stricken by their OCD.
1:36:35 So there are places where SSRIs are valuable.
1:36:54 But I think 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 at that dose or that behavior at that frequency in that population.
1:37:12 But that’s just the nature of reductionist science, plants, on the other hand, as you’ve pointed out before, you know, 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, right?
1:37:14 I’m not suggesting people use kratom.
1:37:23 But, you know, the kratom 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, et cetera.
1:37:24 But you have to kind of wonder.
1:37:29 This is kind of a philosophical slash spiritual question.
1:37:39 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.
1:37:44 Plants, by the way, can also kill you, folks, or make you crazy if you take too many of them.
1:37:47 Legitimately crazy or dead.
1:37:49 But you kind of have to wonder.
1:37:54 Like, you can ask the why question, but you’ll never get there.
1:37:56 I wasn’t consulted at the design phase and neither were you.
1:38:09 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 at just the right way.
1:38:13 And yet, it sounds like such a plant exists.
1:38:13 Yeah.
1:38:16 And that plant is kratom.
1:38:17 This has been the fascinating part.
1:38:27 And I have to just say one of the biggest changes in my entire research program is when we moved to the University of Florida.
1:38:40 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 also work with.
1:38:45 And we’re doing clinical trials with kratom and companion dogs, which is a whole other discussion.
1:38:46 Yeah, animals need pain relief too.
1:38:47 That’s right.
1:38:47 Yeah.
1:38:51 And we have very poor pain control in animals, particularly in dogs.
1:38:54 We can come back to that if you want.
1:39:06 But most universities in the United States, state universities, have either the medical college or they have the agricultural college.
1:39:15 The University of Florida has both 800-pound gorillas, if you will, in the same system.
1:39:35 So the University of Florida is extremely well known around the state of Florida and around the country for their unit called IFAS, 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 the agricultural industry.
1:39:46 And we’ve worked with plant scientists on kratom to understand what is this plant doing and why is it producing what it’s producing.
1:39:48 Why are these chemicals there?
1:39:56 So to get to the answer to your question, we think we’ve figured out why the plants are producing this.
1:39:58 It’s definitely not for our benefit.
1:40:03 So plants produce chemical defense all the time, right?
1:40:07 The alkaloids are, by the way, bitter compounds by nature.
1:40:18 So most of the time they’re anti-fedant to make sure that the passing by deer, giraffe, whatever, is not going to eat all the leaves off of that tree.
1:40:22 They’re going to have a couple and realize this is nasty.
1:40:24 I don’t want to do this.
1:40:25 I’m going to move on to the next plant.
1:40:39 However, interestingly enough, Mitragyna speciosa, the kratom tree, does not grow in a place where it’s going to be attacked by herbivorous animals.
1:40:44 These grow in very swampy conditions.
1:40:49 And in those swampy conditions, it’s very humid.
1:40:50 It’s on the equator.
1:40:53 It’s incredibly hot.
1:40:58 And what grows in hot, humid environments?
1:40:59 Fungus.
1:41:08 These compounds that the tree is producing, which, yes, they seem to interact with our neurotransmitter systems for whatever reason,
1:41:19 are highly effective antifungal agents for the plant to ensure its ability to survive and stay in that environment and thrive in that environment.
1:41:23 Is it a good antifungal, potentially, in humans as well?
1:41:25 So that’s a great question, right?
1:41:30 We’ve decided we would look at this from human pathogenic fungus.
1:41:35 So what fungus disease-causing fungi in humans?
1:41:37 So far, we haven’t seen anything.
1:41:46 But as far as agriculturally important fungus, it seems to be able to be very potent on some of these.
1:41:50 And so we’re actually looking heavily into this area.
1:41:59 So there’s parts of the chemical structures that are conserved on all of the alkaloids that we see this tree producing.
1:42:11 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.
1:42:19 It has the exact same chemical pattern, what we call a moiety or a function in the molecule.
1:42:24 And those are called strobilarins, the molecules that are used.
1:42:30 And they’re used in USDA agricultural industry as natural antifungals.
1:42:51 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.
1:42:56 So there’s a reason that plants are producing the molecules they’re producing.
1:43:15 But through trial and error, as we’ve talked about before, through watching and historical just trying things, the F around and find out, you know, figure out there’s some benefit to humans from these plants, right?
1:43:19 Plants are protecting themselves and trying to evolve just like any other species.
1:43:27 Years ago, I had a friend who’s very serious about Chinese medicine, a practitioner.
1:43:37 And I said, what sorts of goodies does Chinese medicine offer for somebody who’s interested in, you know, supplements and medicine and formal medicine also?
1:43:47 And they gave me an alkaloid that’s from gecko skin that’s been shedded.
1:43:49 And it’s a stimulant.
1:43:55 And it’s very bitter, I know, because I opened the capsule and I tasted it before I took it.
1:43:58 And it was a pretty decent stimulant.
1:43:59 I prefer caffeine.
1:44:03 But it was a, you know, a nice arc stimulant.
1:44:05 And it was clearly a stimulant.
1:44:07 And you think, okay, well, how did they arrive at this?
1:44:18 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.
1:44:23 And that’s the way that the geckos have learned to be less tasty, be bitter.
1:44:23 Yeah.
1:44:32 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.
1:44:33 Species won’t be around long.
1:44:34 Exactly.
1:44:36 So there’s a lot of this out there.
1:44:43 A couple of days ago, I asked my ex-audience, does anyone have any questions about Kratom?
1:44:52 A lot of praise for you and your efforts to really be discerning and nuanced about the messaging around Kratom and for your work.
1:44:57 So someone asked something that I had no idea what it means, but this person is a researcher.
1:44:58 I know them.
1:45:00 They’re a well-known neuroscientist.
1:45:06 And they asked, is there really a difference between white vein, red vein, and brown vein?
1:45:08 What are we talking about here?
1:45:10 I’ll answer the question very quickly.
1:45:11 Most of this is marketing.
1:45:23 But what we realized is that there’s – on the tree itself, the tree’s leaves have veins.
1:45:31 And those veins are red in some cases or green in other cases or white.
1:45:35 You can think about this like rainbow shard at the supermarket, right?
1:45:35 Sure.
1:45:39 You know they’ve got beautiful colors or rhubarb or whatever you want to compare it to.
1:45:41 Blood oranges versus – yeah, sure.
1:45:42 Sure.
1:45:55 So what we have seen – and I’m going to caveat this answer too because a lot of marketing goes into this white vein, red vein, brown vein, green vein, yellow vein.
1:46:00 They’re actually five colors of products that come into the United States.
1:46:08 And it has to do with how those have been cured or dried after they’ve been harvested.
1:46:18 So green leaves, fresh, not dried very much, dried in a cool environment indoors.
1:46:27 They’re going to retain the greenish color and they’re ground and pulverized and that powder comes in green.
1:46:29 That’s it.
1:46:33 That’s your green vein in many cases.
1:46:40 And vice versa, as you go through the colors, it really depends on how the color of the leaf material was.
1:46:50 We grow these trees at the University of Florida and it’s interesting because if they – they can get sunburned and they can – they’re an undercover canopy crop.
1:46:56 So the trees naturally exist sort of underneath a higher canopy of trees.
1:46:59 So they’re shade grown, OK?
1:47:05 If they get direct exposure into the sun, they’ll actually burn and the leaves will start to turn brownish red.
1:47:12 We’ve done that with specific wavelength light studies in greenhouses and whatnot too.
1:47:21 But they’ll also get damaged when it gets cold and they’ll get brownish color or they’ll turn reddish color again.
1:47:24 So there’s some sort of response, chemical response.
1:47:28 But it is a chemical response and this is where I put the caveat in.
1:47:41 Because when we’ve isolated – 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.
1:47:44 So the alkaloid is not changing.
1:47:54 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.
1:47:56 This is more pain.
1:48:02 This is very reminiscent of the indica sativa question that I got around cannabis.
1:48:14 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.
1:48:26 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.
1:48:30 So people will associate a particular effect with a given product.
1:48:34 That product might be labeled green vein or red vein.
1:48:40 So the effects may indeed differ, but it’s hard to trace back to the actual differences in green vein versus red vein.
1:48:41 That’s what I’m gathering for us.
1:48:43 In terms of their alkaloidal makeup.
1:48:49 So when we analyze things – and let me just – let me take a step back here.
1:48:53 So plants produce many classes of chemicals, right?
1:49:03 Alkaloids are the ones that traditionally people think of with pharmacological activity that are interesting, that are going to have psychoactive activity.
1:49:10 So most people focus on alkaloids as being the biologically relevant plant materials.
1:49:11 You mentioned cannabis.
1:49:13 Cannabis has no alkaloids.
1:49:19 So those are terpenes, which is another chemical class of molecules.
1:49:29 They do not contain nitrogens and they – we now interact with specific proteins in our body as well, like cannabinoid receptors.
1:49:36 So plants are producing many classes of compounds.
1:49:38 They produce steroids, what we call phytosteroids.
1:49:50 They produce tannins, which anybody who’s like me and likes wine, you know, you talk about tannins and all the different types of tannins that can be present in a wine.
1:49:50 Or teas.
1:49:52 Or teas, yeah.
1:50:01 And to that point, there’s antioxidant-type compounds in there, you know, all kinds of classes of chemicals.
1:50:09 No one, to my knowledge, has studied anything other than the alkaloids in the crayon plant.
1:50:13 Likewise with cannabis, a lot of it hasn’t been explored besides THC and CBD.
1:50:17 And many of it is because it’s in such low quantity.
1:50:27 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.
1:50:29 It’s easy to isolate, purify.
1:50:34 And if it’s the major alkaloid, by default, it should be causing the activity.
1:50:35 It makes for good science, right?
1:50:45 It’s hard to risk somebody’s PhD career on a gene or molecule that’s in low abundance, yet you want to err towards probability of success.
1:50:49 Okay, so there’s your answer on white vein, red vein, brown vein.
1:50:52 It sounds like it’s more product-dependent and source-dependent.
1:50:58 In terms of the – for the user, the potential user, and maybe you shouldn’t trust the marketing.
1:51:05 I mean, just finalize that with the fact that we don’t know if there’s other changes in chemical composition outside the alkaloids.
1:51:07 So there could be something there.
1:51:12 Is there a potential use for kratom as an antidepressant?
1:51:20 I think that’s probably one of the areas that needs to be investigated much more thoroughly.
1:51:26 We got a specific marching order.
1:51:30 We were looking at many things, including regulation of blood glucose.
1:51:34 So we can talk about a lot of potential things that are going on.
1:51:48 But the mood elevation and the sort of overall well-being feeling that many people report, it’s all anecdotal, right?
1:51:58 But at a certain point, anecdotal is a signal because it tells you once enough people are saying this, it must be something.
1:52:08 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 is true benefit.
1:52:17 Next question for you is, and this was a very common question, how to get off kratom.
1:52:26 This person says, my brother was on it and is having a dreadful time with it.
1:52:28 He takes it now just to feel normal.
1:52:30 He feels like he’s a slave to kratom.
1:52:37 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.
1:52:42 Yeah, and it’s a great question, unfortunately, without answer right now.
1:52:50 But I do want to stress a very important piece of this research and what we’re trying to understand.
1:53:00 I’ve talked a lot more about the chemical nature and the pharmacology and differences in pharmacokinetics and potential benefits with this plant.
1:53:08 But it’s clear that there’s potential harm as well, and we’ve seen that in many, many stories.
1:53:11 These are examples of that.
1:53:25 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.
1:53:33 One of our patients came in an opioid treatment and said they started using kratom, and they’re doing much better, and they’re benefiting.
1:53:38 And then we didn’t see each other for a couple of years because of COVID.
1:53:42 We resumed our lunches, and they said, you won’t believe what we’re seeing now.
1:53:46 People are coming in seeking treatment to get off.
1:53:52 We’ve unpacked a lot of discussions over a lunch table in trying to figure these things out.
1:54:13 Most medical practitioners go to the fact that this is opioid-like, and they’re using buprenorphine or Suboxone, which is one of our gold standard treatments, or even methadone, to get individuals off of kratom.
1:54:23 And they say it’s working, but my problem with that is we’ve said already, this is not a typical opioid.
1:54:26 Kratom is not a typical opioid.
1:54:28 It’s atypical for sure.
1:54:30 It’s having these other pharmacologies.
1:54:44 And so, yes, we may have success in converting people from taking kratom by putting them on an opioid, which many of them might have been trying to get off of in the first place with this.
1:54:58 But the pharmacology of kratom 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 tripartide in its activities, right?
1:55:07 So you’re ignoring the serotonergic piece, you’re ignoring the adrenergic piece by only giving an opioid like methadone or buprenorphine.
1:55:10 Is that the right way?
1:55:11 I don’t know.
1:55:14 I don’t know the answer to that question.
1:55:27 We know that in certain cases when we’ve tested animals and we’ve pushed them into toxic levels of certain alkaloids, not kratom itself.
1:55:34 But we know that in many cases opioid antagonists won’t reverse some of those effects.
1:55:39 Because of these non-opioid pathway effects.
1:55:56 So it sounds like for this person’s brother or sister or somebody that wants to get off kratom, suppressing the same pathways that are used to get people off opioids like buprenorphine, naboxone, et cetera, could be useful.
1:56:02 But there could be still other aspects of dependency related to kratom that those won’t resolve.
1:56:03 That’s what I’m hearing.
1:56:04 That is.
1:56:16 And the concern is by moving someone from a kratom product to a pure opioid product, like are you actually potentially making things worse?
1:56:20 Because it’s going to be hard for them now to get off of those products.
1:56:22 It’s a circular question, right?
1:56:24 It’s very difficult to answer.
1:56:30 And this is one of the things we’re really trying to get to the bottom of what is a better, what is a more appropriate treatment.
1:56:36 But for right now, it seems that what is working is opioid use disorder treatments.
1:56:37 Buprenorphine.
1:56:37 Yeah, buprenorphine.
1:56:48 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?
1:56:48 Just don’t touch it.
1:56:50 There were a lot of don’t touch this stuff.
1:56:53 That’s based on observation, it seems.
1:56:57 It’s conjecture here.
1:57:05 But based on observation that they know people have had a terrible time getting off it, like the best way to avoid dependence is to not start.
1:57:14 There were a couple questions about that specifically and the effect on the serotonin system.
1:57:29 You could imagine if you’re trying to come off kratom because of an opioid-like dependence, taking buprenorphine, maybe doing other things to support the serotonin system at the same time.
1:57:31 It doesn’t have to be just one treatment.
1:57:34 But obviously this has to be overseen by somebody that can prescribe these drugs.
1:57:54 Yeah, no, and I think the key there 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 medication assistance in treatment, but giving you supportive treatment.
1:58:01 In other words, counseling and social aspects of that as well.
1:58:07 I’m going to just tell you one comment that somebody asked I relay to you because I think it’s informative for everybody.
1:58:11 And then I have one more question from the online audience.
1:58:21 Please tell your guest, I quit prescribed topical boot trans patches for lower back pain, cold turkey, by switching to kratom as an alternative treatment.
1:58:23 They want you to know that.
1:58:27 So this is somebody for whom it was effective, and apparently they wanted you in particular to know that.
1:58:36 Yeah, I appreciate that comment, and it’s not an uncommon theme that I’ve heard and I’ve gotten emails from people that have had that story.
1:58:39 They’ve been able to switch cold turkey.
1:58:58 And 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 longtime collaborator, Ed Boyer, who’s an emergency department physician.
1:59:05 And Ed called me and said, you’re not going to believe what I have in the ED, he said, I’ve got someone.
1:59:07 The ED is the emergency department.
1:59:10 Came in with a full-blown seizure.
1:59:14 And this is all in this paper.
1:59:15 It’s unpacked.
1:59:22 It was what we think happened is that he took a modafinil, which is a drug for actually narcolepsy.
1:59:23 He was feeling tired.
1:59:32 His wife had these drugs, and so he took this on top of his well-established use of kratom.
1:59:36 A lot of people use modafinil as a stimulant cognitive enhancement.
1:59:36 Yeah.
1:59:38 Very, very common now.
1:59:42 You have to remember this took place in 2007, okay?
1:59:45 So the only product that was in the market at that point in time was leaf.
1:59:48 So leaf kratom and modafinil.
1:59:48 Yeah.
1:59:53 So it caused him to have a seizure.
1:59:58 In the emergency department, they had no idea what to do.
2:00:05 Luckily, Ed knew me in that we were working on this, and we were working on another thing called salvia divinorum,
2:00:09 which is a whole other study about a hallucinogenic mint plant.
2:00:30 But we started talking, and when this guy came conscious and was fine – by the way, he quit a habit of Dilaudid, which is a prescription opioid, cold turkey, switched to kratom, no issues, kratom leaf.
2:00:38 And then after he had the seizure and came to in the hospital, he quit cold turkey kratom.
2:00:45 The only thing that he had was a runny nose, and he said he had no desire to go back and take it anymore.
2:00:52 Now, at the moment in time that that happened, this was an N equals one case ever.
2:00:58 And my friend Ed said, this sounds like the holy grail.
2:01:00 If you can get off of it –
2:01:01 Off Dilaudid.
2:01:04 You never – off Dilaudid, off of kratom.
2:01:08 And now you don’t even have a craving to go back to it, right?
2:01:13 Now, that’s a huge caveat in this story.
2:01:14 The guy had a seizure.
2:01:24 So significant event occurred that he decided at that point in time he was never going to touch kratom again.
2:01:30 Speaks to the precariousness of polypharmacology done at home.
2:01:31 Yes.
2:01:35 And I once took modafinil, half a dose.
2:01:39 I’m very susceptible to medication, and it kept me up for almost two days.
2:01:39 Wow.
2:01:41 And I took it in the morning time.
2:01:46 Some people I know can take it just fine and use it as a stimulant when traveling,
2:01:50 especially to give talks after whatnot and for narcolepsy, et cetera, as well.
2:01:59 I’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.
2:02:01 You mentioned the coca plant earlier.
2:02:06 I don’t think anyone except a cocaine user would say cocaine is a good thing.
2:02:09 I mean, it seems to destroy a lot of lives.
2:02:18 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.
2:02:21 But it does seem to be a fairly destructive compound on the whole.
2:02:28 And yet, as you mentioned, the coca leaf has these interesting compounds when it’s used as a leaf product.
2:02:36 There’s a similarly sounding leaf, which is the cocoa leaf chocolate.
2:02:37 And then there’s cacao.
2:02:43 And I’m not trying to get down into the romper room version of plant medicines here.
2:02:48 But recently, I started eating roasted raw cacao beans for their polyphenol content.
2:02:49 I actually like the bitterness.
2:02:51 They have a lot of fiber.
2:02:52 You have to not overconsume them.
2:02:55 You have to make sure they’re clean source so you don’t consume heavy metals, et cetera.
2:03:00 But there’s a lot of interesting, healthy stuff coming from plants.
2:03:05 So let’s talk for a moment, if you would, about the cocoa leaf and cocoa and chocolate.
2:03:07 I like 100% chocolate.
2:03:09 100% Venezuelan chocolate.
2:03:10 Delicious.
2:03:12 People might be, it sounds like baking chocolate.
2:03:14 But it’s smooth.
2:03:14 I love it.
2:03:16 It’s got a bitterness, but a little bit of sweetness.
2:03:19 It tickles my brain just right.
2:03:20 It’s healthy.
2:03:20 It doesn’t have sugar.
2:03:21 I don’t overdo it.
2:03:27 And wow, it’s a real thing.
2:03:27 Yeah.
2:03:30 And it’s delicious, and I look forward to it.
2:03:33 And I don’t feel like I’m addicted to it, because I haven’t had any for a little while.
2:03:35 And I’m fine, but I’m looking forward to it.
2:03:40 Tell me about the benefits of cocoa and some of the alkaloids and other things that are in cocoa.
2:03:44 This is not to send people out to ingest a bunch of sugar, sweet, and chocolate.
2:03:47 We’re talking about 100% cocoa or cacao beans.
2:03:48 Right.
2:03:51 There’s real medicinal power in this stuff.
2:03:52 Yeah, yeah, there absolutely is.
2:03:57 And it’s fascinating, too, because there’s a few things that are in there.
2:04:00 And this is not something that I’m an expert on by any means.
2:04:07 But playing around in these areas, you start to learn, and you start to take notice.
2:04:16 One of the main components in chocolate or cacao is a compound called theobromine.
2:04:20 So theobromine is an alkaloid.
2:04:34 It is what we specifically call a xanthine alkaloid, which is identically a cousin, almost maybe like a sibling of caffeine.
2:04:36 Okay.
2:04:50 So caffeine is a molecule, again, a xanthine alkaloid, and it has three nitrogens that contain methyl groups on them.
2:04:55 So a carbon with three hydrogens on them attached to the nitrogens.
2:05:00 And caffeine is an easy one to remember in this class because it is fully methylated.
2:05:07 So I call it high test, full caffeinated, substituted xanthine alkaloid.
2:05:10 And then theobromine has no bromine on it.
2:05:12 It has nothing to do with bromine.
2:05:19 I have no idea where the name came from, but it’s missing one of those carbons that makes it different from caffeine.
2:05:22 But it causes stimulation.
2:05:35 It actually improves respiration when it’s been studied, very similar to things like theophylline that have been used long time for asthmatics.
2:05:42 Before we got to the inhalers and things evolved in terms of our understanding of that treatment.
2:05:58 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?
2:05:59 That was really good.
2:06:01 I want that again.
2:06:09 It’s not like a dopamine release that you get from a hardcore drug like cocaine or something like that.
2:06:11 Never done cocaine, but I agree.
2:06:17 It’s a subtle kind of push toward, yeah, I’d like more of that, but I feel pretty good.
2:06:19 And the anticipation of it is positive.
2:06:22 And you certainly can work and do other things.
2:06:27 It certainly does not destroy, as far as I know, does not destroy lives.
2:06:28 It’s rewarding.
2:06:33 Unfortunately, the industry to harvest is what destroys the lives, right?
2:06:43 So there’s a lot of very poorly sourced and many of the individuals that work those fields and places are really abused.
2:06:47 And it’s a problem in the chocolate industry as a whole.
2:06:57 There’s some really great companies out there that are really promoting good, sustainably sourced, ethically sourced cacao beans.
2:07:08 And that’s just a side note for something to look for when you’re looking for a good, solid chocolate source.
2:07:24 So ethically sourced, and you mentioned cacao beans, so that the raw cacao beans that I’m now eating every morning, usually not immediately in the morning, usually like half hour before my first meal of the day, which for me falls a little bit late morning or closer to lunch.
2:07:26 But I’ll have five or ten of those things.
2:07:28 Boy, do I look forward to it, as I mentioned.
2:07:36 And those raw cacao beans are essentially the same as the 100% chocolate in terms of polyphenol content.
2:07:37 Pretty much.
2:07:41 I think – I mean, again, I’m not an expert and I haven’t done analysis of those.
2:07:50 But I’m pretty sure that most of those would be retained in the processing into chocolate as a food.
2:08:02 You 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.
2:08:15 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.
2:08:27 And so you would walk by and as a kid, I would get this waft of chocolatey smell along with that smell of the roses, you know.
2:08:28 And it’s like –
2:08:29 It’s like Valentine’s Day.
2:08:32 It’s like these things were meant to be together, right?
2:08:36 So it’s just a weird side note, just a memory that you brought back.
2:08:38 I love that.
2:08:45 And I really think there’s something pseudo-spiritual or spiritual about these combinations of molecules that exist in plants.
2:08:51 And sure, the plants are fending for themselves and the fungi are fending for themselves and the birds and the geckos and the humans.
2:08:58 But the same biological motifs are used over and over again throughout nature.
2:09:05 And of course, some species like insect species rely more on one neuromodulator.
2:09:10 We’re more a cocktail of serotonin, dopamine, epinephrine, and acetylcholine.
2:09:15 But there does seem to be something to it.
2:09:21 Maybe AI will pull out some of the thematics of that going forward.
2:09:22 So cacao, great.
2:09:26 So I’m not alone in my love of raw cacao beans and 100% chocolate.
2:09:28 But look for sustainably sourced.
2:09:30 Ethically sourced.
2:09:32 Ethically, excuse me, ethically sourced.
2:09:33 No, that’s an important distinction.
2:09:41 So there’s a myth that Coca-Cola at one point had cocaine in it, not just the coca leaf, but actual cocaine.
2:09:47 But then you hear various versions of this myth slash legend.
2:09:51 What’s the deal with Coca-Cola, the coca leaf, and cocaine?
2:09:53 Yeah, so it’s a great old story.
2:10:10 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.
2:10:12 So Coca-Cola.
2:10:16 And put this together, sold it as a tonic.
2:10:21 It’s an interesting, just a quick segue on soft drinks in general.
2:10:23 So soft drinks came about because they weren’t hard drinks.
2:10:25 So it was an alternative to liquor.
2:10:28 So they weren’t hard alcohol.
2:10:31 They were soft drinks or soft beverages.
2:10:35 They also generally had effervescence to them or carbonation.
2:10:40 And most of those were available at a pharmacist’s soda fountain.
2:10:46 So 7-Up had lithium in it in the past, and it was, you know, for mind wellness.
2:10:51 Pepsi had pepsinogen, which is a digestive peptide in it.
2:11:01 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.
2:11:16 So all these soft drinks have a really cool history, but John Pemberton’s story of Coca-Cola was—actually, it goes way back farther than Coca-Cola in terms of putting coca leaf into beverages.
2:11:19 But we’ll just stick with Coca-Cola.
2:11:26 So Coca-Cola definitely had cocaine in its original setting.
2:11:38 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.
2:11:52 And so what they realized was the coca leaf—and many people that chew coca leaf talk about the different varieties that are available within South America and different flavor profiles that are there.
2:12:01 Well, the specific one that they used for Coca-Cola has a definitive flavor profile to it.
2:12:08 And when they took that out, it lost the flavor that people were used to.
2:12:12 And so they decided to keep this in there.
2:12:19 And Coca-Cola is still the major importer of coca leaves into the United States to this day.
2:12:22 They do it through a company called the Stepan Company in New Jersey.
2:12:35 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.
2:12:40 They then process the leaf into two parts.
2:12:46 So they take all of the cocaine and all of the cocaine metabolites, essentially the alkaloids, right?
2:12:47 We talked about these alkaloids.
2:12:58 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.
2:13:04 A lot of people probably don’t know this, but cocaine is the best local anesthetic that’s ever been discovered.
2:13:11 It was the template for all the local anesthetics that we use now, like lidocaine or papivacaine.
2:13:13 It was the template.
2:13:16 And it is still the best one that we have.
2:13:26 And it’s used almost exclusively for nasal and eye surgeries now, where you have to stay awake and you have to be functioning, and we can’t intubate you, and we can’t do these things.
2:13:30 So this is the ideal drug.
2:13:38 It’s also obviously put into lots of drug testing kits and supplies and whatnot for the forensics industries.
2:13:43 But what’s the fate of what’s left, right?
2:13:55 Well, that coca leaf extract, the dealkalinated extract, decoconized extract, if you will, is the secret sauce, if you will, for Coca-Cola still.
2:14:03 So that is a grass substance, a G-R-A-S, generally recognized as safe food substance.
2:14:08 And that is the flavoring agent that gives Coca-Cola its unique flavor.
2:14:18 And there was a period of time, I believe it was in the 80s, where Coca-Cola really wanted to distance itself from the cocaine industry.
2:14:23 Cocaine became hugely the drug of choice, sort of drug of abuse.
2:14:28 Len Bias, one NBA basketball player, died from overdose.
2:14:34 It just became a very nationally aware drug of abuse.
2:14:36 And there was a problem associated with cocaine.
2:14:40 And so Coca-Cola said, we’re going to cut our ties with the coca plant completely.
2:14:43 They came out with this product called New Coke.
2:14:50 And it didn’t last long because the flavor profile couldn’t be replicated to the old Coke.
2:15:00 And so, indeed, they re-upped their sort of contract and have been bringing it in ever since.
2:15:06 And to this day, Coca-Cola Classic and Coke Zero are the two products.
2:15:12 Interestingly enough, you know, Diet Coke does not taste very much like Coca-Cola original.
2:15:15 And a lot of people complained about that for a long time.
2:15:23 They got smart and made this product called Coke Zero that has the flavoring agent from the coca plant in it.
2:15:29 And lo and behold, everyone started saying, gosh, this tastes a lot more like Coca-Cola does.
2:15:32 Well, yeah, it’s got the flavoring ingredient in it.
2:15:38 And so everybody in the United States almost has had a Coke at one point in time.
2:15:42 So you’ve all had coca leaf already in your dietary chain.
2:15:49 And I think it’ll be interesting to see where things develop as we start to do more research,
2:15:57 as the World Health Organization reconsiders removing coca leaf from an international ban
2:16:05 and looking at it as a potential product to work into food products and develop further.
2:16:09 And so, you know, it supposedly has no abuse potential as the leaf.
2:16:18 But again, it’s that story of isolating that one alkaloid out and sort of destroying the rest of it forever.
2:16:28 However, Coca-Cola was smart enough to keep sort of a monopoly, if you will, on keeping that plant alive in their product.
2:16:30 And so it’s there.
2:16:38 And the next time you have a Coca-Cola or a Coke Zero, just realize that it’s got natural product in it.
2:16:40 That’s incredible.
2:16:43 And I’ll keep that in mind the next time I have a Coke Zero.
2:16:53 Is there any evidence that what’s still retained from the coca plant in Coca-Cola is psychoactive and not just there for flavor?
2:16:55 That’s a great question.
2:16:58 And that’s been debated quite a bit.
2:17:04 So the one thing that we know is that probably it is not having any psychoactivity.
2:17:11 And the other thing that we know, back to my pharmacy days, we used to sell Coke syrup.
2:17:23 So when Coke is sold for fountain beverages, it’s the syrup that’s then blended with the carbonated water to make Coca-Cola.
2:17:34 And that’s why a lot of people say Coca-Cola out of a fountain is so much better than out of a can or a bottle because it is a sort of formulated on-the-spot product, if you will.
2:17:35 On tap.
2:17:36 Yeah, on tap.
2:17:48 And Coke syrup we used to sell out of the pharmacy for nausea and vomiting, particularly in pregnant women, is one of the safest things you could use.
2:17:52 And it really calms and settles the GI tract.
2:18:10 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.
2:18:13 Of course, the Coca-T has got all the alkaloids in it.
2:18:18 But that same GI tract benefit is still there.
2:18:26 And that’s probably what’s still remaining within that extract that’s now devoid of the alkaloids.
2:18:29 And you are not paid for by Coca-Cola?
2:18:30 No.
2:18:41 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.
2:18:53 And 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 extract.
2:18:59 And they’ve also got all that cocaine that they’ve pulled out of the coca leaf in this plant in New Jersey.
2:19:02 I can only imagine what the security is on this place.
2:19:03 I don’t know.
2:19:09 But, you know, you can fact check me on Wikipedia, which is not a great place to fact check.
2:19:11 You got my agreement there.
2:19:22 But the Stepan Company is listed there in New Jersey and their connection to Coca-Cola and this whole story is actually out there in front of everybody to see.
2:19:26 It just takes knowing where to look and find it.
2:19:27 Love it.
2:19:30 Last question about soda.
2:19:32 Is there still lithium in 7-Up?
2:19:32 No.
2:19:36 Lithium has gone from 7-Up.
2:19:38 But that was the whole idea, right?
2:19:41 Up, mood, lift your mood up.
2:19:42 Lithium.
2:19:48 And we know lithium carbonate is still used to this day as a treatment for psychosis.
2:19:51 I’m curious a bit about you.
2:19:54 You know, like I know a few chemists.
2:19:56 There are a couple of good jokes about chemists.
2:20:09 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.
2:20:10 I’m not a psychologist.
2:20:13 But kind of the psychology behind all of this as well.
2:20:18 When you were a kid, were you always – were you playing with a chemistry set?
2:20:20 Yeah, you would think, right?
2:20:20 No.
2:20:31 Interestingly enough, my father was a pharmacist and I just never really – I never really paid attention.
2:20:33 But I was always under tow.
2:20:46 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.
2:20:57 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.
2:21:00 And I always thought that to be noble.
2:21:14 And my mother, interestingly, she was a stay-at-home mom, raised us kids, but was very much into education and was a teacher prior to myself being born.
2:21:15 I’m the oldest.
2:21:21 I have a sister, younger sister, Lisa, who’s a nurse, by the way, nurse practitioner.
2:21:27 So medicine has stayed within the family and science has stayed within the family.
2:21:36 But my mother, once we were old enough to be on our own, if you will, she went back and became a comprehensive science teacher at the high school level.
2:21:52 And so just watching her work through getting her recertification, the education process, and how passionate she was about educating others obviously stuck with me as well.
2:21:55 And so those are the things that drove me.
2:22:03 I have no idea where the sort of, I really think, innate passion came for the chemistry side of things.
2:22:08 But when I was in high school, I did an independent chemistry project coming back to caffeine.
2:22:17 I was just curious, like, what’s the best caffeinated beverage for me to be drinking so I can stay up as late as I can and have fun?
2:22:21 Well, at the time, it was Jolt Cola, which doesn’t exist anymore, right?
2:22:24 But Jolt Cola, Mountain Dew was second.
2:22:27 Yeah, drank a lot of Dye Mountain Dew in graduate school.
2:22:29 I can’t say I recommend it.
2:22:29 No.
2:22:33 I mean, that was our, I was a band geek in high school.
2:22:35 What instrument?
2:22:37 I played trumpet and I played piano.
2:22:44 And a bunch of buddies and I would get together on Friday nights and we would drink a case of Mountain Dew.
2:22:46 You know, it was like everyone else is out drinking beer.
2:22:51 We were doing musical things and drinking Mountain Dew.
2:22:53 So it was kind of crazy.
2:22:56 But I just wanted to know what was there, right?
2:23:04 And I wanted to see and I got Vibrin tablets and I extracted the caffeine out of the Vibrin tablets to quantify how much caffeine was in those.
2:23:08 And still, I didn’t really think anything of it.
2:23:16 I decided very late in my high school career that I needed to do something with my life.
2:23:18 I was bored in high school.
2:23:20 I did not do well.
2:23:21 I was not a great student.
2:23:26 I think if I was lucky, I graduated with a 3.0 from high school.
2:23:32 And my father said, you need to decide on something.
2:23:36 And so I said, well, pharmacy looks like it’s been pretty good to you and our family.
2:23:38 We’ve had a good life.
2:23:58 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 in age, just thought the world of this guy.
2:24:05 And he said, hey, I’m looking for anybody who’s interested in working in the lab to come work in the lab.
2:24:07 And I was like, well, chemistry, he’s cool.
2:24:08 I’d like to get to know him.
2:24:11 So I went to the lab, started working in the lab.
2:24:17 And he told me, he said, you know, you have some gift here or some talent.
2:24:19 You should really explore it.
2:24:20 I’m like, yeah, I’m going to be a pharmacist.
2:24:21 What are you talking about?
2:24:32 He said, no, I’m going to set you up with my PhD advisor, which happened to be the guy who tasted the stuff I talked about earlier, down at the University of Georgia for the summer.
2:24:49 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 and left there, went back to Ohio Northern University where I did my pharmacy degree, finished out all my clinical rotations.
2:24:54 I was getting ready to graduate and take my boards and become a pharmacist.
2:25:08 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.
2:25:16 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.
2:25:17 What’s going on?
2:25:19 And I said, I’m not going to graduate school.
2:25:21 I’m about to finish pharmacy school.
2:25:26 And 15 minutes later, he was a great salesman.
2:25:28 He had me going to graduate school.
2:25:32 And so that really changed the course of my life.
2:25:44 And I ended up going to Georgia, sitting for my pharmacy boards in Georgia, becoming a licensed pharmacist in Georgia, practiced pharmacy while I was in graduate school, which today is almost a no-no.
2:26:04 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.
2:26:15 But, you know, 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.
2:26:24 But, you know, got done with a PhD and was working as a pharmacist during that time.
2:26:36 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.
2:26:45 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.
2:26:49 It interacts with this protein and it does this and it does all these great things.
2:26:51 And you’re so lucky to be trying this.
2:26:55 I’ll be anxious to hear if, you know, how it works for you.
2:26:58 And they would just look at me and say, do I take it with food or not?
2:27:07 And that was the – I realized I was standing in the wrong place to impact the public, right?
2:27:16 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.
2:27:30 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-wise.
2:27:37 And then obviously doing the research and following that passion, I was lucky.
2:27:53 I mean my PhD was around synthesis of analogs of a natural product called lobeline, which came from Indian tobacco, Native American Indian tobacco, not cigarette tobacco that was used actually as a respiratory stimulant.
2:27:54 So this is hoppe?
2:27:58 No, this was lobella inflata was the plant.
2:27:58 Okay.
2:28:03 And so lobeline was the compound that we worked on and made analogs of.
2:28:23 We were looking at it, interestingly enough, coming back to the cholinergic 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.
2:28:28 And so it also left the caveat of do they actually live long enough to develop dementia?
2:28:28 What’s the answer?
2:28:30 We don’t know.
2:28:43 However, since that time in the 90s, the whole cholinergic hypothesis of Alzheimer’s disease evolved and those are the major treatments we have for dementia through the FDA approved process now.
2:28:45 I’m so glad you mentioned it.
2:28:58 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.
2:29:03 People will take that, cut that, run with it, come back later and say I’m addicted to nicotine pouches.
2:29:07 I always follow that statement with it raises blood pressure.
2:29:15 It’s highly habit-forming slash addictive and has a bunch of other issues that might make most people want to avoid it.
2:29:28 But nonetheless, nicotine, which stimulates the cholinergic pathway, as you point out, does seem to be protective against a loss of cognitive function, at least somewhat, and loss of neurons, dopamine and cholinergic neurons.
2:29:32 I don’t get paid by big nicotine.
2:29:39 Yeah, and that’s what drove a lot of research back in those days to really see, could we find something?
2:29:57 The idea was, the hypothesis really was, could we find a nicotine that, one, wasn’t addictive, two, didn’t interact with the cardiovascular system, and three, ideally, that we could put in a vitamin every day that people could take to ward off neurodegeneration.
2:29:58 And?
2:29:58 No.
2:30:00 Darn.
2:30:00 Darn.
2:30:03 Otherwise, I don’t think I’d be sitting here talking to you.
2:30:04 No, no, you’d be on a yacht someplace.
2:30:06 Actually, I take that back.
2:30:12 You’d probably be on a yacht someplace that has a small chemistry lab, and you’d be probably running mass spec.
2:30:13 Like, marine natural products.
2:30:14 Exactly.
2:30:19 Yeah, but I think, you know, that led to me going to a postdoc at the University of Minnesota.
2:30:31 I’m working for opioid chemists that really defined chemically the opioid receptors through analogs of naturally occurring opioids like morphine.
2:30:39 And then it kind of launched me into my own career of saying, hey, I’ve worked now on natural products.
2:30:49 Even though 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.
2:31:02 And so when I got to the University of Mississippi, which happens to be a natural products mecca for pharmaceutical natural products research, there’s the National Center for Natural Products Research there.
2:31:08 There’s the National Institute on Drug Abuse’s Federal Marijuana Farm is there.
2:31:17 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.
2:31:29 And so that’s where I started working on salvia divinorum, and salvia divinorum generated a compound called salvinorin A, which is to this day thought to be one of the most potent hallucinogens.
2:31:41 Non-nitrogen containing, diterpene, we talked about terpenes, very similar, not very similar structurally to cannabinoids, but in composition, just carbon, hydrogen, oxygen.
2:31:47 It interacted with kappa opioid receptors.
2:31:54 And kappa opioid receptors, there’s a huge difference between mu opioid receptors, kappa opioid receptors, and delta opioid receptors.
2:32:00 Those are the three sort of traditionally accepted opioid family receptors.
2:32:12 Mu is actually the Greek letter and was defined by Morpheus, the god of dreams, which is morphine got its name, and that’s where the mu receptor sort of nomenclature came from.
2:32:17 And since it was related back to Greek mythology, they gave it the Greek symbol mu.
2:32:25 And then when they found these other receptors, kappa and delta, they just maintained that Greek sort of nomenclature.
2:32:30 We all know that mu is the primary target for clinically used analgesics.
2:32:31 It also causes the euphoria.
2:32:42 Kappa opioid receptors also have analgesic effects, and it was for a long time thought that targeting kappa opioid receptors was the holy grail of painkillers,
2:32:52 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.
2:32:58 So they’ve moved into human clinical trials, and we learned something in psychiatry at that moment,
2:33:02 that kappa opioid receptors cause dysphoria instead of euphoria.
2:33:04 So people don’t like the effect.
2:33:05 So people don’t like the effect.
2:33:10 However, there’s a group of people out there that tend to like whatever that is.
2:33:10 Being miserable.
2:33:13 That makes them feel better.
2:33:16 Maybe they’re miserable by nature, and that makes them feel better.
2:33:24 I don’t know what is there, but there was a whole group of people using salvia divinorum plant.
2:33:25 It’s called diviner sage.
2:33:32 It’s a mint from Oaxaca, Mexico that was used by a shaman there to diagnose people.
2:33:40 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.
2:33:49 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.
2:33:51 So this is a fascinating plant.
2:33:56 And that plant is the plant that led me to Mitragyna speciosa.
2:34:13 So I was funded by NIDA, National Institute on 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,
2:34:21 I’d like to invite you to this neuroscience meeting and give a talk on naturally occurring pain medications or substances.
2:34:24 And so I said, that sounds cool.
2:34:25 That should be easy.
2:34:26 There’s aspirin.
2:34:27 There’s morphine.
2:34:28 There’s this.
2:34:37 And so I dove into the literature and started looking for all these different sources of naturally occurring pain medications.
2:34:50 And lo and behold, there was Mitragyna speciosa with an incredible track record of study by SmithKline and French, which was now GlaxoSmithKline.
2:34:55 Back in the 60s, they isolated Mitragyna out of the plant.
2:35:00 They did as much, and to this day, it’s still the most complete study in the literature.
2:35:06 So 19, I think it’s a 1972 paper by Mako et al.
2:35:13 I can’t remember the journal, but it detailed all the clinical development of Mitragyna.
2:35:24 And at the end of the day, they decided to not pull the trigger on full development because it was no better than codeine as an analgesic.
2:35:39 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.
2:35:44 You know, we’ve come to learn there’s problems with NSAIDs as well, like ibuprofen.
2:35:45 Liver issues.
2:35:48 Liver, kidney, GI bleeding.
2:35:50 Also, they’re not that potent.
2:35:50 Yeah.
2:36:01 No, they’re for mild pain, and Mitragyna was even recognized back then as being very comparable to codeine, which is really for more moderate pain.
2:36:03 It’s not morphine.
2:36:08 That’s a whole other discussion, but it’s much less potent than morphine codeine is.
2:36:18 It has great anti-tussive properties for cough, and that’s why they put it in cough syrups, and it works better for that than it really does for pain control.
2:36:28 But it was just equivalent to that, and they said there’s no point in trying to compete with this new class that’s safe, right, or thought to be safer.
2:36:31 So they shelved the project at SmithKline and French.
2:36:39 Thank God they did, because that’s what I found, and that was when I realized nobody’s touched this plant.
2:36:41 Fantastic arc.
2:36:42 Yeah.
2:36:50 And one that really reflects a constant curiosity and willingness to see when a door opens and go through it.
2:36:51 Yeah.
2:36:54 So it’s really wonderful that you did.
2:37:08 Clearly, that’s in your nature, and I think one consistent theme throughout, there are several, but what I heard were themes related to intense curiosity, a real practical grounding.
2:37:09 You’re a practical guy.
2:37:10 It’s clear.
2:37:16 It comes from your pharmacist father and your mom, who impressingly—
2:37:19 My wife may not agree with this, but—
2:37:29 And your mom, who impressively is what I meant to say, went back and, you know, after raising you guys and became a scientist in her own right and teacher.
2:37:34 And then this element of public education, teaching pharmacists, teaching neuroscientists.
2:37:45 I’ve long wanted to do an episode about Kratom, and for a variety of reasons, the most important one being that many people ask about it,
2:37:52 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.
2:37:54 You hear, this is the greatest thing ever.
2:37:56 Help me or someone I know get off opioids.
2:37:59 And then you also hear, this stuff is dreadfully bad.
2:37:59 Right.
2:38:11 In the course of, you know, researching Kratom, it’s not hard to find your name because you’re responsible for publishing, you know, an enormous percentage of the work on Kratom.
2:38:16 But I would also hear things from people like, got to get Chris McCurdy on.
2:38:17 He’s the man.
2:38:19 I heard he’s the man a lot.
2:38:25 And so I just really want to thank you for coming here today with the intention to teach.
2:38:26 I’ve clearly learned.
2:38:28 Everyone’s learned so much from this—
2:38:28 Thank you.
2:38:30 —from hearing you today.
2:38:36 And your nuanced perspective that when someone says, is Kratom good or bad, safe or not safe, you break it down.
2:38:39 Look, here are the different things we’re talking about when we’re talking about Kratom.
2:38:41 And I list off some of the key takeaways earlier.
2:38:43 Serving size matters.
2:38:47 Kratom-derived products versus isolates.
2:38:49 Why are you using Kratom?
2:38:52 Maybe the F around and find out reason is not a good reason.
2:38:53 But is it pain relief?
2:39:01 Is it to avoid or trying to alleviate a much more serious condition or addiction in some cases?
2:39:03 Drug interactions.
2:39:04 There’s your pharmacist side.
2:39:09 This case example of a seizure and on and on.
2:39:16 I mean, you’ve just done a spectacular job of explaining the nuance that one has to address that question with.
2:39:34 I 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.
2:39:41 And that’s a beautiful dance, and you’re clearly encyclopedic about all of it.
2:39:45 So thank you so much for coming here, for sharing all this knowledge so clearly.
2:39:49 People are going to be safer and are going to make excellent use of this knowledge, I’m sure.
2:39:59 And as things evolve in the world of Kratom and coca leaf and cacao, please come back and share with us what you discover.
2:39:59 Absolutely.
2:40:01 Thank you so much for having me.
2:40:06 Thank you for giving me your platform as well to get this education out there.
2:40:19 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.
2:40:20 Well, it’s been a pleasure.
2:40:21 Thank you.
2:40:25 Thank you for joining me for today’s discussion with Dr. Chris McCurdy.
2:40:28 To learn more about his work, please see the links in the show note captions.
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2:41:06 For those of you that haven’t heard, I have a new book coming out.
2:41:07 It’s my very first book.
2:41:11 It’s entitled Protocols, an Operating Manual for the Human Body.
2:41:17 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.
2:41:25 And it covers protocols for everything from sleep to exercise to stress control, protocols related to focus and motivation.
2:41:31 And of course, I provide the scientific substantiation for the protocols that are included.
2:41:34 The book is now available by presale at protocolsbook.com.
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2:41:39 You can pick the one that you like best.
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2:42:22 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.
2:42:27 We have a foundational fitness protocol that covers cardiovascular training and resistance training.
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2:42:43 Thank you once again for joining me for today’s discussion with Dr. Chris McCurdy.
2:42:47 And last, but certainly not least, thank you for your interest in science.
2:43:01 And as I 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.
2:43:12 If you go to livemomentus.com slash Huberman, you will find many of the supplements that have been discussed on various episodes of the Huberman Lab podcast, and you will find various protocols related to those supplements.