1 year ago
Andrew Huberman, PhD, is a neuroscientist and tenured professor at Stanford University’s School of Medicine. Andrew is also the host of the Huberman Lab podcast, which aims to help viewers and listeners improve their health with science and science-based tools. New episodes air every Monday on YouTube and all podcast platforms. www.hubermanlab.com
The course of a lot of these drugs and how they hit market is super interesting. I've been learning more and more about this because one of my colleagues who works on aggression and mating behavior, which fascinates me, has identified some peptides that can really reduce anxiety. They put these to the pharmaceutical industry. Pharmaceutical industry wasn't interested in them at all, even though the safety margins are huge. So you say, why wouldn't they want this? Well, it turns out these same drugs failed in a schizophrenia trial a long time ago. So no one will go near it with a 10 foot pole. So the way the pharmaceutical industry generally approaches drugs is they love to remarket drugs for which there's already FDA approval because then they don't have to go through all the safety stuff. And when they do that, they can renew the patent. This is crucial, right? Because if you can get the generic version now with things like GoodRX and these little apps you can get them, you can go into a pharmacy, hit GoodRX and it'll say, oh yeah, we've got some stuff that's about to expire. This $300 a month drug is $10. I've had this happen. It's amazing. If they can keep it out of the generic market, that's huge. And the way to do that is to find a new clinical use. So I don't know which one came first, narcolepsy or these focusing ADHD uses or as a performance enhancer. But if the pharmaceutical industry, the people that own the patent to that drug can find a new legitimate use, they just bought themselves, I think, another 10 years on the patent. So this was originally prescribed for schizophrenia and then they were going to use these peptides for mating? Yeah. So in terms of the aggression, this is really interesting. This is the work of a guy at Caltech named David Anderson and he works on mating and aggression and the relationship- Human beings. In what he has work related to humans and the neighboring lab works on humans, but in mice and in humans. But these areas of the brain are really conserved. We can talk about which brain area. But what he discovered is- Conserved? Meaning, sorry, that in mice and in humans, these brain structures look identical. And that the same classes of neurons exist that if you were to stimulate them, because neurosurgeons have done this, people go into a rage or in animals, if you stimulate them, the animals go into a rage. In fact, there are these videos online, they're incredible, where this is Da-Yu Lin's work when she was in David Anderson's lab. So you take two mice, a male mouse and a female mouse and they're mating, as it were. And then they stimulate these neurons because they can do that now using light, believe it or not. And the male immediately tries to kill the female. You can even just put him in a cage alone with a glove filled with air. It's walking around, you stimulate these neurons and he just goes into a rage. Just trying to destroy this glove. But here's what's super interesting and no one understands. If you put this animal into a cage alone and stimulate, it looks pretty normal. It doesn't do anything. So it's not like it attacks itself. And every time there's this horrible news event, like the school shooting thing or something like that, I always think, you know, like what's going on in the, there's a certain brain area, it's called the ventromedial hypothalamus. This is a brain area that's really interesting because it has a population of neurons that control mating. You stimulate them and animals will just start trying to copulate with basically whatever is around. If you give them a choice of their usual preference of, you know, females, if they're male, males if they're female, because that's the way mice go, one or the other, they will just try and start mating. You stimulate the other group of neurons and they will try and kill the other mouse. So these are like switches in the hypothalamus. Are these like very distinct? When we talk about like neurons and switches, like how do you distinguish between the, can you see them? Like what is the difference? Great question. So for many decades, it was known that if you stimulate this brain area, you could get aggression. This is actually Nobel prize winning work of a guy named whose last name is Hess. And what they found was if you stimulate this brain area, cats would go into either two kinds of aggression. It was either defensive aggression, kind of with, with, you know, hair up, or you would stimulate a little bit more and they would do the, you know, predatory aggression. Right? I'm probably doing this wrong, but you know, like ears forward and you know, you're the hunter. Last time I'm still learning about, you know, animal behavior in this way. But what's really interesting is that for years, no one could understand why if you also stimulate this brain area and you used a different pattern stimulation, you get mating behavior. Turns out that the neurons are mixed in there like salt and pepper. David Anderson's lab figured out that these are molecularly distinct neurons. And what makes them distinct is really interesting. If they stimulate only the neurons that have the estrogen receptor, they become aggressive. And this again goes back to this thing that we talked about a while ago, which is that testosterone can aromatized, converted into estrogen has these incredible effects on aggression and masculinization of the brain. And a lot of people think, in fact, people heard me say that last time and said, oh, you're trying to say that estrogen is doing everything testosterone is doing. No, it's that things like testosterone and estrogen control gene expression. And so the fact that it's estrogen or testosterone, it doesn't really matter. It's the fact that these are molecularly distinct neurons. They can trigger these neurons and they can get very distinct outputs of behavior. But what's crazy is you stop stimulating the animal just goes back to doing whatever and then it goes, oh, yeah, I think I'll try and mate again. Now eventually the females like, hey, this is getting confusing. But this it's clear that these sorts of things are also happening in humans. But normally we have kind of a weighting of aggression versus mating behavior. Some people choose to combine those. There's kind of extremes with that. Rape, there's rough sex, there's all sorts of, it's uncomfortable for people to think about that. But there's a continuum between aggressive versus approach type behaviors. And for whatever reason, this drove me to start looking at different mating behaviors of animals online. Like if you watch Ferrets mating, it's like he's biting the back of her neck. She's squealing all over the place. Like this is uncomfortable for some people to see, but some people probably like watching this stuff. But you look at animals mating and there's a kind of a balancing act between what looks, it's not, you wouldn't call it lovemaking. Let's put it that. You'd call it mating that's pretty aggressive. And that's very common in the animal kingdom. Is it common in the animal kingdom because in order to have strong genes that pass on, you need a strong animal and so they express themselves in this aggressive way to prove to the female that they're strong enough to mate and procreate? Like what is the reason for that sort of aggressive, is there a reason? Well it's a great question. So there's this theory called hydraulic pressure theory. This was developed by Conrad Lorenz, which is another Nobel Prize winner who studied animal behavior. And here's the idea is that all of these different populations of neurons are in the hypothalamus. This is a little tiny, tiny thing. I mean it's the size of like a little gob stopper candy, like a little gumball. And you've got neurons for aggression, neurons for mating, neurons that turn on to make sure that animals don't try and mate with the wrong species. We take this for granted. Like how come a cat doesn't try and mate with the dog? Now the dog might hump, but that's a different thing altogether. So it's all harbored in there. This hydraulic theory is that all of these things are kind of weighted probabilities. So there's never zero probability that any of this will happen unless they're in sleep. But maybe it's 10% aggression, 80% mating while they're mating. Maybe another male enters the arena and now there's sort of like a confusion, like am I going to have to fight or can I keep mating? These kinds of things. Because oftentimes these animals are communal in some way. And so the way that Anderson explained this to me, and we had a conversation about this recently, is that the brain might actually get confused in certain moments. And there's also a kind of opioid pain relief thing that gets released during sexual activity. Pain threshold goes way up. And we were talking about this in the context of fetishes because if you look at fetishes, they're not random. True fetishes can be pathologies where people actually require the presence of some thing in order to become aroused. And those things almost always, if you look at true fetishes, are things like feet, dead bodies, feces, animals, things that are all very infectious. Exactly. Your facial expression illustrates it perfectly. My facial expression for those listening is yuck. Exactly. So that's disgust. And you have circuits in your brain that are for disgust that are about getting you away from that thing because it's infectious, putrid, disgusting and out of context. And then you think about sex and food appetite and all that, and it's all appetitive as they call it. It's moving towards it. It's bringing in more of those molecules as opposed to trying to get away from vomit or something. Right, but the feet thing, isn't it? Guys like pretty feet? We're very visual animals, and so it may cross over into visual perception. And what arouses people differs, obviously. People have their different proclivities. But true fetishes are a kind of a confusion of this circuitry, right? Where people confuse or learn arousal associated with something that's actually quite dangerous. I mean, you take the extreme one like dead body, it's like incredibly- Is that normal? No, no, no. Excuse me, not normal. Common. Like the dead body one? Not common. Not common. Common enough that you brought it up though. Well, I've been reading up on this because I'm fascinated by the primitive as in addition to the more evolved parts of the brain. So the way Anderson describes it is you'll see animals mating and then all of a sudden he'll bite the back of her neck or sometimes she'll bite him. And the theory is that some of the neurons, and they've seen this in brain imaging in real time because they can do that in animals, some of the neurons that are responsible for aggression will just suddenly spike up there, right? And will kind of overtake the other behavior and then they'll go back to mating. Now when you're talking about studies on animals and they're doing this, there's these ethical questions if you're going to do a study on humans. If you wanted to stimulate those same neurons and try to incite aggression or hostility or even arousal, but has anybody done it? They have. They have. They have. So a good friend of mine, Eddie Chang, he's the chair of neurosurgery at UCSF. He spends his life and he makes his living probing around in the brain of people who have epilepsy, looking for the site where if they stimulate the person will have a seizure so that they can burn that area out or make some other manipulation. And he's told me that he's been poking. You can't poke around at random, right? Every scientist would love to just do that experiment, just go in and kind of search. But there are sites where they'll stimulate thinking they might evoke a feeling of pleasantness or no feeling at all. And the person will go into a rage in the OR, in the operating room, because they're wide awake. You've probably seen these things of people with neurosurgery and they're playing the violin and things of that sort. Occasionally they'll hit an area where the person will say, I'm feeling super angry right now. And they'll say, let's back off a little bit from there. And they'll chart where they were in the brain. That is wild. So there's just like a spot. Yeah, there is. And we have switches, right? I mean, we have switches for rage, switches for all these things. I mean, that's like the psychologist Carl Jung, this idea that we have all things inside of us. I mean, people vary in their propensity for rage or for love or for anything. But at some level, we do have all things inside of us. We have the circuitry within us. And do you feel like that variation is neurochemical? I think it is neurochemical and I think it is learned as well. This peptide that we were talking about earlier becomes relevant in this context. So David's lab discovered there's a peptide called tachykinin. It's related to another molecule that's involved in pain relief called substance P that we all make. Tachykinin has a bunch of different forms, but in humans there's tachykinin 1 and tachykinin 2. In mice or humans that are socially isolated for a period of time, tachykinin levels go through the roof. This is very relevant to the recent past of around the pandemic, in my opinion. It goes through the roof and what happens? It creates anxiety, anger, and in particular, aggression. And so there are drugs that are tachykinin inhibitors. And I asked David, I said, well, why aren't we giving tachykinin inhibitors to people that are feeling anxious and aggressive and kind of tamp that down? And we just had yet another school shooting and we could talk about what that's about or not. And he said this drug is actually approved. It's very safe. Stop. What are you saying? There's a drug that can block... No, no, but you're saying what that's about but we're not? Oh, sorry. The tachykinin, I mean, was it elevated in, for instance, the kid that went and shot all those kids? How could they find that out post-mortem? I think they could do what's called mRNA and C2 hybridization. They could see how much of the gene for tachykinin was being made. I think they should do post-mortem. I don't know how he was killed if his brain is still intact. I think, like most people, there's very little concern about him and more concern about the victims as it should be. But just like with CT and football players, you want to know where the damage was. And also, whether or not there was a brain thing there. And if that brain thing was there, it doesn't mean necessarily that he was born with a bad brain. He might have been born with a dysfunctional brain. But social isolation increases anxiety and aggression. There's no question. And actually, I was in... Social isolation increases aggression. Absolutely. Really? Absolutely. Feelings of aggression and friction with the world. Us, them kind of thinking. I was in New York, this was a few months back, and it was the most eerie experience because we were there recording some podcasts and something came over the news that there was literally Killer Loose. It was that guy in Brooklyn went into a subway, released some smoke bombs and shot people. They found him in the Lower East Side walking around. Someone found him. So Killer on the Loose in New York became a real thing for the time we were there. It was super weird because we're staying down near the Lower East Side. And they get the guy, and what do they say? They say the same thing they always say about these guys. He was a loner. He was socially isolated. Then you find the angry posts. You find the things online. It's never like, okay, you've got crazies like the BTK killer and people who were in their church and stuff, but were sociopathic killers on the sly. But these kind of random, what seem like random acts of aggression, almost always these people were highly socially isolated. I'm not evoking sympathy. I want to be very clear. I know what you're saying. Nothing makes me more ... I think everyone is furious and frustrated about this situation with the shooting. But I asked David about this. I was like, why aren't these drugs being used or prescribed? He said, because years ago, there was a trial at a pharmaceutical company exploring the role of this drug in schizophrenia for reasons that aren't clear. And it didn't work. And it cost the company a ton of money, so now no companies want to go near it. There's this kind of blacklisting of drugs that failed in trials. As a consequence, there's probably dozens, if not hundreds, of very useful medications out there that are just not being explored.