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Speaker A: Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, my guest is doctor Nolan Williams. Doctor Williams is a medical doctor and professor of psy... |
Speaker B: Yeah. |
Speaker A: But before we get into that discussion, I wanna ask you about depression, broadly speaking. |
Speaker B: Sure. |
Speaker A: Intractable depression. How common depression is or isn't. I heard you say in a wonderful talk that you gave that depression is perhaps the most debilitating condition worldwide. And yet, in contrast to other medical conditions like cancer, we actually have a fairly limited number of tools to approach depres... |
Speaker B: Yeah, absolutely. So depression is a condition that has a lot of manifestations. So you can have kind of a depression that's primarily loss of interest. You can have folks who feel very anxious and they're kind of overactive. You can have people who don't have any anxiety at all, and they're very underactive... |
Speaker A: There's a lot to unpack there. One thing that you said, I'd like to focus on a bit more, because I think we hear that the brain and the heart are connected. But you described, I believe, a direct relationship between areas of the brain associated with emotion and heart rate. Yes, and that makes perfect logic... |
Speaker B: Brain is it the first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's the sense of control governor of the brain. And then what we know is that when you use a magnet, use what we call Faraday's law, this idea of using a magnetic pulse to induce an electrical current in ele... |
Speaker A: So you mentioned left dorsolateral prefrontal cortex. Anytime I hear about lateralization of function, I get particularly curious, because obviously we have two mirror symmetric sides of the brain. There are rare exceptions to this, like the pineal and things of that sort that are only. There is only one pin... |
Speaker B: Yeah. So left dorsolateral is thought to be the side that when you excite it, when you kind of do excitatory stimulation, potentiating sort of stimulation, that you can reduce depressive symptoms. And a guy by the name of Mike Fox at Harvard has demonstrated that if you have strokes in the brain that cause d... |
Speaker A: It's incredibly interesting. And just so people know, if you're curious, what the connectome is, connectome is a term that was built out of this notion of genomes being large collections of sequencing and mapping of genes. They're proteomes of proteins, of connectomes, those so called connectomics of connect... |
Speaker B: Yeah, it's a great question, and it hasn't been worked out, which your original question was around in a left handed individual, which, as you know, 25% of those folks end up having a right brain dominance, or 1% of right handed people have a right brain dominance if it's flipped. Unfortunately, that study s... |
Speaker A: Interesting. Well, in that case, going with what we do know, that stimulation of dorsolateral prefrontal cortex slows the heart rate down transiently, but slows it down and seems to alleviate at least some symptoms of depression, leads me to the question of, why would that be the case? Does it tell us anythi... |
Speaker B: Yeah, that's a great question. I'll answer the second question first. We know that there are ongoing trials of this. If you stimulate in the vagus nerve in an implanted vagus nerve stimulator, you can actually have this afferent parts of the vagus project, ultimately up to the DLPFC, through the cingulate, t... |
Speaker A: What if I were somebody who did not have a stimulating electrode in my vagus nerve and I was dealing with minor depression, and I decided I wanted to take some other approach to slow my heart rate down via the vagus. For instance, exhale, emphasized breathing, or deliberately slow cadence breathing, things o... |
Speaker B: Absolutely, yeah. So there's a number of studies implicating DLP, the dorsal lateral, and say, meditation, mindfulness, that sort of thing. And they're small studies, but pretty well design studies suggesting that behavioral interventions in mild depression actually work quite well. There seems to be a volit... |
Speaker A: So I'm both intrigued and a little bit perplexed by this relationship between heart rate and depression. On the face of it, I would think of depression as depressed. So lower heart rate might make somebody more depressed. You've mentioned catatonia or somebody that just doesn't seem motivated or excited to d... |
Speaker B: Yeah. And to be clear, the deceleration of the heart rate is in the moment when the stimulation is happening, but it's not something that's necessarily maintained chronically. It's more of an indicator that you're in the right network more than it appears to be itself central to the mechanism. That heart rat... |
Speaker A: I'm so glad you mentioned the parasympathetic nervous system, which, of course, is most people think of as the rest and digest, or the calming side of the autonomic nervous system. As I'm hearing you say all of this, and in particular what you just told me, which is that it's not as if having a lower heart r... |
Speaker B: Yeah, absolutely. Absolutely. Okay. |
Speaker A: I just want to make sure that I'm framing this correctly in my mind. |
Speaker B: Yeah, absolutely. And in some studies, if you do the same identical stimulation on the right dorsolateral, you can get an acceleration, you know, just kind of further confirming this idea of lateralization. Right. That even. It appears that even the prefrontal cortex, you know, cortical areas seem to be late... |
Speaker A: We've talked about transcranial magnetic stimulation for getting into these networks. And I also just want to take a brief tangent and say, because I've heard you say this before, I think it's so vital what you're saying, that it's really not about stimulation of areas or any specific brain area or vagus ner... |
Speaker B: Yeah, no, it's a great question. So, one of the studies that we've been working on, in addition to the depression work, is actually trying to change trait hypnotizability. So David Spiegel and I have been working on this, and he's found and published this ten years ago, that a different part of the left dors... |
Speaker A: You have to suppress a response. |
Speaker B: Yeah, yeah, exactly. And so. I'm sorry, you name the color, and you see the word written in a different way. And so, basically, if you stimulate in a way that inhibits the left dorsolateral prefrontal cortex, or either one, you can actually knock out the ability to do that well, and it'll take longer for peo... |
Speaker A: I'd like to take a quick break and acknowledge one of our sponsors, athletic greenshouse. Athletic greens, now called ag one, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the ... |
Speaker B: Okay, that's right. |
Speaker A: Okay. A rule in some sense is like that is a transiently adopted belief system. So I could imagine that in depression, which has all sorts of backstory to it, that of course the psychiatrist or psychologist or friend can pull on that thread. Like, for instance, somebody might believe that they are bad or tha... |
Speaker B: That's right. |
Speaker A: And it seems like there's something about prefrontal cortex that, in principle, gives flexibility to rules based on what we know on the Stroop task. So, given its connectivity, can we assume that the talk therapy that occurs in a. The psychiatrist's office or with a friend, or through journaling out somethin... |
Speaker B: Yeah, absolutely. So, in a kind of standard cognitive behavioral therapy session, what the therapist is trying to do is identify those beliefs and. And kind of determine how fixed they are. If they're flexible, as you're saying, and then help folks to find another explanation for them and to kind of reintegr... |
Speaker A: So you're not talking about, obviously physically moving these structures. You're talking about, in time, their activation. So in one case, it's like the coach telling the player what to do, and in the other case, like the player telling the coach what to do. And you restore order to the game. |
Speaker B: Or order to the game. What it looks like is depression, to your point, is a bunch of spontaneous content that's semi volitional, that's being generated out of this conflict detection system. The cingulate that seems to sense conflict and feed that information gets overactive in depression. And then in depres... |
Speaker A: Can we therefore say in crude terms that the dorsolateral prefrontal cortex really is the governor of how we interpret physiological signals and spontaneous thoughts. |
Speaker B: It places a lens that the rest of the brain sees things through. And you can do these experiments where you can put a normal, healthy control person in the scanner, and you can make them feel like they have a loss of control, and then you can see that region come offline, so you can experimentally manipulate... |
Speaker A: You mentioned the cingulate and the anterior cingulate in particular, because now I feel like for the first time in my career, I have some sense of what prefrontal cortex might actually be doing besides providing a bumper for the rest of the brain. The cingulate, it seems, is a more primitive structure in th... |
Speaker B: Yeah, so that Stroop task, those incongruent word color associations, the dorsal part of that, for obsessive compulsive disorder patients, certain kind of triggers. You'll see some of the neuroimaging studies will point to anterior cingulate. In the very crude psychosurgery world 50 years ago, the anterior c... |
Speaker A: Is it involved in some of the dissociative states that sometimes people who are very stressed or depressed experience? You said catatonia being an extreme one. But I know someone, for instance, that when they get really stressed, and it can even be if someone yells at them or someone's angry, even if someone... |
Speaker B: Yeah. Yeah, there's. So you see catatonia as an extreme outcome of depression and of sometimes schizophrenia and other illnesses. Dissociation is an extreme outcome, or even some cases a less extreme outcome of PTSD and trauma. And it's also a phenomenon that happens naturally in some people that are highly ... |
Speaker A: I am highly hypnotizable. David's hypnotized me a number of times. In fact, we have a clip of that on our Huberman lab clips channel. I've always, always started my early teens, I started exploring hypnosis. I'm extremely hypnotizable. And self hypnosis or assisted hypnosis, I don't know that I ever go into ... |
Speaker B: Yep. |
Speaker A: And my assumption is that as a dissociative anesthetic, that it leads to dissociative states where people can sort of third person themselves and feel somewhat distanced from their emotions. I've also been hearing that there are emerging treatments, psilocybin being one of them, but some other treatments, MD... |
Speaker B: Yeah. |
Speaker A: And can also lead to relief of depression. Now, whether or not this, again, reflects that depression is many conditions as opposed to just one, or whether or not somehow tickling or in some cases pushing really hard on the opposite ends of the scale, really matter. I am absolutely fascinated and again, also ... |
Speaker B: Yeah, that's a great question. Yeah. So for ketamine, the level of dissociation appears to be correlated with the therapeutic effect. It appears to be necessary but not sufficient to produce an antidepressant effect. And so, folks that don't have any psychological change from the ketamine or don't experience... |
Speaker A: Was this low dose in altrexone, 50 milligrams. |
Speaker B: So it's pretty high dose, yeah. And so we gave a typical ketamine therapeutic dose, and then we gave 50 milligrams of naltrexone or placebo. And then in the same individuals, we gave two infusions, one with each of those conditions. And if they had an antidepressant effect, we waited until they relapsed, and... |
Speaker A: That's required. |
Speaker B: That's required to cover the pain. But what may be happening is it's not just treating physical pain, maybe treating emotional pain as well. Right. At least transiently, it seems to have an antidepressant effect. Chronically it seems to have a very pro depressing effect. It can make people treatment resistan... |
Speaker A: It's so critical, and it's so critical to the other conversation that we'll surely get to, which is the progression of psychedelics from illicit, illegal drugs to clinically validated, and presumably at some point either decriminalized or legal drugs, which has not yet happened, at least not in the US. Um, b... |
Speaker B: Yeah. That experiment that I described a bit ago around the naltrexone and ketamine is the first time I'm aware of where we were able to essentially eliminate an antidepressants effect by using a second drug as a blockade. And it highlights a bigger issue. The issue that we haven't had a good way of really u... |
Speaker A: The sense of control. |
Speaker B: The sense of control, the sense of they're not doing the stimulation themselves, they're not administering the drug in these trials themselves, and they probably never will. These will probably be medical treatments, but they are choosing to do it, and in that sense, they are in control. |
Speaker A: I have a good friend. I won't out him, for reasons that'll become clear in a moment, who was quite obese and lost a lot of weight and was really proud of himself. And then I guess we could say he sort of relapsed, in a sense. Not all the way, but far along, but his tone around it was very different. He knew ... |
Speaker B: Yeah. So the first question, I think it's an evolutionary neurobiology answer, right? At the individual person level, it doesn't make a whole lot of sense that when we're really stressed out, some of us want to eat more, right, at the individual person level, because it's like, that's not particularly that g... |
Speaker A: Obviously, a placebo for a psilocybin journey is hard to imagine. |
Speaker B: We've been thinking about this, and maybe that ketamine study that I was talking about earlier, if we could give people naltrexone and ketamine, maybe that's a good placebo condition, because we know that we can block any of the actual antidepressant effects academy they still haven't experienced. That's one... |
Speaker A: And what do those generally say? I mean, that they are effective for a number of people after one session, two sessions. What's sort of the general contour? Let's start with psilocybin and MDMA. |
Speaker B: Yeah. So MDMA appears to, in one to a few MDMA sessions, have an anti PTSD effect that seems to be outside of the kind of standard assumed levels of PTSD improvement that you can observe in individuals with this level of PTSD. So what we call the effect size, which is essentially like a Cohen's d effect size... |
Speaker A: So does that mean that for people that have trauma who do a. And again, we're talking about in a clinical setting, they take one or two doses of. Of MDM. I think the standard maps dose is 150 to 175 milligrams. Again, doing this with a physician, et cetera, controlled clinical trial. Legal. |
Speaker B: Yep, exactly. |
Speaker A: They do it once or twice. And broadly speaking, what percentage of people who had trauma report feeling significant relief from their trauma afterward? |
Speaker B: It's about two thirds of people had a clinically significant change in their PTSD. |
Speaker A: It's impressive. |
Speaker B: Which is impressive. Right. |
Speaker A: And how long lasting was that? I mean, these trials were ended pretty. |
Speaker B: Recently, so it appears to last for a while. In the earlier trials, where they followed people out, it seemed to last for kind of in the years range for some people. And so it's, you know, it's pretty. It's pretty compelling. Psilocybin, you know, in contrast that with ketamine, which only on average lasts a... |
Speaker A: So they have to get repeated infusions of ketamine every ten days or so. |
Speaker B: Yeah, forever for some people. Or they end up getting like a bunch of doses for a couple of weeks, and then for some people, that seems to last a while. That's where I think the psilocybin story for depression and the MDMA story for PTSD seemed more interesting to me. |
Speaker A: So for psilocybin, what is the rough percentages? And this would be relief not from trauma, but from depression. |
Speaker B: Yeah, yeah, exactly. So it's an open label studies. It's closer to, like half to two thirds of people end up getting better depending upon their level of treatment resistance. In the blinded trials, it was more like a third or so of people experienced relief. And this is a press release of the data, and so i... |
Speaker A: For many years, it was reported in the popular press, and there was a paper published in science that MDMA was neurotoxic, that it would kill serotonin neurons. This was what was always said. Then I saw another paper published in Science that wasn't a retraction of the previous paper, but rather was a second... |
Speaker B: There's an interesting study that I think the guy's name is Halpern. Last name's Halpern. |
Speaker A: Not Casey Halpern. |
Speaker B: I think Joshua Halpern. I'm blank on his first name. |
Speaker A: Casey Halpern was a guest on this podcast and is a former colleague of ours at Stanford, who, unfortunately, we lost to University of Pennsylvania, and maybe someday we'll bring him back. |
Speaker B: Yeah, that's right. So this individual received some NIH funding to, actually, Nidae National Institute for Drug Abuse funding to explore individuals of the Mormon faith in Utah who partake in only MDMA. So the way this works is that MDMA happened kind of after a lot of the religious documents were developed... |
Speaker A: Drug list, the banned substance above. |
Speaker B: Banned substance list. |
Speaker A: I have some good friends who are lds. |
Speaker B: Yeah, great people. I do as well, just to kind of set a facts. And so these folks only use MDMA, but they don't. They're not the problem with some people using drugs. They're poly substance users, right? So you can't say it's the MDMA if they've also taken other psychedelics and they've taken opiates and the... |
Speaker A: So does that mean that it was not damaging? |
Speaker B: It was not damaging. It's hard to know, because to really do this study well, you'd have to track these folks down before they ever took MDMA and do a pre post and compare to people that didn't. But this is about as good of a study as you can do, given the situation to be able to check this out. Additionally... |
Speaker A: Interesting. Yeah, I know that sourcing is key. And here we're talking about clinical trials where purity is assured. And years ago, when so called raves were really popular, maybe they're still popular. Never been to one, so neither wouldn't know if they're happening or not. That's how in the know I am. But... |
Speaker B: Yeah, it makes sense. I mean, the difference between, say, MDMA and psilocybin is that MDMA is kind of an amphetamine of sorts, right? So it has effects in dopamine, and the psilocybin is pretty neutral and maybe a little bit of dopamine effects, but kind of much more of a serotonergic focused drug. And so, ... |
Speaker A: Since you mentioned psilocybin, let's talk a little bit about the neurochemistry of psilocybin as a serotonergic agent. My understanding is it operates on these. Is it the five ht, serotonin, two C receptors, two a, two a. Excuse me, two a and receptors. And that I've seen a bunch of different reports in ter... |
Speaker B: Yeah. |
Speaker A: De Gates. The thalamus, right through the reticular thalamic structure. So, what is the evidence that any of that is true, and are there other phenomena? Is there involvement of dorsolateral prefrontal cortex that we are aware of? And where I'm really headed here in a few minutes? Is there a place for combin... |
Speaker B: Yeah, definitely. So, David Nutt and Robin Carhart Harris's work around neuroimaging psychedelics, they were some of the first folks to do that work. And to their great surprise, they thought there was going to be an increase in activity on psychedelics. And what they found is the opposite. There's an overal... |
Speaker A: I want to ask you about this phenomenon I've heard about during psilocybin journeys. I heard about this from doctor Matthew Johnson, who's running a lot of the clinical trials at Johns Hopkins and has been a guest on this podcast. He said that there's something seems to be important about the patient who's d... |
Speaker B: Yeah, so I'll talk a little bit about something called exposure and response prevention therapy. That's a typical kind of gold standard treatment for OCD. And I'll help to kind of help this a little bit conceptually. And so what that really is, it's a letting go therapy. And so exposure and response preventi... |
Speaker A: Fascinating. You said it's exposure response therapy is the traditional name. Exposure response, prevention, prevention therapy done outside of the psychedelic journey. |
Speaker B: It's done outside the psychedelic journey. But that idea of letting go is present in both of those, you know, psychotherapy, kind of straight up, totally sober, non psychedelic, non anything, psycho manualized psychotherapy that we know works really well for OCD and then in that psychedelic state. And so peo... |
Speaker A: When I was in college, I developed a compulsive superstition. I'm not afraid to admit this. I somehow developed a knock on wood superstition. And I would have. I was actually kind of ashamed of it because it rationally made no sense. I don't consider myself a superstitious person. Never was a superstitious k... |
Speaker B: Yeah. And I think a lot of people, it's interesting, if you look at, say, the OCD scale or the depression scale or whatever, we don't define normal as zero. We define normal as some number range above. So zero to, in the case of the Montgomery Asperg depression rating scale, one of the depression scales, we ... |
Speaker A: It's good to know. I actually feel some relief just hearing this, because I am slightly, I wouldn't say ashamed. I was sort of embarrassed by it, but I offer it as a, you know, it is what it is, as they say, and it certainly doesn't seem to hinder my life much. Knock on wood. So if we could talk a bit about ... |
Speaker B: Yeah, that's fair. So ibogaine is one of the alkaloids that you can extract from iboga tree root bark that's typically growing in the country of Gabon, Africa. So Gabon is one of the west african countries, kind of middle of Africa, on the west coast. And Gabon has a group of folks called the bwiti. It's a r... |
Speaker A: How long does it last? Is it truly one night? |
Speaker B: It's usually, you know, it can go depending upon if you get redosed or anything go sometimes depending upon how fast you metabolize it, sometimes 24, sometimes 36 hours. Sometimes it can be shorter. But it is a long time. Wow, it's a very long time. So it's definitely the longest acting psychedelic substance... |
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