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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. My guest today is Doctor Matthew Hill. Doctor Matthew Hill is a professor of cell biology and ana... |
Speaker B: Thanks for having me. |
Speaker A: Delighted to have you here, because you're an expert in the biology of cannabis, a topic that many, many people are curious about for a variety of reasons. So just to kick things off, maybe we can get people up to speed on what cannabis is, a little bit about how it works in the brain and body to produce the... |
Speaker B: I mean, cannabis is a plant that has been around for some time. It's kind of got like a very rich history of use around the world for different cultures, for both kind of medicinal and spiritual and recreational purposes. Over several centuries, the plant has kind of become, I mean, in the west, it really wa... |
Speaker A: Fascinating plant. You mentioned the psychoactive effects. Some people listening to this and watching this presumably have experienced those psychoactive effects. Others perhaps have not. How could we describe for both groups what the psychoactive effects are? You mentioned the higher the concentration of TH... |
Speaker B: So, I mean, the way that people would usually describe the intoxicating effects of cannabis is they would. I mean, people often refer to it as there being some euphoria or some positive mood, not on the same order as what people would describe with, say, cocaine or some other stimulants, but there certainly ... |
Speaker A: That's interesting. Is that true even if they've never used cannabis before? |
Speaker B: I'm not actually certain if you are allowed to have someone in a drug study, if they've never done something before, I think they have to have had some previous experience with a drug, and they pay. |
Speaker A: So now pot smokers everywhere are running to look at such a thing. |
Speaker B: But I don't think you can use drug naive people. I mean, I don't run human clinical lab studies, so I can't explicitly say it, but that's my understanding, is that someone has to have had even limited, like, you know, not much, but at least once or twice they have to have experienced the drug before. So I do... |
Speaker A: Interesting. |
Speaker B: If they're not expecting it. |
Speaker A: What about the effects of cannabis on time perception? There's this reputation that cannabis has for disrupting time perception, that people will think a long period of time has passed, when in fact, very little time has passed. Maybe it's sometimes even the reverse. Is the mechanism by which cannabis can ad... |
Speaker B: I wouldn't say it's well worked out. There definitely seems to be some, like, temporal dilation, like you're saying, where people think things have, you know, someone will be high and someone will ask them, how long do you think time has passed? They would report usually longer periods of time have passed th... |
Speaker A: You mentioned effects of cannabis on appetite, and I know one of the medical uses of cannabis is in people that are undergoing treatment for cancer in order to stimulate appetite, because oftentimes they have very low or even no appetite due to the cancer treatment. Is the mechanism by which cannabis can sti... |
Speaker B: I think we almost need to take a step back, actually, to talk about how cannabis works in the brain before we kind of go into that. So THC, as a molecule, exerts almost all its effects. They're acting at this one receptor, for the most part, that's widely expressed through the brain called the cannabinoid ty... |
Speaker A: CB one. |
Speaker B: Yeah, CB one is the shorthand for it. People tend to create analogies to describe what receptors are. For those of you who don't know, most people use a lock and key analogy that a receptor would be a protein that sits on a cell and a molecule that binds to it, like THC, is the key that fits in that lock. Wh... |
Speaker A: Although cannabis users everywhere use that argument. |
Speaker B: I know people love to leverage things. If it's a plant, it's, you know, it's natural and safe, and there's obviously issues we'll talk about with that. But I mean, really, this is just biological redundancy. I mean, nature only has so many ways to create something, and so there's going to be things that end ... |
Speaker A: Where in the body is, it's mostly immune cells. |
Speaker B: So you'll see CB two s mostly on, like, macrophages or other kind of. |
Speaker A: Immune cells gobble up debris. |
Speaker B: Yeah. And that basically regulate inflammatory processes. And so the main role of CB two seems to be much more about, like, regulating inflammation. So that's kind of a separate role that can certainly impact the brain in different ways. But when we talk about the effects on the central nervous system in the... |
Speaker A: So sort of a homeostatic scale and trying to maintain a middle range. |
Speaker B: Yeah, I mean, at the end of the day, no matter how you discuss it and what system you discuss it, I think the majority of people in the cannabinoid field would agree that the primary physiological role of endocannabinoids is to maintain homeostasis. That's what they do. They keep everything in its happy plac... |
Speaker A: And that's probably why the cb one receptor is so widely distributed, is that neurons can excite or inhibit each other, that is, raise or reduce the amount of electrical activity in the, let's say, nearby neuron, because we're talking about retrograde signaling. But ultimately, you don't want runaway excitat... |
Speaker B: Exactly. |
Speaker A: And you don't want runaway inhibition because that looks like suppression of ability to think, move, et cetera. Exactly. |
Speaker B: So you want to keep things in where they should be, but you don't want them to get overexcited. Endocannabinoids, in kind of a very prototypical sense, act as this circuit breaker, essentially, where they go back and gate how much is coming in. And they do this by, through various mechanisms, essentially tur... |
Speaker A: So inhibiting the inhibitor leads to more excitation. |
Speaker B: Exactly. I usually liken it to basically taking the brakes off of a car while you're going downhill kind of thing. Like, you're, you know, you'd use your braking system to keep things in check, but if you want to go faster, you take the foot off the brakes and you let things accelerate. And so this can be re... |
Speaker A: Interesting, if I may. Earlier you mentioned one of the potential psychoactive effects of cannabis is euphoria. Does that mean that the euphoria associated with cannabis use is independent of dopamine and is more reliant on something like perhaps the opioid receptor system or the serotonergic receptor system... |
Speaker B: I wouldn't say that cannabinoids don't affect dopamine because what we understand in the ventral tegmental area, which is kind of the hotspot of dopamine neurons, or at least the ones that are involved in motivation and stuff, those neurons are regulated by a lot of inhibitory neurons that dump out inhibitor... |
Speaker A: So there's an opportunity for indirect neurons. |
Speaker B: Exactly. So what you have is those neurons that regulate the dopamine neurons are very rich cannabinoid receptors. This is actually kind of similar to how mu opioid receptors work for things like morphine or heroin. And essentially what the cannabinoid receptors will do is when they're activated, they'll tur... |
Speaker A: And so he discovered anandamide and decided to call it bliss because he had familiarity with cannabis or because he took anandamide as a direct experience. It takes a lot for a scientist to discover a molecule, but then for scientists to discover a molecule and then name it bliss for a particular reason, you... |
Speaker B: Ravi. Michele was also the guy who isolated and discovered THC. So, I mean, he has a very. He's kind of the grandfather of a whole cannabinoid field. So he has a landmark paper from 1964, which, ironically, and this is one of these weird pop culture things, I don't know if this is true, that paper was publis... |
Speaker A: Well, now that potential myth is definitely going to propagate. |
Speaker B: But, yeah, so he'd been in the field for a while, and so he had studied cannabis on that side. And then in 1990, his lab isolated anandamide as being the first molecule that activated the receptor endogenously. And so it was kind of. Yeah, I think it was a little tongue in cheek that he named it the way he d... |
Speaker A: Your thermostat analogy is perfect here. |
Speaker B: So, in that context, it kind of is like just the thermostat of the house, whereas two ag is like, let's say, the pinch hitter who gets brought in to do the heavy lifting. And so two ag, during a situation like, let's say something like, even like a seizure, is an extreme example where you have a huge amount ... |
Speaker A: Very interesting. A lot of aficionado questions about the receptor biology. I'll just spare everyone the details by just highlighting something that you already said far more eloquently. Than I will, which is, I think it is fascinating that this whole system has both a tonic, like a steady release capability... |
Speaker B: So, yeah, if you go back to the munchies question you had. So if we tie into that one of the. So there's a few ways. I mean, cannabinoids and feeding are a really interesting thing because proto, like, if you ask people, like kind of the prototypical responses to consuming cannabis, most people would usually... |
Speaker A: We just had an episode with Zack Knight from HHMI and UCSF where he talked about the Ag RP neurons and different neurons of the hypothalamus. We can link to that in the show. Note captions nowadays, a rich understanding of the neurons that stimulate food seeking craving. |
Speaker B: And then, so we know that, like cannabinoids, they regulate, again, those inhibitory inputs around a g RP neurons, for example. And so one thing they can do is disinhibit those Ag Rp neurons, so they become more active and that can drive food seeking behavior. So that's certainly one mechanism of it. But the... |
Speaker A: Work proof that even under the influence of cannabis, animals will work hard. |
Speaker B: Yeah, for food. I don't know about other stuff, but for food, they certainly will. I mean, at least Wiertz and Cassie Moore have done this at Hopkins as well. They've shown similarly using what we call progressive ratio, which is essentially a thing where it's like, the first time you press a lever, you imme... |
Speaker A: As many of you know, I've been taking ag one for more than ten years now. So I'm delighted that they're sponsoring this podcast. To be clear, I don't take ag one because they're a sponsor. Rather, they are a sponsor because I take ag one. In fact, I take ag one once and often twice every single day, and I've... |
Speaker B: Yes, I mean, they dynamically change all. |
Speaker A: The time, but you're talking about experimentally or recreationally adjusting their levels. But how does one do that without using THC? |
Speaker B: So, okay, few things there. We'll take a step back so THC itself isn't going to. It does its thing by acting directly on the cannabinoid receptor. |
Speaker A: So it sort of mimics the anandamide and two ag. |
Speaker B: Yeah. So THC, going back to kind of the pharmacology of this. So THC, if you look at how it interacts with the receptor, it's not a heavy duty molecule. So, I mean, this was kind of one of the things that came up before as well, is this idea that THC is a sledgehammer and it overrides endocannabinoids. |
Speaker A: By the way, Matt's referring to the fact that I said that in a previous solo episode about this, and there I was nesting it in the concentrations of THC that can be found in high THC cannabis. So essentially what I was saying is that at very high THC concentrations, the amount, maybe not the binding affinity... |
Speaker B: I mean, you don't really actually need much THC in the brain to produce psychoactivity. It's a little bit of a mystery, to be honest, exactly how it works. I mean, I think the main way that most people in the cannabinoid theory field would look at this is that THC is not like a very strong agonist. I mean, e... |
Speaker A: So you said anandamide is high affinity, low efficacy. |
Speaker B: So THC is the same. THC is actually only a partial agonist. It's not even a full agonist at CB one. |
Speaker A: But it is high affinity. |
Speaker B: It's high affinity. So it has the ability. But the tricky thing with that is it can outcompete two ag, but because it's a lower efficacy agonist than two ag, in that sense, it's almost blocking the effects, not amplifying them, blocking the. |
Speaker A: Effects of two ag. But does it block the effects of. |
Speaker B: Anandamide, THC and anandamide? The way I would visualize it is because they seem to have relatively similar affinities and efficacies of the receptor. They might, let's say, dance around. So it'd be somewhat interchangeable. The difference there is, and this, I think, is the big point about what THC does ve... |
Speaker A: That's a very interesting point that we should highlight. So there are drugs that now exist that can block the breakdown of anandamide, make more available, presumably by disrupting some enzymatic breakdown. |
Speaker B: Exactly. |
Speaker A: And therefore lead to more binding of the now elevated levels of anandamide that are available to cb one. And you see no psychoactive. No psychoactive people are not aware that they've. |
Speaker B: Yeah, you can do. No one can guess. Yeah, no one can guess. |
Speaker A: What is it used for? |
Speaker B: Well, I mean, it was developed, the first molecule really was developed by Pfizer to look at if it could work on pain. The first trial that was done did not work. It was like a yemenite kind of strange, osteoarthritic knee pain trial that was like, even in that trial, the positive control of naproxen barely ... |
Speaker A: Aleve. |
Speaker B: Yeah, essentially, yeah. And that drug didn't work that great to begin with. So it was maybe some issues with the trial, but it essentially killed the development of the drug from that point on, because everyone's like, oh, it's not gonna work. So it kind of shelved for a while. A colleague of mine, Marcus H... |
Speaker A: It seems like a lot of gymnastics to basically confirm what they already knew, which is that even greatly elevating the anandamide by blocking this enzymatic breakdown of anandamide leads to, at least from what I'm understanding, vastly different subjective experience than ingesting or smoking THC. Which bri... |
Speaker B: So what's it doing? |
Speaker A: And cannabis. So I think it seems that this thing that we call cannabis and THC are overlapping with the endogenous effects of anandamide. But here you're not talking about endogenous normal levels, you're talking about pharmacologically greatly increasing anandamide. No psychoactive effect, no euphoria, no ... |
Speaker B: Yeah, I mean, I think. I would say the main way that we think about this is the difference between endocannabinoids and THC is endocannabinoids are going to be released in a very specific spatial and temporal manner. |
Speaker A: They evolved to do that. |
Speaker B: Yeah. So there's going to be, and I think it's very clear that anandamide, for example, is not active at every synapse that has cb one. And so when we boost anandamide signaling by inhibiting its metabolism, all we're doing is amplifying anandamide signaling at the synapses, it already exists. Whereas THC, w... |
Speaker A: You're introducing the ligand, the thing that binds the receptor. This is far and away different than, say, like the actions of amphetamines, which are disrupting the normal biology in a way that's giving you an amplification of an endogenous mechanism. If that was all just nerd speak, for those listening in... |
Speaker B: I think the problem is when you just blanket activate all the cb one receptors in the brain indiscriminately, like you do when you consume cannabis with THC, the resulting effect is the intoxicating state. And it's probably because there's a lot of cb one receptors in the cortex, and those are going to be di... |
Speaker A: And so you're changing all the networks simultaneously. |
Speaker B: Yeah. So if you hit a whole bunch of networks simultaneously, you're just going to change the way that information processing and perception occurs. And I think as a consequence of that, that's what produces the intoxicating state. Not that THC is like a super duper version of an endocannabinoid or that it's... |
Speaker A: That's very helpful. So the analogy that I was considering using coming in here, like the difference between endogenous testosterone or estrogen versus pharmacologic testosterone or estrogen given as a therapy. Yeah, it doesn't apply is very different because that's a levels issue. This is a levels and an ex... |
Speaker B: Yeah. This is a lot more to do with just the nature of how it hits everything, because so, for example, if we talk about feeding, we know it's been established at this point that, for example, if an organism doesn't eat for like day, so you fasted at that point in those feeding circuits in your brain, like t... |
Speaker A: Super interesting. Well, I have to imagine that there are many people who use cannabis not to stimulate appetite, but for other reasons. They either like the euphoria or to adjust their anxiety. What are some other known mechanisms by which cannabis can change people's psychology? Let me focus in on one part... |
Speaker B: I mean, honestly, this is a bit of a tricky one to speak to, because I just don't think there's good evidence for it either way. Or I just don't. I mean, as far as I'm aware, it hasn't been studied in a lot of depth. I mean, there's some things, you know, a lot of the stuff that's been done is usually more l... |
Speaker A: My understanding is that people who use cannabis have certain forms of memory, but not necessarily poorer memory across the board, is that correct? |
Speaker B: I don't think I would say that. I don't think you could lump anything in that context. I mean, I would say the only thing you can say confidently that I would be comfortable saying is that acutely, while someone's intoxicated on cannabis, there is definitely short term effects on memory processing. |
Speaker A: So people tend to negative effects or enhancements or decrements. |
Speaker B: I would say most of it has to do with recall or consolidation. So there does seem to be some. I mean, certainly the animal evidence is very compelling there. But again, we can talk to what some of the limitations of that are. But in humans, I would say most of the work that's been done would suggest there is... |
Speaker A: And so I should just say this point has often been confused by undergraduates and others to assume that just because one can gain proficiency at a task while under the influence of a substance does not mean that you have higher proficiency at that particular task while under the influence. In fact, the way i... |
Speaker B: I don't think better off, no. But they would probably score better than someone who had never studied drunk and came to the test drunk. |
Speaker A: Correct. |
Speaker B: Just because they had had some state dependent learning. And so I think when we're talking about. If you're talking about someone who's a chronic cannabis user, they're going to have done a lot of cognitive tasks while they're under the influence. So if you acutely test them, the impairment you might see in ... |
Speaker A: Yeah, thanks for clarifying that. And also thank you for clarifying the discrepancy between endogenous cannabinoid binding and affinity for CB one versus THC. I really appreciate that, because that's something that you and I discussed in light of the solo episode I did about cannabis, and now you've made it ... |
Speaker B: Yeah, I mean, I don't actually even think it matters if it's high THC in the cannabis. I think some people can get very intoxicated off of very, very low doses of cannabis. |
Speaker A: Is that right? |
Speaker B: I mean, you look at edibles, for example. I mean, this may be an interesting segue into root of administration stuff. Cause I think it's an important point that a lot of people don't recognize is the difference between someone inhaling cannabis versus someone orally consuming cannabis. Like a different game. |
Speaker A: Yeah. Let's talk about this, because I know that you and I arrived at different understanding of the fastest, typical, and slowest routes of entry for THC into the system to arrive at the brain. The numbers I gave in the previous discussion about this were related to how quickly inhaled smoke moves from the ... |
Speaker B: Which is very fast. |
Speaker A: Right. Which is very fast. |
Speaker B: I don't know if it's different than nicotine. I'm not sure. Again, I don't know if I would say that. But, yeah, it's very fast. |
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