Datasets:

MasaFoundation

/

huberman_lab_Dr__Matthew_Hill_How_Cannabis_Impacts_Health__the_Potential_Risks

like 0

Follow

Masa Foundation 4

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 anatomy at the University of Calgary. His laboratory studies cannabis and its effects on stress, its effects on feeding, and its effects on the behavioral impacts of cannabis exposure at different stages of development. The origin of Todays podcast episode is a bit unique, so id like to share a little bit of that background with you. Previously I did a solo episode of the Huberman Lab podcast about cannabis, the biology of cannabis, some of its medical applications and uses, as well as some of its potential harms. That episode came out several years ago now and remains a very popular episode. Its had millions of views and millions of listens. Several months ago, we posted a clip of that episode to X, formerly known as Twitter. And Doctor Matthew Hill responded to that clip on x with criticism about the specific points made within that clip, most notably my discussion of the data that cannabis use can, in some individuals, cause psychosis. He also took issue with some of the specific points I made in that clip related to potential differences in the biology of the effects of different strains of cannabis, most notably indica versus sativa strains, and a few other points as well. Now, as somebody who's been in the field of science for several decades now, I'm very familiar with the fact that every field, every single field within science, has debates within it, controversies, and sometimes outright battles. And to me, that's part of what makes science interesting. It's an evolving process. It's something for which we should all be very curious to try and understand what we know, what we don't know, and try and get to the real answers. So right off the bat on X, I invited Doctor Hillen onto the podcast, and he accepted the invitation. So today's episode is really a unique one in that, first of all, we cover an enormous amount of biology and clinical data as it relates to cannabis. Meaning today's discussion is not a debate. It is really an up to date discussion about how cannabis works. So we talk about THc versus CBD. We address the question of whether or not indicas versus sativas have different biological and subjective effects or not. We, of course, talk about the potential correlation, maybe even causation, between cannabis use and psychosis. I think you'll find that discussion very interesting. And we talk about how cannabis relates to hunger, to memory, to anxiety and to the treatment of anxiety. I'm certain that, given the widespread use of cannabis nowadays, that you'll find the discussion to be both an informative and potentially useful one that could help guide decisions as to whether or not you or others should or should not use or avoid cannabis, as well as one that can simply inform about this very interesting compound. And of course, you'll learn a lot of neuroscience and biology along the way. Before we begin, I'd like to emphasize that this podcast is separate from my teaching research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is eight sleep. Eight sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity I've spoken many times before on this podcast about the critical need to get sleep, both enough sleep and enough quality sleep. Now, one of the key things to getting a great night's sleep is that your body temperature actually has to drop by about one to three degrees. In order for you to fall and stay deeply asleep and to wake up feeling refreshed, your body temperature actually has to increase by about one to three degrees. One of the best ways to ensure all of that happens is to control the temperature of your sleeping environment. And with aidsleep, it's very easy to do that. You program the temperature that you want at the beginning, middle, and the end of the night, and that's the temperature that you're going to sleep at, and it will track your sleep. It tells you how much slow wave sleep you're getting, how much rapid eye movement sleep you're getting, which is critical. And all of that also helps you dial in the exact parameters you need in order to get the best possible night's sleep for you. I've been sleeping on an eight sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better. Eight Sleet recently launched their newest generation pod cover, the pod four ultra. The pod four ultra cover has improved cooling and heating capacity, higher fidelity sleep tracking technology, and the pod four cover has snoring detection that will automatically lift your head a few degrees to improve airflow and stop your snoring. If you'd like to try an eight sleep mattress cover, you can go to eightsleep.com huberman to save dollar 350 off their pod four ultra eight sleep currently ships to the USA, Canada, UK, select countries in the EU and Australia. Again, thats eightsleep.com huberman todays episode is also brought to us by element. Element is an electrolyte drink that has everything you need and nothing you dont. That means the electrolyte, sodium, magnesium and potassium in the correct ratios, but no sugar. Now I and others on the podcast have talked a lot about the critical importance of hydration for proper brain and bodily function. Research shows that even a slight degree of dehydration can really diminish cognitive and physical performance. Its also important that you get adequate electrolytes in order for your body and brain to function at their best. The electrolytes, sodium, magnesium and potassium are critical for the functioning of all the cells in your body, especially your neurons or nerve cells. To make sure that I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of element in about 16 to 32oz of water when I wake up in the morning and I drink that basically first thing in the morning. I also drink element dissolved in water during any kind of physical exercise I'm doing, especially on hot days if I'm sweating a lot and losing water and electrolytes. If you'd like to try element, you can go to drinkelement.com huberman spelled drinklmnt.com Huberman to claim a free element sample pack with the purchase of any element drink mix. Again, that's drinkelement.com huberman to claim a free sample pack. Today's episode is also brought to us by Better help. Betterhelp offers professional therapy with a licensed therapist carried out entirely online. There are essentially three things that make up great therapy. First of all, great therapy consists of having good rapport with somebody that you can really trust and talk to about the issues that you're dealing with. Second of all, that therapist should provide support in the form of emotional support or directed guidance. And third, expert therapy should provide useful insights, insights that allow you to better understand not just your emotional life and your relationship life, but of course also your relationship to yourself and to career goals and school goals. Meaning excellent, therapy should also inspire positive action. Betterhelp makes it very easy for you to find an expert therapist with whom you really resonate with, and that can provide the benefits that I just described. Also, because Betterhelp therapy is done entirely online, it's very time efficient and it's easy to fit into a busy schedule because it involves no commuting to a therapist's office, finding a parking spot, or sitting in a waiting room. If you'd like to try betterhelp you can go to betterhelp.com Huberman to get 10% off your first month again. That's betterhelp.com hubermandhenne and now for my discussion with doctor Matthew hill. Doctor MATT Hill, welcome.

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 various effects that it produces and how some of that comes to be, and then we can dig into some of the nuance. I have a lot of questions about different types, if you will, of cannabis, the relationship to mental health, potentially to mental illness. We're going to drill into all of that. So just to kick things off, what is cannabis?

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 wasn't a thing mainstream wise until about the sixties, and then it became kind of introduced as like a drug of choice that a lot of people started using during the rise of the hippie era. And I think that was a lot of the time that cannabis got popularized. And then I'd say more recently, cannabis has, into the nineties and on, has become kind of a very heavily used drug by the, a large swath of people ranging from teenagers on up in terms of what it is inside it. I mean, it's a plant with a lot of very complex chemistry and biology behind it. So there's a lot of molecules that it carries in it. We call these cannabinoids, and they come in a lot of different flavors. But the main one, that's the most important one when we talk about cannabis and what drives the kind of intoxicating and what I would refer to as psychoactive effects of cannabis is delta nine tetrahydrocannabinol, or what we call THC. And that really is what dictates the psychoactive and intoxicating properties of the plant. And so the amount of THC that is within the cannabis plant will influence how high a person's gonna get when they consume it. There are probably 70 to 100 in some odd other cannabinoids that are within cannabis. Most of them are pretty trace levels, and they vary from different types to cannabis from one another. But the other one that's had a lot of attention is cannabidiol, or what we call CBD. CBD is structurally looks pretty similar to THC, but doesn't behave anything like THC. It's not intoxicating at all. I'm not sure. I would probably say it's not psychoactive in the sense that people can't tell if they're on it or not. But some people still say it's psychoactive because people claim it can affect anxiety state or mood state or other things. So in that context, maybe psychoactive is still somewhat appropriate of a word to use. And then there's a whole bunch of other things like cannabinol, cannabigerol, and these other minor cannabinoids, most of which we really don't understand any of the biology of. We don't know what they're doing. They may influence some of the effects of THC, they may not, but they're there. And they vary in their composition from different flavor of different cannabis to different flavor. And then there's those other things called terpenes, which are kind of highly volatile compounds, but they're not specific to cannabis. They're found in tons of other plants. So this is a lot of which seems to contribute at least to some of the smell and the flavors of cannabis. So these are things like limonene, which gives some cannabis kind of a citrusy odor or flavor to it. Pinene, which gives things more of, like, a earthy tree kind of smell. Beta caryophyllene, myrcene. And these terpenes are also some of which do have known biological activity, some don't. And they vary quite heavily across different kinds of cannabis as well. And again, there's some thought that they may be influencing some of the psychoactive or intoxicating properties of cannabis. But the reality is we really don't know a lot about them at this point. There's kind of some emerging work that's starting to come out now that kind of plays with giving someone THC and adding in one other terpene or one other minor cannabinoid and seeing how it influences things. You can imagine with the plethora of molecules that exist in cannabis, doing this in a piece wise manner could take decades to really get to a point where we understand all the interactive components of cannabis, but people tend to refer to this as an entourage effect. That's kind of a phrase that gets used quite widely in the cannabis world. And the idea behind that is that if you took pure THC, and so there are some distillate pens and things that exist out there now in the product market, which are basically isolated, THC with trace levels of anything of other stuff would be very different than if you had THC in combination with some of these other molecules and how they might influence how THC itself is working or not.

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 THC, the higher someone will get, the greater the intensity of the high. What is the high? And I know people are probably chuckling, saying, does Huberman not know because he's never done it? That's my own business. I just want people to understand what you mean by psychoactive.

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 is some kind of positive aspect. I mean, if there wasn't, people wouldn't be using it if they didn't feel positive about it afterwards. There can be, you know, other aspects in terms of changes in feeding behavior. People might find things funnier than they found things. It might change the way they perceive various environmental stimuli, but it can also, for some people, create a bit of a dissociative state to some degree, where people might feel a little bit out of body. So it's kind of a complicated, intoxicating state to describe, I would say. Because usually, if someone's referring to something like a stimulant, they're just like, oh, people feel like they're God, they're like, possibility everywhere. Yeah, exactly. They're very happy, and they're kind of jacked up. And I think with cannabis, the way people would describe it would be very different. It's kind of an introspective state. You might be more aware of your bodily feelings and states that are going on inside of you, your kind of internal state, but you also have a different perspective on external stimuli. You might process information a bit differently, focus on things a bit differently. So it's kind of a complicated state to describe, I would say. Usually when people are assessing if someone's intoxicated, the kind of lab work that people get someone high, they just kind of use what we call a visual analog scale, which is like a one to 100 or something, or zero to 100, and say, do you feel high? Do you enjoy this? Would you say you feel euphoric? Is your mood elevated? So they're kind of scaling things like that. So I think that's more typically in a lab setting, how you would define if someone's high or not from it. And this is why when people do studies with something like a placebo cannabis or a very low THC cannabis, you'll see kind of a scaling. So even if you give someone a placebo cannabis, if they think that they're getting cannabis, a lot of people still respond by saying they feel a bit high.

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 don't know if you would take someone who was completely blind. Cause I don't know how they would replicate that state.

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 adjust time perception known?

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 than I actually have. I feel like there is some older work I could dig up to see if I could find that is either in, like, it might even be in pigeons, but it might be in rodents. That's looking at, like, temporal ordering. And they give animals cannabinoids, and that's kind of a cleaner way of seeing because they are very good at learning. Like, if I wait ten minutes, and then I engage in a behavior, I get a reward. And so you can really train animals to have this ordinal timing where they kind of know distinct periods of time. And if they give them cannabinoids, they respond differently. So in that context, it does still seem to produce some state where there's an altered perception of time passing. And so I think if we were going to really understand the mechanism of it, that would probably be the way to go. But I'm not super familiar with the work because no one's. I mean, anything I can think of is pretty old. I can't think of anything modern where people have actually looked at this interesting.

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 stimulate appetite known? And if so, what is the general trend of effect? It makes people hungrier, obviously, but we hear, again, in kind of recreational terms, of people getting the munchies, becoming exceedingly hungry. Is that related to some cannabis induced effect on, say, blood sugar, like insulin or glucose regulation, or is it happening at a different level?

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 type one receptor.

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. When it activates it, it triggers some biological process in the cell, in this case, a neuron, that changes its activity in some capacity. THC acts on these CB one receptors, which are very widely expressed. In fact, outside of, like, kind of ion channels that are expressed in the brain, the cb one is, I think, one of the most, if not the most widely expressed receptor in the brain. It's everywhere. So it's really important. And I think, as kind of you had alluded to previously, it doesn't exist in the. You know, this didn't evolve in humans in the hopes that one day humans would find cannabis. This is just.

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 up overlapping in the way that they function. And so the receptor that's in the brain and throughout the body, the cb one, and there is also a cb two receptor. It's not really expressed in the brain. It's in some of the immune cells in the brain, and maybe, maybe some limited distribution in actual brain cell neurons.

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 brain and behavior, we're talking almost entirely about cb one. And so both the cb one and cb two receptors, like I said, don't exist because nature was like, humans are going to find cannabis. This will all work together now. So there are molecules our body produces which we call endocannabinoids, and they are kind of funny little molecules because they don't really behave like, certainly in the brain, they don't behave like a normal neurotransmitter. So, I mean, I assume most people who listen to your podcast are relatively adept with the basic idea of how neurons work. So you have neuron a, let's call it the presynaptic neuron, because you have that gap between the two cells where they communicate called the synapse. So neuron a releases a transmitter, and it can be some that excites the neighboring cell, neuron b, or it can inhibit it. And so the way that we always kind of talk about neurotransmission in the brain is neuron a releases a chemical that crosses the synapse, acts on neuron B, and it can either jack that neuron's activity up or it can scale it down. And that affects brain wide patterns of activity. And we call that anterograde because it moves from neuron a to neuron B, which is kind of the general flow of things. And how we usually think about it, endocannabinoids are this little bit of an oddity in the sense that they could do the reverse. Endocannabinoids are actually made in neuron B on the postsynaptic side, and then they go backwards and act on neuron a to regulate how much transmitter is released. In many ways, this is like, I kind of liken it to a thermostat model for the most part. Certainly, we're talking about something like excitability. So if neuron a is dumping out something that excites neuron Bjdev glutamate, which is an excitatory neurotransmitter, as neuron B gets too excited, it's going to start releasing endocannabinoids to go back and tell Neuron a to stop driving it.

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 place, let's say.

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 excitation because that looks like epilepsy.

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 turning off the electrical activity of that presynaptic neuron so that it stops releasing neurotransmitter. They can also regulate, though, inhibitory neurotransmitter release as well. And this is usually done through a little bit more of a complex process where it's driven by excitation, but then it regulates the inhibitory pathway.

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 really important for things like forms of synaptic plasticity or neuroplasticity, let's say, where you want synaptic strengthening to happen. So, like, under a learning event or something, you want that synapse to really hardwire better. And so having endocannabinoids kind of turn off the inhibitory component is one of the mechanisms to facilitate that. But at the same time, if you want to have a bit more adaptive flexibility, endocannabinoids can weaken that synapse at the same time by acting right at the excitatory terminal itself. And so their ability to kind of play with the relative activity of a circuit is really dependent on which neuron they're acting on. And so they can regulate excitation or inhibition differentially. And, I mean, cb one receptors are found on virtually every single kind of neuron in the brain except one. I think you'll find this interesting because it's dopamine, and dopamine neurons are basically the only neurons in the brain that don't really, at least as far as we've been able to characterize to date, express cannabinoid receptors.

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 inhibitory transmitter and keep those neurons kind of quiet.

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 turn off that inhibitory control, and that allows dopamine neurons to kind of move into a state where they're more prone to go into burst firing and have big dumps of dopamine. Whether or not that relates to the positive affect or the euphoria, I don't think anyone has cleanly demonstrated that. I mean, obviously dopamine very complicated in terms of its relation to endpoints and whether it's reward or motivation. But cannabinoids definitely do have an influence on dopamine transmission. They just don't tend to do it directly. And I think that's this very bizarre and interesting component of cannabinoid signaling, is why the brain would have evolved in a way to allow every other neurotransmitter system to be actively and directly regulated by endocannabinoids. But dopaminer is kind of spared from this. So I don't know. I mean, obviously, you can always just theoretically guess as to why someone would do that. I don't know what the reason for it would be, but it is something that has kind of intrigued a lot of people, because every other system in the brain is so tightly controlled to some degree by endocannabinoids, and in this one circuit is kind of free of it. The main role of endocannabinoids is really to regulate plasticity or homeostasis, allow flexibility of circuits to either goose up their activity or ramp it down if they need to, depending on the environment, depending on the experience of the organism. So there's a lot of roles that endocannabinoids play in that domain. But even within the endocannabinoids, I mean, there's two primary endocannabinoids. And again, this is one of the weird things about how endocannabinoids work, because if you talk about things like serotonin or dopamine, you have a single molecule that gets released in the typical anterograde way, and it diversifies at the level of the receptor. So serotonin has like, I don't know, like 15 receptors or 20 or something. No, dopamine has at least five. And so the different actions that serotonin or dopamine will have is all driven by the diversification of the receptors. It's one molecule, whereas cannabinoids are the reverse. Not only do they work backwards across the synapse and work in this retrograde fashion, but really you have one receptor that is regulated by two molecules. So the diversification happens more at the level of the molecule than at the receptor, which is, again, very unique. And the two molecules that we know are kind of the bona fide endocannabinoids. There could be more. They're called anandamide, which is actually kind of a funny name because it comes from the sanskrit word anand for bliss. And so Rafi Meshulam, who was in Israel when he discovered the molecule 30 odd years ago, wanted it to reflect inner bliss, and so he named it anandamide. So it's like inner bliss with an amide bond is kind of the joke he had for it.

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 have to speculate that they had some familiarity with the.

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 published on April 20, 1964. And so the joke is, is this where 420 came from? Because the original, like, birth date of the first THC paper was 420 1964.

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 did a few years later. The second molecule, which is just called two arachidonoglycerol, or what we call two ag, that was discovered kind of in tanner, both again by Michulin, but also by a japanese group. And so we understand these two molecules don't do the same thing. They are a bit different. So the way anandamide binds the receptor is, it's what we would call a high affinity, but low efficacy agonist or molecule, at least. And what I mean by that is very low levels of anandamide are required to actually bind to the receptor. But once it binds, its ability to stimulate a biological response in that neuron is kind of caps out pretty fast. So it doesn't have, like, a sledgehammer effect, whereas two ag seems to require a bit more concentration in the synapse to be able to bind to the receptor. So it has a lower affinity for the receptor. But once it binds to the receptor. It's, like, pretty heavy duty, so it evokes a very robust intracellular signaling response. And so why we have two endocannabinoids, we're not totally sure. Some of us have theories. I'm of the camp that I think they may play somewhat differential roles, either based on the synapse of the circuit that they're working in, or this idea that maybe anandamide might be more of a tonic molecule. And what I mean by that is, we'll say it's like a stage setter. So, like, anandamide might just be kind of made by neurons on an ongoing basis and just released. And its job may be to kind of keep the steady state of a brain circuit in a desired range so that under resting conditions, it's not too active or too quiet.

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 of neural activity. Those neurons that are getting heavily activated during massive amounts of neural activity start dumping out huge amounts of two ag. And that acts as the. Okay, we really need to turn off this circuit very quickly. In this situation, and in most of these forms of, like, synaptic plasticity, like I was saying earlier, where you need to either strengthen or weaken a synapse in response to a change in the environment or in response to an experience or something that's going on, most of that is driven by two ag signaling. And so all these forms of turning things up or down in a kind of rapid and on demand manner, that's mostly two ag. So most people who study neurophysiology and, like, record activity in neurons and look at endocannabinoids, they're almost entirely talking about two ag when they play with stuff. So, yeah, that's kind of one of the ways we do it. We say that anandamide may be more tonic, and two ag might be more phasic and, like, brought online when needed, but doesn't do a lot. There is some evidence that two ag may also have a role to regulate some circuits under kind of resting conditions as well. And there certainly are some situations where anandamide might get brought into play to affect plasticity. But as kind of like an umbrella idea of how we look at it, that's often how we divide those two up. So we kind of have these two molecules. They, end of the day, do the same thing. They're regulating neurotransmitter release through retrograde signaling. But what stimulation brings them online or what drives their activity may differentiate. And we don't really understand all the details behind that, outside of the fact that we very clearly know two ag is activity dependent. So as that neuron becomes more active, it's going to make two ag to regulate its inputs. So, yeah, you have this very complex system, and it's really widely distributed in, you know, it's everywhere. The cannabinoid receptors and the endocannabinoid molecules are in the cortex. They're in the hypothalamus and striatum, the hippocampus, the cerebellum, all over the brain, except the one area where it's really interesting, actually, where you don't really see much receptor, is in brainstem populations that regulate, you know, kind of unconscious cardiac and respiratory function. So this is one of the things that really differentiates cannabis from opiates, because a lot of the signaling mechanisms between opioid receptors and cannabinoid receptors are quite similar. But as it's been well established, people can overdose fatally and die from opiates relatively easily. And the way that that tends to happen is when you activate the opiate receptors in the kind of cardiorespiratory parts of the brainstem, it depresses neural activity. So as the person loses consciousness, they also unconsciously will stop regulating their own heart and breathing. And it can be a fatal response, because cannabinoid receptors don't really exist in those regions. You don't get the same kind of impact in terms of suppressing heart rate and breathing function. And so that's. I mean, there's always the saying, like, there's never been an account of someone actually dying from a cannabis overdose or a thc overdose. I mean, certainly people can do stupid things while they're intoxicated that result in their death, but in the same manner that someone can die from consuming too much opiates, that doesn't seem to be physically possible to cannabinoids, as far as we've seen so far. And a lot of that is just because of the localization. Like, for some reason, there's just not the receptors in that part of the brain.

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, and aphasic. So the ability to spike, forgive the pun, the neuroscientists will know what I'm talking about, to spike more activity of this system superimposed on that tonic activity. Because this is something that you see in the dopamine system. This is something that you see in essentially every neuromodulator, neurotransmitter system. But it seems that the endocannabinoid system has accomplished this quite a bit differently. So, very interesting, unique system in a number of ways that raise a number of key questions.

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 say munchies is one of the things that pops up pretty regularly. And so the cannabinoid receptors are very, they are expressed in these feeding circuits in the hypothalamus, and there's a lot of complex circuitry there that can regulate food seeking behavior.

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 there's also a huge reward component to this in terms of the munchies. We know that you can also just dump anandamide, for example. Steve Mahler and Kent Barch did this work years ago, where they just put an animide into the nucleus accumbens, and that can also stimulate palatable food intake. So you also have this ability to integrate with the reward circuitry. And then there was also this fascinating paper from a japanese group in pnas, I think, about twelve years ago. And what they found was they would give a rodent a cannabinoid, and then they would stimulate different taste bud populations, and then they would look at the gustatory cortical response to stimulating the populations. And what they found is under the influence of a cannabinoid, if you stimulated sweet taste buds, you got an enhanced response in the gustatory cortex, but not if you did salty, bitter, or sour. I don't know if they did umami in that one, but it was very explicit to sweet tasting. And so you have this kind of ability to, like, jack up the way the brain is processing sweet tasting foods. You have this engagement of the reward circuitry, and then you also have this ability to regulate a G RP neurons as well as the palm c neurons. There's kind of both sides to that in the arcuate nucleus to regulate multiple components of feeding. But a big question is, my lab has become kind of interested in this as well, because we have a component in my lab that studies feeding behavior. And one of my postdocs has been doing these projects for years now, trying to understand, almost like at a behavioral mechanism level, what the munchies are. And what she's been looking at is we kind of started thinking about the idea that, you know, what is it? That because it's not just food seeking and it's not just like, just want to consume something, there's a maintenance of eating. And so we know from humans and animals, you can satiate them, you can make someone full and then get them high on cannabis, and they'll re initiate eating. So that's an interesting thing in and of itself, because that means you're disrupting either the ability of the brain to detect satiety, or you're messing with a process we call reward devaluation. And so reward devaluation is like, if you haven't eaten for a day and you see like a picture of a pizza, someone brings a pizza in front of you, it just looks delicious. That first slice tastes amazing. It's salty, it's fatty, it's delicious. You eat five of those slices, it feels greasy and nasty. And so that process of how you perceive the food and its reward salience degrades as you eat and as your brain basically shifts into a thing of, we don't need to consume calories and food anymore. We're okay, we're full now. And so we've done a series of experiments in the lab where you get the animals and either satiated in advance, where they have already devalued the food, and under a normal state, they won't eat it anymore, they won't work to get access to it, and you get them high on, like, a cannabis extract. We have these vape chambers that are, like, I don't know how else to describe it. Outside of, like, a little hot box, it's probably the best way to. Cause it's essentially a kind of a locked, airtight box that the rat goes in, and it gets, like, vapor puffs, and it fills up, and then they inhale this, and then it clears out, and they get another puff, and then it fills up. And we do this for, like, 15 minutes. And we've titrated all this to get exactly blood levels of THC that you would achieve in someone who's consuming cannabis through smoking. And so we get them to that point and then give them access to food, and they will go gangbusters. They eat food. Doesn't matter what you give them. You give them plain chow. They go to town. You give them fatty, you give them sweet. They love it all, but you presatiate them, and they get them stoned. They will reinitiate eating again, and you make them work for it, where they have to, like, lever press, and you get them stoned, and they will go to town on that, and they will.

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 immediately get a sugar. Next time, you got to hit it twice to get a pellet. Then you have to hit it four times to get one. Yeah, then you got to hit it 16, and then it kind of scales exponentially up. I mean, we've had this one female we kind of joke about in the lab, this one female rat, and you get her high, and she'll do, like, 300 lever presses to get one sugar pellet, like, she really wants it. So you can really kind of goose up their motivation to eat. And so there's clearly a rewarding aspect of this because they're motivated to engage enough in working to get access to the food. But you can also do another way of testing this question, which is you can pair a food with something that will make the animal feel nauseous, like lithium chloride. This is kind of the way that you would test condition taste aversion. So you give them access to a food, and then you give them something that makes them feel nauseous, and the animals will avoid that food. And so that's another way to kind of devalue a food is by pairing it with a nausea, so the animal no longer likes it. So again, same situation. You can get the animal stoned and it will reengage in eating that food that it had devalued through being paired with a nausea through either satiety or making it a negative associated flavor because the animal got nauseous before. You can override these effects by giving THC. That could be a complex process that either involves changes in the reward circuitry. This could be something that's from the orbit of frontal cortex, which is a very important part of the brain that scales reward and assesses how much someone wants to work, or an organism wants to work to achieve a reward at the end. So we haven't figured out the circuitry of this and where exactly it's acting. But I would say a lot of the stuff that we and others have done kind of supports this idea that a lot of what the munchies is, is this ability to kind of almost lock in the reward value of food so that it doesn't decay despite satiety, despite eating over time. It just keeps it highly salient so that they want to work for it. And then similarly, we've also, we and others have also done work to show it can block satiety signals. So we know endocannabinoids, at least, are capable of overriding leptin. So leptin is an anorectic molecule, comes out from the fat, and usually we release it when we've eaten a lot. And it's one of these things that tells our brain stop eating. It works through, again, populations in the arcuate nucleus and changes the way those neurons function to drive food seeking behavior. And we and others have shown previously that if you elevate endocannabinoids, you can override that. And actually, one of the mechanisms by which leptin seems to suppress feeding is actually by turning on the metabolism of endocannabinoids so that their levels decline. And so as you lose that endocannabinoid function, the animal is less interested in eating. And so you can prevent these anorectic effects of leptin by, like, goosing up endocannabinoid activity.

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 done that since starting way back in 2012. There is so much conflicting information out there nowadays about what proper nutrition is, but here's what there seems to be a general consensus on whether you're an omnivore, a carnivore, a vegetarian, or a vegan. I think it's generally agreed that you should get most of your food from unprocessed or minimally processed sources, which allows you to eat enough but not overeat. Get plenty of vitamins and minerals, probiotics and micronutrients that we all need for physical and mental health. Now, I personally am an omnivore and I strive to get most of my food from unprocessed or minimally processed sources. But the reason I still take ag one once and often twice every day is that it ensures I get all of those vitamins, minerals, probiotics, etcetera. But it also has adaptogens to help me cope with stress. It's basically a nutritional insurance policy meant to augment, not replace, quality food. So by drinking a serving of ag one in the morning and again in the afternoon or evening, I cover all of my foundational nutritional needs. And I, like so many other people that take ag one, report feeling much better in a number of important ways, such as energy levels, digestion, sleep, and more. So while many supplements out there are really directed towards obtaining one specific outcome, ag one is foundational nutrition, designed to support all aspects of well being related to mental health and physical health. If youd like to try ag one, you can go to drinkagone.com huberman to claim a special offer. Theyll give you five free travel packs with your order, plus a year supply of vitamin D. Three k two again, thats drinkag one.com hubermande. You're talking about increasing endocannabinoid activity. And we've said all this in the context of cannabis. So maybe we could talk a little bit about how the components in cannabis, THC mainly, but also cbD, impact these receptors, the cb one. And let's just leave cb two out for the moment, because it sounds like it's more of an immune system thing. But just to make it very clear, is there a way to increase the activity of endocannabinoids without ingesting THC?

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, but the amount of THC that is available to the cb one receptors is going to exceed what's normally found in terms of the amount of anandamide that can bind to cb one receptors. Because what you're talking about is a supraphysiological condition.

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, even if you look at its ability to trigger an intracellular response, it's much lower than two ag. It's actually more like an andamide.

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 versus endocannabinoids. Because we know now, through the pharmaceutical development of drugs that can boost anandamide levels, which exist, we have inhibitors that prevent their metabolism. We can elevate them. There's no intoxication and no psychoactivity associated with elevating anandamide.

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 worked. But because the FAW inhibitor, which is take a step back, faws the enzyme that chews up anandamide. So the drug that is developed inhibits that enzyme. So you prevent the enzymatic breakdown of anandamide. So we just call them FaW inhibitors. So this drug will boost anandamide levels quite high. And in animal research, showed some efficacy in modulating pain. And so they put it in a trial and it didn't work. Work against the positive control of naproxen, which is like an nsaid, just like Advil, basically.

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 Heilig, and Leah Mayo. Leah's now a colleague of mine in Calgary, but at the time, she was a postdoc with Marcus in Sweden. And they were able to get access to this molecule right before COVID essentially. And they did a trial in just healthy controls with it, which, again, this is kind of jumping the gun on some of the other stuff I'll talk about. So I'll tether back to that. But what they did was they dosed people for ten days on this drug. And then we looked at stress and fear, because this is something that I study, this is something that they were interested in. And we did find that boosting anandamide with this drug over ten days was sufficiently capable of dampening stress induced autonomic responses. So, like, looking at heart rate or skin conductance, I think skin conductance was the measure we did in there, but it's a proxy for, like, adrenaline release. So it blunted that, and it blunted subjective feelings of stress as well. So people had lower levels of saying they actually felt stressed, and it kind of helped remove this, like, conditioned fear memory that they had trained people to do. And so I worked with them on kind of doing the biochemistry of this to make sure the drug was working properly. But it was very interesting because we did see in that situation where elevating anandamide produced kind of like a reduction in stress perception, a reduction in stress physiology responses, and kind of helped kind of reduce fear. And so that is kind of an interesting outcome because it tracks with some of the stuff we know about cannabis, and I'm sure we'll talk about some of the PTSD stuff and anxiety later. So that's kind of one of the things. The drug has not really been used that widely yet. It's still. It's one of the frustrations I have as a scientist who does a lot of translational work with clinical partners like Leah, is that getting access to these molecules is not easy when they're not kind of wide. They're not, like, out in the market. So you can just go and get them. You really have to try and get access from the drug companies to be able to do trials with them. And so we are in the midst of trying to do that. We did just complete a trial that Leah and Marcus ran that I worked with them on as well that was on PTSD. And so there are various potential indications for this. I mean, Johnson and Johnson developed one as well, and they looked at it in social anxiety disorder. They had some moderate efficacy in their trial. So I'd say the jury's still out on exactly what we're going to do with these, but they have some potential, I think, in certain clinical settings, we just have to figure that out. Exactly. But I think going back to where we started this from, they're not psychoactive. And so, I mean, when Pfizer first made the drug, they were actually initially concerned that it wasn't getting in the brain because no one could tell they were on the drug. I mean, this was the wild west at this point. No one had any idea what endocannabinoids were actually going to do. People were basing it on what we knew about THC. So the assumption was people would have psychoactivity, but they didn't. Pfizer then actually had to do. They did a sleep study to show that it did have some effects on sleep cycle, the same way THC does. And then they also did, like, an in vivo pet binding study to show that they could displace a radioactive molecule that would bind to the enzyme in the brain.

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 brings us back to THC.

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 munchies, etcetera. Then people smoke, are taken edible of THC or cannabis, and you get a vastly different set of effects. So maybe we could talk about THC and the cb one receptor. And since we're here, we might as well talk about CBD. And I think you're going to tell us the lack of interaction with cb one receptor. What is cannabis doing at the level of these receptors? Because it makes me wonder whether or not these receptors are the whole story, or whether or not cannabis is, as you mentioned, 70 plus active molecules in there, terpenes and a bunch of other things that may modify their action, that this thing we call cannabis has many more actions than just mimicking the endogenous cannabinoid system.

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, when you consume it orally or inhalation wise, and it gets into your blood and into your brain, it's just blanket activation. You're just carpet bombing the whole system indiscriminately.

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 the context of amphetamines, what you're doing is you're taking an endogenous system, a naturally occurring system, and you're greatly amplifying the amount of dopamine, the amount of norepinephrine that's available. With what we're discussing today, the endocannabinoid system seems to be producing a set of effects that might overlap with the THC effects. But THC is doing a bunch of other things, and that's because THC, and we'll talk about CBD, but at least THC is acting as the ligand. It's in some sense, we don't want to say replacing, but it's masking the effects of anandamide.

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 differentially regulated at different times by endocannabinoids, whereas when THC hits them, all of them are going to get affected at once. And if you think of the way that I had described how cannabinoid receptors work, by essentially, I mean, at its simplest form, what cannabinoid receptors do is they change the way that two neurons talk to each other.

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 boosting endocannabinoids. It's kind of like just indiscriminately activating all the receptors, as opposed to a system that's very finely tuned to do very specific things at very specific times.

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 extent issue.

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 the arcuate area where these AGRP neurons and stuff are, you'll start seeing elevations in endocannabinoids. So endocannabinoid levels start kind of going up and up following kind of fasting periods. And part of this is because they're trying to engage that feeding circuitry now and they're shifting the activity of those neurons to promote food seeking behavior. Because an organism is basically like energy detecting its periphery and saying, oh, you know, we might be burning through our energy reserves, we should probably eat more. And so there are obviously a few mechanisms that do this. NPY is another one, and ghrelin and things like that. So there's a lot of redundancy in these systems. But endocannabinoids are just one of the molecules that seem to fine tune the feeding circuitry. And so in states of fasting, endocannabinoids go up explicitly in that circuit. And there's some evidence they also go up in, like, the nucleus accumbens and affect some of the reward circuitry. So they're probably driving food seeking behavior and enhancing the rewarding aspects of food at the same time. And so that's like a natural endogenous mechanism to regulate feeding based on nutritional state. THC, on the other hand, you know, it hits the brain. Yes, some of it's going to be the intoxication, but in tandem, you're going to hit the cb one, receptors that are in those feeding circuits as well. And the consequence of that is going to be, I mean, the way I kind of analogize it to people is, I say it's almost like tricking the brain into thinking that you've been fastest because you're now activating receptors that are normally activated following kind of a fasting state. And as a consequence of that, it pushes someone or an organism or human or whatever into a state of food seeking behavior, because now food also has high reward value and they're kind of the way their food circuitry is responding in the brain, at least seems to be similar to what would happen if they've been fasted. And the thought is, that's why when people, you know, when someone gets stoned, they're not, like, going to eat lettuce, high calorie food. They tend to like things that are high carb, high fat. That combo seems to be what people like when they're intoxicated with cannabis, and that comes with a lot of calories. And the point of that would be you're trying to replenish lost energy stores. And so this, at least is the kind of the theory that I have about what it is that it's doing is, you know, and I think you can make this analogy for multiple different things. You know, if we talk about pain or stress, we can say similar kinds of things are going on, is that endocannabinoids normally do one thing, but when THC hits the brain, it's still activating these circuits in addition to everything else it hits. So you still drive that response that the endocannabinoid system normally physiologically controls. But you're almost like tricking the brain into thinking you're in that state now. And so then, yeah, you go into food seeking behavior mode.

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 particular aspect of subjective experience, which is focus. Do you think that some people use cannabis because it allows them to focus better? And I raise this specifically because I think that in the past, cannabis has had a bit of a reputation for making people spacey. You use the word stoned kind of out of it, and yet I've heard of some potential uses for enhancing focus.

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 like kind of acute memory tasks, like a working memory or recall or something like this, as opposed to explicitly studying focus. Anecdotally, there is certainly a lot of people that report that.

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 some short term memory deficits that are present during the intoxicated state. I have not seen very much compelling evidence of long term effects that emerge, like when someone's not intoxicated, but they use cannabis somewhat regularly. I don't think there's anything compelling for that. And even in that case, like Kerry Cutler, who's at Washington state, she's done a lot of this stuff, looking at cognitive processing and different kinds of memory tasks in users while they're stoned, often and within a person, either they have adapted to using it as much as they do, or they've developed some form of tolerance to it. But even in regular users, the impact on memory processing is usually not super robust. It's still there. I mean, I think the effects that are more often seen in kind of, let's say, smaller laboratory studies where they're using people who've used canvas but aren't regular users might be a little bit more profound because they may not be used to that state, let's say. I mean, there's certainly something we call state dependent learning, which I'm sure you're familiar with. And this is something people. I mean, I remember learning about this in undergrad through alcohol. So, like, someone, first time they get drunk, tries doing something, they're very bad at the task. But if every time they're drunk, they do that task, they become better at doing it under the influence. And so then all of a sudden, they regularly do this task while they're drunk, and someone tests them, and they don't look like they're impaired at all because they've done it so much.

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 it was presented to me when I was an undergraduate was incorrect. I remember the lecturer said, and later corrected himself, I won't call him out here because that's unfair. He's not here to defend himself. But it happens in lectures that people who studied drunk would be better off coming to the exam drunk. That is not true, from what I understand.

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 them is probably less than you would see in someone who's relatively naive or a much less experienced user. That being said, I think it's relatively well established most people would agree that acutely intoxication with cannabis does impair memory processes in some capacity. What explicit form of memory I don't think I could speak to comfortably, just because I'm not a memory researcher, and I know there's very specific things of, like, episodic and declarative and whatnot, so I can't say that, but I'd say it's kind of generally. And, I mean, again, you can replicate this in animals where if you train them on a task while they're under the influence, they don't seem to have consolidated that information as well. But, again, I don't really think there's super compelling evidence that there's kind of long term permanent effects on cognitive function in individuals who use cannabis. At least, I've never seen anything that's replicable or reliable or stable in any way.

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 clear that THC does not bind with much higher affinity. It's just as I think your words were assuming, high THC levels in the cannabis carpet bombs all the networks, as opposed to binding more with higher affinity at particular receptors.

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 lungs to the bloodstream and crosses the blood brain barrier.

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.