How Cannabis Impacts Health & the Potential Risks | Dr. Matthew Hill

Andrew Huberman 0:00 (uptempo music) 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 Dr. Matthew Hill. Dr. 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 today's podcast episode is a bit unique, so I'd 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. It's 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 Dr. 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 Dr. Hill 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 and 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. 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Andrew Huberman 7:16 Matthew Hill. Dr. Matt Hill, welcome.

Dr. Matthew Hill 7:19 Thanks for having me.

Andrew Huberman 7:20 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-

Dr. Matthew Hill 7:51 Mm-hmm.

Andrew Huberman 7:51 ... um, 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?

Dr. Matthew Hill 8:00 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, (sighs) um, for both kind of medicinal and spiritual and recreational purposes over several centuries. Um, the plant has kind of become... I mean, in the West, it really wasn't a thing mainstream-wise until about the '60s, uh, 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. Um, and then I'd say more recently, cannabis has, you know, into the '90s and on, has become kind of a very heavily used drug by a large swath of people ranging from teenagers on up. Uh, 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. Uh, 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, uh, delta-9 tetrahydrocannabinol, or what we call THC, um, and that really is what dictates, you know, the psychoactive and intoxicating properties of the plant. And so the amount of THC that is within the cannabis plant will influence the, you know, how high a person's going to get when they consume it. Uh, there are probably 70 to 100 and some odd other cannabinoids that are within cannabis. Most of them are at pretty trace levels, like, and they vary from different types to cannabis from one another, uh, but the other one that's had a lot of attention is cannabidiol, or what we call CBD. Uh, CBD is... structurally looks pretty similar to THC, but doesn't behave anything like THC. It's not intoxicating at all, um. 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 I would... Some people still say it's psychoactive because people claim, you know, 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. Um, 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, um, they may influence some of the effects of THC, they may not, um, but they're there and they vary in their composition from, you know, different flavor of different cannabis to different flavor. Uh, and then there's those other things called terpenes-

Andrew Huberman 10:30 Mm-hmm.

Dr. Matthew Hill 10:30 ... 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, uh, you know, gives some cannabis kind of a citrusy odor or flavor to it, um, pinene, which gives things more of, like, a earthy tree kind of smell, uh, 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, you know, giving someone THC and adding in one other terpene or one other minor cannabinoid and seeing how it influences things, and so you can imagine with the plethora of molecules that exist in cannabis, doing this in a piecewise manner could take decades to kind of really get to a point where we understand all the interactive, um, components of cannabis. But people tend to refer to this as like 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, um, and so there are some, like, 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, so.

Andrew Huberman 12:08 Mm-hmm.Fascinating plant. You mentioned the psychoactive effects. Um, 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, um, what the quote unquote psychoactive effects are? You mentioned, um, the higher the concentration of THC, the quote unquote higher someone will get, right?

Dr. Matthew Hill 12:35 Yeah.

Andrew Huberman 12:35 The greater the intensity of the high. Um, what is the high? Um, and I know people are probably chuckling saying, "Does Huberman not know because he's never done it?" I mean, that's my own business. I- I just want people to understand what you mean by psychoactive effects.

Dr. Matthew Hill 12:49 So, I mean, the way that people would usually describe the- the intoxicating effects of cannabis is, uh, they would, they... 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. Uh, there can be, you know, other aspects, uh, in terms of changes in feeding behavior, people might find things funnier than they found things, it might change the way they perceive va- various environmental stimuli. Um, 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, a complicated intoxicating state to describe, I would say-

Andrew Huberman 13:37 Mm-hmm.

Dr. Matthew Hill 13:37 ... 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, you know, jacked up.

Andrew Huberman 13:43 Possibility everywhere. (laughs)

Dr. Matthew Hill 13:45 Yeah, exactly. Like, 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 like kind of an introspective state. You might be more aware of your bodily feelings and, um, states that are going on inside of you, your kind of internal state, but you also have like 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, a complicated state to describe, I would say. Usually when people are assessing if someone's intoxicated, like, um, the kind of lab work where people get someone high, they just kind of use a, what we call a visual analog scale, which is like a one to a hundred or something, or zero to a hundred 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.

Andrew Huberman 14:35 Mm-hmm.

Dr. Matthew Hill 14:35 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, um, 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.

Andrew Huberman 14:49 That's interesting. Is that true even if they've never used cannabis before?

Dr. Matthew Hill 14:54 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-

Andrew Huberman 15:01 Hm.

Dr. Matthew Hill 15:01 ... they have to have had some previous experience with a drug, uh, to be enrolled.

Andrew Huberman 15:06 Mm-hmm. And they pay you, so now-

Dr. Matthew Hill 15:06 Yeah. (laughs)

Andrew Huberman 15:06 ... pot smokers everywhere are running to look at some-

Dr. Matthew Hill 15:08 Yeah, but I think, yeah, 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-

Andrew Huberman 15:16 Mm-hmm.

Dr. Matthew Hill 15:16 ... 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-

Andrew Huberman 15:28 Mm-hmm. Interesting.

Dr. Matthew Hill 15:29 ... um, if they're not expecting it.

Andrew Huberman 15:31 What about the effects of cannabis on time perception? You know, there's this, um, reputation that cannabis has, uh, for disrupting time perception, that people will think a long period of time has passed when-

Dr. Matthew Hill 15:45 Yeah.

Andrew Huberman 15:45 ... in fact very little time has passed. Maybe it's sometimes even the reverse. Um, well, is the mechanism by which cannabis can adjust time perception known?

Dr. Matthew Hill 15:55 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 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, uh, 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, 'cause they are very good at learning, like, "If I wait 10 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 it, in that context, it does still seem to produce some state where there's a, an altered perception of time passing.

Andrew Huberman 16:43 Mm-hmm.

Dr. Matthew Hill 16:43 And so I think if we were gonna really understand the mechanism of it, that would probably be the way to go. But I'm not super familiar with the work 'cause no one's... I mean, anything I can think of is pretty old.

Andrew Huberman 16:53 Mm-hmm.

Dr. Matthew Hill 16:53 I can't think of anything modern

Dr. Matthew Hill 16:55 where people have actually looked at this.

Andrew Huberman 16:56 Interesting. Uh, you mentioned effects of cannabis on appetite. And I know one of the, um, medical uses of cannabis is in people that are undergoing treatment for cancer-

Dr. Matthew Hill 17:06 Mm-hmm.

Andrew Huberman 17:07 ... in order to stimulate appetite because oftentimes they have very low or even no appetite due to the cancer treatment. Um, is the mechanism by which cannabis can stimulate appetite known? And if so, um, what is the general trend of, of effect? Makes people hungrier, obviously, but we hear again in, um, kind of, uh, recreational terms of people getting the munchies, you know, becoming-

Dr. Matthew Hill 17:31 Yeah.

Andrew Huberman 17:31 ... exceedingly hungry. Is that related to some cannabis-induced effect on say, blood sugar, like insulin or glucose regulation? Or is it happening at, at a different level?

Dr. Matthew Hill 17:39 Yeah, I think we almost need to take a step back actually to talk about how cannabis works in the brain-

Andrew Huberman 17:43 Mm-hmm.

Dr. Matthew Hill 17:43 ... before we kind of go into that.

Andrew Huberman 17:44 Great.

Dr. Matthew Hill 17:45 So THC as a molecule exerts almost all its effects are acting at this one receptor for the most part, that's widely expressed through the brain called the cannabinoid type one receptor. Um-

Andrew Huberman 17:55 CB1.

Dr. Matthew Hill 17:56 Yeah, CB1 is the shorthand for it.

Andrew Huberman 17:58 Mm-hmm.

Dr. Matthew Hill 17:58 And I think, um, you know, as people tend to create analogies to describe what receptors are, for those of you who don't know, it's most people use like a lock and key analogy that like 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. Um, and so THC acts on these CB1 receptors, which, um, are very widely expressed. In fact, outside of like...... kind of ion channels that are expressed in the brain. The CB1 is, I think, one of the most, if not the most widely expressed receptor in the brain. It's everywhere.

Andrew Huberman 18:35 Wow.

Dr. Matthew Hill 18:35 So it's really important. Um, and I think as, as kind of you had alluded to previously, uh, it didn't, 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-

Andrew Huberman 18:47 Although cannabis users everywhere will use that argument. (laughs)

Dr. Matthew Hill 18:50 Yeah. Um, I know, people love to leverage, uh, 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. Um, but I mean, really this is just biological redundancy. I mean, you know, nature only has so many ways to create something and so there's gonna 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 CB1, and there is also a CB2 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, um, actual brain cell neurons.

Andrew Huberman 19:22 Hm. Where, where in the body is it expressed?

Dr. Matthew Hill 19:24 It's mostly immune cells. So you'll see CB2s mostly on like macrophages or other kind of immune cells.

Andrew Huberman 19:29 Cells that gobble up debris.

Dr. Matthew Hill 19:31 Yeah. And that basically, you know, regulate inflammatory processes. And so the main role of CB2 seems to be much more about like regulating inflammation, um, so that's kind of a separate role. That can certainly impact the brain in different ways. But, uh, when we talk about the effects on the central nervous system and the brain and behavior, we're talking almost entirely about CB1. And so both the CB1 and CB2 receptors, like I said, don't exist because nature was like, "Humans are gonna find cannabis. They'll, this will all work together now." So there are molecules our body produces, which we call endocannabinoids, um, and they are kind of funny little molecules 'cause 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 something that excites the neighboring cell, neuron B, or it can inhibit it. Um, 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, you know, jack that neuron's activity up or it can scale it down, and that affects, you know, brain-wide patterns of activity. Uh, and we call that anterograde because it moves from neuron A to neuron B, which is kind of the general flow of things, um, and how we usually think about it. So endocannabinoids are kind of this, you know, little bit of an oddity in the sense that they could do the reverse. And so 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. And so in many ways this is like, I kinda liken it to a thermostat model for the most part. Certainly if we're talking about something like excitability. So if neuron A is dumping out something that excites neuron B, like glutamate, which is an excitatory neurotransmitter, as neuron B gets too excited, it's gonna start releasing endocannabinoids to go back and tell neuron A to stop driving it, so-

Andrew Huberman 21:32 So sort of a homeostatic scale-

Dr. Matthew Hill 21:34 Yeah.

Andrew Huberman 21:34 ... and trying to maintain a middle range.

Dr. Matthew Hill 21:35 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. So like, uh-

Andrew Huberman 21:52 And that's probably why the CB1 receptor is so widely distributed-

Dr. Matthew Hill 21:55 Exactly.

Andrew Huberman 21:55 ... is that neurons can excite or inhibit each other, um, that is raise or reduce the amount of electrical activity in the, let's say, nearby neuron 'cause-

Dr. Matthew Hill 22:03 Yeah.

Andrew Huberman 22:03 ... you know, we were talking about retrograde signaling. But, um, ultimately you don't want runaway excitation-

Dr. Matthew Hill 22:08 Yeah.

Andrew Huberman 22:08 ... 'cause that looks like epilepsy.

Dr. Matthew Hill 22:09 Exactly.

Andrew Huberman 22:10 And you don't want runaway inhibition because that looks like, um, suppression of-

Dr. Matthew Hill 22:15 Yeah.

Andrew Huberman 22:15 ... ability to think, move, et cetera.

Dr. Matthew Hill 22:17 Exactly.

Andrew Huberman 22:17 Okay.

Dr. Matthew Hill 22:18 So you wanna keep things in the, in where they should be. And so you want neurons to get excited, but you want them, you don't want them to get overexcited. And so endocannabinoids in kind of a very prototypical sense act as this circuit breaker essentially-

Andrew Huberman 22:27 Mm-hmm.

Dr. Matthew Hill 22:27 ... 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.

Andrew Huberman 22:38 Mm-hmm.

Dr. Matthew Hill 22:39 Um, 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.

Andrew Huberman 22:51 So inhibiting the inhibitor-

Dr. Matthew Hill 22:53 Yeah.

Andrew Huberman 22:53 ... leads to more excitation.

Dr. Matthew Hill 22:54 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, 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, CB1 receptors are found on virtually every single kind of neuron in the brain, um, except one. I think you'll find this interesting 'cause it's dopamine. (laughs) Uh, 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.

Andrew Huberman 24:07 Interesting. Uh, if I may, um, earlier you mentioned one of the potential psychoactive effects of, uh, cannabis is euphoria.

Dr. Matthew Hill 24:15 Yeah.

Andrew Huberman 24:15 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?

Dr. Matthew Hill 24:26 So yeah, I wouldn't say that cannabinoids don't affect dopamine-

Andrew Huberman 24:29 Mm-hmm.

Dr. Matthew Hill 24:29 ... because, um...... 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, um, those neurons are, are regulated by a lot of inhibitory neurons that dump out inhibitory transmitter and keep those neurons kind of quiet. Or at least-

Andrew Huberman 24:47 So there's an opportunity for indirect regulation.

Dr. Matthew Hill 24:49 Exactly. So what you have is those neurons that regulate the dopamine neurons are very rich in cannabinoid receptors. This is actually kind of similar to how mu opioid receptors work for things like morphine or heroin. Um, 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, uh, 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, you know, the positive affect or the euphoric, I don't think anyone has cleanly demonstrated that. I mean, obviously dopamine's very complicated in terms of its relation to endpoints and whether it's reward or motivation. Um, 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've evolved in a way to allow every other neurotransmitter system to be actively and directly regulated by endocannabinoids. But dopamine is kind of spared from this. So I don't know. No one... 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, uh, intrigued a lot of people (laughs) because every other system in the brain is so tightly controlled to some degree by endocannabinoids and then this one circuit is kind of free of it. So, um, but yeah, so the main role of endocannabinoids is really to, to regulate plasticity or homeostasis, allow flexibility of circuits to either goose up their activity or, 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 kind of roles that endocannabinoids play in that domain.

Dr. Matthew Hill 26:19 But even within the endocannabinoids, um, I mean there's, 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 a receptor. So serotonin has like, I don't know, like 15 receptors or 20 or something now. Uh, dopamine has at least five. Uh, 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 bonafide endocannabinoids, there could be more, um, they're called anandamide, which, um, is actually a kind of a funny name because it comes from the Sanskrit word anand for bliss. And so, um, Rafi Mechoulam, who was in Israel when he discovered the molecule, you know, 30 odd years ago, uh, wanted it to reflect inner bliss (laughs) . 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. And so-

Andrew Huberman 27:36 He discovered, um, anandamide and decided to call it bliss because he had familiarity with cannabis or because he-

Dr. Matthew Hill 27:42 Yeah.

Andrew Huberman 27:42 ...he took anandamide as a, as a direct experience?

Dr. Matthew Hill 27:45 No, no, I mean-

Andrew Huberman 27:45 Because it takes a lot for a scientist to discover a molecule, but then for a scientist to discover a molecule and then name it bliss-

Dr. Matthew Hill 27:51 Yeah.

Andrew Huberman 27:51 ...for a particular reason, you have to speculate-

Dr. Matthew Hill 27:54 (laughs) Well-

Andrew Huberman 27:54 ...that they, they had some familiarity with-

Dr. Matthew Hill 27:56 I mean-

Andrew Huberman 27:56 ...with the compound.

Dr. Matthew Hill 27:56 ...Rafi Mechoulam was also the guy who, who isolated and discovered THC. So I mean, he has a very, he's kind of the grandfather of the whole cannabinoid field. So he has a landmark paper from 1964, which ironically, um, and this is one of these weird pop culture things, I don't know if this is true. That paper was published on April 20th, 1964. And so the joke is, is this where 4/20 came from? Because the original like birthdate of the first THC paper was 4/20/1964.

Andrew Huberman 28:22 Well, now that, that-

Dr. Matthew Hill 28:23 (laughs)

Andrew Huberman 28:23 ...now that, um, potential myth is definitely gonna propagate.

Dr. Matthew Hill 28:27 Yeah.

Andrew Huberman 28:27 Um, interesting.

Dr. Matthew Hill 28:28 But yeah, so he, he had, 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, um, it was kind of, uh, 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 2-arachidonylglycerol or what we call 2-AG that was discovered kind of in tandem both again by Mechoulam but also by a Japanese group. Um, and so we understand these two molecules don't do the same thing. Like they are a bit different.

Andrew Huberman 29:00 Mm-hmm.

Dr. Matthew Hill 29:00 So the way anandamide binds to the receptor is it's what we would call a high affinity but low efficacy, um, 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 2-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, um, 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 or 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. Um-

Andrew Huberman 30:16 Mm-hmm. Your thermostat analogy is perfect here.

Dr. Matthew Hill 30:18 Exactly. So in that context, it kind of is like just the thermostat of the house.

Andrew Huberman 30:22 Mm-hmm.

Dr. Matthew Hill 30:22 Whereas 2-AG is like let's say the pinch hitter (laughs) who gets brought in to do the heavy lifting. And so 2-AG during a situation like let's say something like even like a seizure as an extreme example where you have a huge amount of neural activity, those neurons that are getting heavily activated during, you know, massive amounts of neural activity start dumping out huge amounts of 2-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 2-AG signaling. And so, um, you know, all these forms of like turning things up or down in an, in a kind of rapid and on-demand manner, that's mostly 2-AG. So most people who study like neurophysiology and like recorded activity in neurons and look at endocannabinoids, they're almost entirely talking about 2-AG when they play with stuff. Um, so-Yeah, that's kind of one of the ways we do it. We say that anandamide might be more tonic and 2-AG might be more phasic.

Andrew Huberman 31:30 Mm-hmm.

Dr. Matthew Hill 31:30 And like brought online when needed, but doesn't do a lot. There is some evidence that 2-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, um, to affect plasticity but as kind of like an umbrella idea of how we look at it-

Andrew Huberman 31:48 Mm-hmm.

Dr. Matthew Hill 31:48 ... that's often how we divide those two up. So we kinda have these two molecules, they end of the day do the same thing, they're regulating neurotransmitter release, um, 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 2-AG is activity dependent, so as that neuron becomes more active it's gonna make 2-AG to regulate its inputs.

Andrew Huberman 32:14 Mm-hmm.

Dr. Matthew Hill 32:15 Um, so yeah, you have this very complex system and it's really widely distributed in, you know, it's everywhere. There's cannabinoid receptors and the endocannabinoid molecules are in the cortex, they're in the hypothalamus, they're in the striatum, the hippocampus, the cerebellum.

Andrew Huberman 32:26 All over the brain.

Dr. Matthew Hill 32:27 Ev- except the one area where it's really interesting actually, um, where you don't really see much receptor is in brainstem populations that regulate, um, you know, kind of unconscious cardiac and respiratory function.

Andrew Huberman 32:38 Hm.

Dr. Matthew Hill 32:38 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, um, as has been well established, people can overdose and fatally and die from opiates relatively easily and the way that that tends to happen is, uh, 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, um, they also unconsciously will stop regulating their own heart and breathing and they can... 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, um, and breathing function and so that's, I mean, you know, 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 with cannabinoids as far as we've seen so far, um, 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

Dr. Matthew Hill 33:46 the brain, so.

Andrew Huberman 33:46 Mm-hmm. Very interesting.

Dr. Matthew Hill 33:48 Yeah.

Andrew Huberman 33:48 Um, a lot of, uh, kind of, uh, aficionado questions about the receptor biology I'll just, um, spare everyone the details by just, um, 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, uh, a phasic, you know, so the ability to spike, forgive the pone-

Dr. Matthew Hill 34:13 Yeah.

Andrew Huberman 34:13 ... pun. The neuroscientists will know what I'm talking about, to spike, um, more activity of the system superimposed on that tonic activity because this is something that you see in the dopamine system.

Dr. Matthew Hill 34:21 Yeah.

Andrew Huberman 34:21 This is something that you see in essentially every neuromodulator and neurotransmitter system, um, but it seems that the endocannabinoid system has accomplished this, uh, quite a bit differently.

Dr. Matthew Hill 34:31 Yeah.

Andrew Huberman 34:31 So very interesting, um, uh, unique system-

Dr. Matthew Hill 34:35 Yeah.

Andrew Huberman 34:35 ... in a, in a number of ways that raise a number of, uh, key questions.

Dr. Matthew Hill 34:38 So yeah, if you go back to the munchies question you had, um, so if we tie into that one of the... So there's a few ways, I mean, cannabinoids and feeding are a really interesting (laughs) 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, you know, the cannabinoid receptors are very, um, they are expressed in these feeding circuits in the hypothalamus, um, and you know, there's a lot of complex circuitry there that can regulate food seeking behavior and...

Andrew Huberman 35:12 Yeah, we just had an episode with Zach Knight-

Dr. Matthew Hill 35:14 Yeah.

Andrew Huberman 35:14 ... from HHMI and UCSF where he talked about like the AgRP neurons-

Dr. Matthew Hill 35:19 Yeah, exactly.

Andrew Huberman 35:19 ... and different neurons of the hypothalamus. We can link to that in the show note captions. Um, uh, nowadays a rich understanding of the neurons that stimulate food seeking-

Dr. Matthew Hill 35:28 Yeah.

Andrew Huberman 35:29 ... craving and, and, and then needing.

Dr. Matthew Hill 35:30 And so we know that like cannabinoids, they regulate again those inhibitory inputs around AgRP neurons for example, and so one thing they can do is disinhibit those AgRP neurons-

Andrew Huberman 35:39 Mm-hmm.

Dr. Matthew Hill 35:39 ... 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, um, in terms of the munchies. And so we know that like you can also just dump anandamide for example. This is, you know, Steve Muller and Kent Berich did this work years ago where they just put anandamide into the nucleus accumbens and that can also stimulate palatable food intake. So you also have this ability to inte- integrate with the reward circuitry. Um, and then there was also this fascinating paper from a Japanese group in PNAS I think about 12 years ago and what they found was they would, um, 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 AgRP neurons as well as the POMC neurons, there's kind of both sides to that in the, in the arcuate nucleus, um, to regulate multiple components of feeding. But a big question is like my lab has become kind of interested in this as well because we have a, a component of my lab that studies feeding behavior and one of my post-docs 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... 'Cause it's not just food seeking and it's not just, you know, like they just want to consume something, there's, 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, you know, if you haven't eaten for a day and you see, like, a picture of a pizza or 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." Um, and so we've done a series of experiments in the lab where you'd 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. Um, and you get them high on like a cannabis extract. We have these vape chambers that are like, um, I don't know how else to describe it outside of like a little hot box. (laughs) It's probably the best way to des-

Andrew Huberman 38:31 Mm-hmm.

Dr. Matthew Hill 38:31 'Cause it's essentially a kind of a, 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, you know, consuming cannabis through smoking. Um, and so we get them to that point and then give them access to food and they will, you know, 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 pre-satiate them and they, get them stoned, they will re-initiate eating again. And you make them work for it where they have to like lever press um, and you get them stoned and they will go to town on that and they will work. And, you know-

Andrew Huberman 39:17 Proof that even under the influence-

Dr. Matthew Hill 39:18 (laughs)

Andrew Huberman 39:18 ... of cannabis, um, animals will work hard.

Dr. Matthew Hill 39:21 Yeah. They ... Uh, for food. (laughs)

Andrew Huberman 39:23 Mm-hmm.

Dr. Matthew Hill 39:23 I don't know about other stuff, but for food, they certainly will. I mean, and Elise Weertz and Cassie Moore have done this at Hopkins as well. They've shown similarly using what we call progressive ratio, which is, uh, 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.

Andrew Huberman 39:40 That's like life.

Dr. Matthew Hill 39:40 Yeah. Then you got to hit it 16 and then th- and it kind of scales exponentially up. Um, 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. Um, so you can really kind of goose up their motivation to eat. And so there's clearly a rewarding aspect to this because they're motivated to engage enough in working to get access to the food. But you can also, um, do another way of testing this question which is, you can pair a food with, um, something that will make the animal feel nauseous like lithium chloride. This is kind of the way that you would test, uh, conditioned 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, um, that's another way to kind of devalue a food is by pairing it with a nauseant 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 nauseant. So through either satiety or making it, um, kind of a, a negative associated flavor because the animal got nauseous before, you can kind of override these effects by giving THC. And so that could be a complex process that either involves changes in the reward circuitry. This could be something that's like from the orbitofrontal cortex, which is a b- a very important part of the brain that scales reward and kind of 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, you know, 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 still. Um, and then similarly, we've also, we and others have also done work to show we can block satiety signals. So we know endocannabinoids at least, um, are capable of overriding leptin. So leptin is, uh, 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." You know?

Andrew Huberman 41:47 Mm-hmm.

Dr. Matthew Hill 41:47 It works through, again, uh, populations in the arcuate nucleus and changes the way those neurons function to drive food-seeking behavior. Um, and we and others have shown previously that, you know, 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, 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

Dr. Matthew Hill 42:17 goosing up endocannabinoid activity.

Andrew Huberman 42:20 As many of you know, I've been taking AG1 for more than 10 years now, so I'm delighted that they're sponsoring this podcast. To be clear, I don't take AG1 because they're a sponsor, rather they are a sponsor because I take AG1. In fact, I take AG1 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 where 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 AG1 once and often twice every day is that it ensures I get all of those vitamins, minerals, probiotics, et cetera, 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 AG1 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 AG1, 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, AG1 is foundational nutrition designed to support all aspects of well-being related to mental health and physical health. If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs with your order, plus a year's supply of vitamin D3 K2. Again, that's

Andrew Huberman 44:06 drinkag1.com/huberman. You, you're talking about increasing endocannabinoid activity, um, and we've said all this in the context of cannabis.

Dr. Matthew Hill 44:15 Mm-hmm.

Andrew Huberman 44:16 So maybe we could talk a little bit about how the components in cannabis, THC mainly but also CBD, uh, impact these receptors, the CB1 and let's just leave CB2 out for the moment-

Dr. Matthew Hill 44:27 Yeah.

Andrew Huberman 44:27 ... because it sounds like it's more of an immune system thing. Um, but just to make it very clear, um, is there a way to increase the activity of endocannabinoids without ingesting THC?

Dr. Matthew Hill 44:41 Yes. I mean, they dynamically change all the time, so-

Andrew Huberman 44:43 W- w- but you're ta- I'm talking about, um, you're talking about experimentally or recreationally-

Dr. Matthew Hill 44:47 Yeah.

Andrew Huberman 44:47 ... adjusting their levels, but how does one do that, um, without using THC?

Dr. Matthew Hill 44:52 So, okay, few things there. We'll take a step back. So THC itself isn't going to, um... it does its thing by acting directly on the cannabinoid receptor, not- not-

Andrew Huberman 45:03 So it sort of mimics the-

Dr. Matthew Hill 45:05 Yeah.

Andrew Huberman 45:05 ... uh, anandamide and, and 2-AG.

Dr. Matthew Hill 45:07 Yeah. So THC, going back to kinda the pharmacology of this, so THC, if you look at how it interacts with the receptor, um, it's not, it's not a heavy-duty molecule. So I mean, this was kinda one of the things that came up before as well is this idea that THC's a sledgehammer and it overrides the endocannabinoids.

Andrew Huberman 45:25 Right. By the way, um, Matt's referring to the fact that I said that in a previous solo episode about this. Um, and there I was nesting it in the concentrations of THC that can be found in high-THC cannabis.

Dr. Matthew Hill 45:35 Yeah.

Andrew Huberman 45:35 Um, 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 CB1 receptors is going-

Dr. Matthew Hill 45:48 Is high.

Andrew Huberman 45:49 ... to exceed what's normally found in terms of the amount of anandamide that can bind to CB1 receptors because what you're talking about is a super physiological condition.

Dr. Matthew Hill 45:57 Yeah. It's, I mean, you don't really actually need much THC in the brain to produce psychoactivity. Like, it's, it's a little bit of a mystery-

Andrew Huberman 46:03 Mm-hmm.

Dr. Matthew Hill 46:03 ... to be honest exactly how it works. I mean, I think the main way that most people in the cannabinoid theory, uh, 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 2-AG. So-

Andrew Huberman 46:21 So-

Dr. Matthew Hill 46:21 ... it's actually more like anandamide.

Andrew Huberman 46:22 So you said anandamide is high affinity, low efficacy.

Dr. Matthew Hill 46:25 Yeah. So THC is the same. THC is actually only a partial agonist. It's not even a full agonist at CB1.

Andrew Huberman 46:30 But it is high affinity.

Dr. Matthew Hill 46:32 It's high affinity, so it has the ability... so but the tricky thing with that is it can out-compete 2-AG, but because it's a lower efficacy agonist than 2-AG-

Andrew Huberman 46:43 Mm-hmm.

Dr. Matthew Hill 46:43 ... in that sense, it's almost blocking the effects, not, um, amplifying them.

Andrew Huberman 46:47 Blocking the effects of 2-AG-

Dr. Matthew Hill 46:49 Yeah.

Andrew Huberman 46:49 ... but does it block the effects of anandamide?

Dr. Matthew Hill 46:51 Um, it... you know, to it, THC and anandamide, I would kind of, 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 g- 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.

Andrew Huberman 47:22 That's a very interesting point that we should highlight.

Dr. Matthew Hill 47:24 Yeah.

Andrew Huberman 47:24 So there are drugs that now exist that can block the breakdown of anandamide-

Dr. Matthew Hill 47:28 Yeah.

Andrew Huberman 47:28 ... make more available, presumably by disrupting some enzymatic breakdown.

Dr. Matthew Hill 47:31 Yeah, exactly.

Andrew Huberman 47:32 And therefore lead to more binding of the now elevated levels of an- anandamide that are available to CB1 and you see no psychoactive effects?

Dr. Matthew Hill 47:40 No, no, no psychoactive.

Andrew Huberman 47:41 People are not aware that they've-

Dr. Matthew Hill 47:42 No. Yeah, you can do-

Andrew Huberman 47:43 They're no euphoria, interest-

Dr. Matthew Hill 47:43 ... no one can guess. Yeah, no one can guess.

Andrew Huberman 47:45 What is it used for?

Dr. Matthew Hill 47:46 Um, well, I mean, it was developed, the first molecule really was developed by Pfizer to look at if it could work on pain. Um, the first trial that was done did not work. It was like a kind of strange osteoarthritic knee pain trial that was like... even in that trial, the positive control of naproxen barely worked, but because the PHA inhibitor, which is, uh, take a step back, PHA is 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 PHA inhibitors. Um, so this drug will boost anandamide levels quite high, and an animal research showed some efficacy in modulating pain. And so they put it in a trial and it didn't work against the positive control of naproxen which is like an NSAID just like Advil basically.

Andrew Huberman 48:32 Aleve.

Dr. Matthew Hill 48:33 Yeah. Essentially, yeah.

Andrew Huberman 48:33 Yeah.

Dr. Matthew Hill 48:34 So, um, 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. Um, 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. Um, and they did a, a trial in just healthy controls with it, which again, this is kinda jumping the gun on some of this stuff I'll talk about so I'll tether back to that, but what we di- what they did was they dosed people for 10 days on this drug and then we looked at stress and fear because this is something that I study, this is something that they're interested in, um, and we did find that boosting anandamide with this drug over 10 days, uh, 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. Um, so it blunted that and it blunted subjective feelings of stress as well so people had lower levels of saying they actually felt stressed. Um, and it kind of helped remove this like conditioned fear memory that we had, 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. Um, 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, um, help kind of reduce fear. And so that is kind of an interesting outcome because it, 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, but, um, so that's kind of one of the things. The drug has not really been used that widely yet. It's still, uh, it's one of the frustrations I have as, um, a scientist who does a lot of translational work in, with clinical partners like Leah, uh, 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. Um, we did just complete a trial that Leah and Marcus ran that I worked with them on as well that was on PTSD. Um, and so there are various potential indications for this. I mean, Johnson & 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 gonna do with these, but, um, 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 gonna do, people were basing it on what we knew about THC, so the assumption was people would have psychoactivity, but they didn't. Um, Pfizer then actually had to do, they did a sleep study to show that it did have some effects on sleep cycle, um, the same way THC does, and then they also did like, uh, an in vivo PET binding study to show that they could displace, um, a radioactive molecule that would bind to the enzyme in the brain, so they-

Andrew Huberman 51:50 Seems like a lot of gymnastics to basically confirm what they-

Dr. Matthew Hill 51:52 Yeah.

Andrew Huberman 51:52 ... 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-

Dr. Matthew Hill 52:03 Yeah.

Andrew Huberman 52:03 ... subjective experience than ingesting-

Dr. Matthew Hill 52:06 THC.

Andrew Huberman 52:06 ... or smoking THC.

Dr. Matthew Hill 52:07 Yeah. Yeah.

Andrew Huberman 52:07 Which brings us back to THC-

Dr. Matthew Hill 52:10 So what's it doing? (laughs)

Andrew Huberman 52:11 ... and, and cannabis, like, you know-

Dr. Matthew Hill 52:12 Yeah.

Andrew Huberman 52:12 ... um-

Dr. Matthew Hill 52:13 So I think-

Andrew Huberman 52:13 ... it seems that this, 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-

Dr. Matthew Hill 52:30 Yeah.

Andrew Huberman 52:30 ... no munchies and, you know, et cetera, then people smoke or take an edible of-

Dr. Matthew Hill 52:35 And, yeah.

Andrew Huberman 52:36 ... THC or cannabis,

Andrew Huberman 52:38 and you get a vastly different set of effects. So maybe we could talk about, uh, THC and the CB1 receptor.

Dr. Matthew Hill 52:44 Yeah.

Andrew Huberman 52:44 And since we're here, we might as well, um, talk about, uh, CBD and-

Dr. Matthew Hill 52:48 Yeah.

Andrew Huberman 52:48 ... and the, I think you're gonna tell us, the lack of interaction with CB1-

Dr. Matthew Hill 52:52 Yeah.

Andrew Huberman 52:52 ... receptor, right? Um, and what is cannabis doing at the level of these receptors?

Dr. Matthew Hill 52:57 Yeah, so-

Andrew Huberman 52:57 Because, um, it makes me wonder whether or not these receptors are the whole story or whether or not cannabis is, you know, as you mentioned, you know, 70 plus, uh, 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.

Dr. Matthew Hill 53:18 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 gonna be released in a very specific spatial and temporal manner. So-

Andrew Huberman 53:30 They evolved to do that.

Dr. Matthew Hill 53:31 Yeah.

Andrew Huberman 53:31 Yeah.

Dr. Matthew Hill 53:31 So there's gonna be, and I think like it's very clear that like anandamide, for example, is not active at every synapse it has CB1. 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.

Andrew Huberman 53:47 Mm-hmm.

Dr. Matthew Hill 53:48 Whereas THC, when you consume it orally or inhalation-wise and it gets into your blood and into your brain, um, it's just blanket activation, you're just carpet bombing the whole system indiscriminately. And so-

Andrew Huberman 54:00 You're introducing the ligand, the thing that binds the receptor.

Dr. Matthew Hill 54:03 Yeah.

Andrew Huberman 54:03 This is far and away different than say like the actions of amphetamines-

Dr. Matthew Hill 54:08 Yes.

Andrew Huberman 54:08 ... which are disrupting the normal biology in a way that's giving you an amplification of an endogenous mechanism-

Dr. Matthew Hill 54:13 Yes.

Andrew Huberman 54:13 ... right? Um, if that was all just, uh, nerd speak for those listening, it's one, i- 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.

Dr. Matthew Hill 54:29 Yeah.

Andrew Huberman 54:29 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 s- 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 wanna say replacing, but it's masking the effects of anandamide.

Dr. Matthew Hill 54:52 I think the problem is when you just blanket activate all the CB1 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 CB1 receptors in the cortex and those are gonna be differentially regulated at different times by endocannabinoids, whereas when THC hits them, all of them are gonna get affected at once. And if you think of the way that-

Andrew Huberman 55:16 Mm-hmm.

Dr. Matthew Hill 55:16 ... I described how cannabinoid receptors work by essentially, I mean, in its simplest form, what cannabinoid receptors do is they change the way that two neurons talk to each other. Um, and so-

Andrew Huberman 55:27 So you're changing all the networks simultaneously?

Dr. Matthew Hill 55:28 Yeah, so if you hit a whole bunch of networks simultaneously, you're just gonna 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, you know, 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-

Andrew Huberman 55:53 Got it.

Dr. Matthew Hill 55:53 ... to do very specific things at very specific times.

Andrew Huberman 55:56 Got it. That's very helpful.

Dr. Matthew Hill 55:57 Yeah.

Andrew Huberman 55:57 So the analogy that I was considering using coming in here, like the difference between endogenous testosterone or estrogen versus pharmacologic, uh, testosterone or estrogen-

Dr. Matthew Hill 56:07 Yeah.

Andrew Huberman 56:07 ... given as a therapy-

Dr. Matthew Hill 56:08 Yeah, it doesn't apply.

Andrew Huberman 56:08 ... is very different because-

Dr. Matthew Hill 56:09 Yeah.

Andrew Huberman 56:09 ... that's, that's an, that's a levels issue.

Dr. Matthew Hill 56:11 Yeah.

Andrew Huberman 56:11 This is a levels and an extent issue.

Dr. Matthew Hill 56:14 Yeah, this is a lot more to do with just, yeah, the nature of how it hits everything because-

Andrew Huberman 56:18 Mm-hmm.

Dr. Matthew Hill 56:18 ... like so for example, if we talk about feeding, we know, uh, it's been established at this point that, for example, if an organism doesn't eat for like a day, so you fasted, um, at that point, in those feeding circuits in your brain, like the arcuate area where these AgRP neurons and stuff are, that you'll start seeing elevations in endocannabinoids. So endocannabinoid levels start kind of going up and up, um, 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, uh, ghrelin and things like that. So there's a lot of redundancy in these systems, but-

Andrew Huberman 57:06 Mm-hmm.

Dr. Matthew Hill 57:06 ... endocannabinoids are just one of the molecules that seem to fine-tune like 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, based on nutritional state. THC, on the other hand, you know, it hits the brain, yeah, some of it's gonna be the intoxication, but in tandem, you're gonna hit the CB1 receptors that are in those feeding circuits as well and the consequence of that is gonna 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 fasting 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 that their food circuitry is responding, in the brain at least, seems to be similar to what would happen if they'd 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. They want high-calorie food. They tend to like things that are high carb, high fat. That, 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.

Andrew Huberman 58:48 Mm-hmm.

Dr. Matthew Hill 58:48 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.

Andrew Huberman 58:57 Very interesting.

Dr. Matthew Hill 58:57 And so then you, then yeah, you go into food-seeking behavior mode.

Andrew Huberman 59:00 Hmm. 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. Um, what are some other, uh, known mechanisms by which, um, cannabis can change people's psychology? Um, let, let me focus in on one particular, uh, aspect of subjective experience, which is focus. Do you think that some people use cannabis because it allows them to focus better? Um, and I raise this specifically because I think that in the past, uh, cannabis has had a bit of a reputation for making people spacey.

Dr. Matthew Hill 59:40 Mm-hmm.

Andrew Huberman 59:40 Um, you used the word stoned.

Dr. Matthew Hill 59:41 Yeah.

Andrew Huberman 59:41 Um, kind of out of it. And yet I've heard of some potential uses for enhancing focus.

Dr. Matthew Hill 59:47 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. Um...

Andrew Huberman 59:52 Either way or...

Dr. Matthew Hill 59:54 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. S- anecdotally, there is certainly a lot of people that report that, so...

Andrew Huberman 1:00:12 My understanding is that people who use cannabis have poorer certain forms of memory, but not necessarily poorer memory across the board. Is that correct?

Dr. Matthew Hill 1:00:21 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. So people tend to...

Andrew Huberman 1:00:36 Negative effects or en- enhancements or decrements?

Dr. Matthew Hill 1:00:40 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. Um, 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.

Andrew Huberman 1:01:00 Mm-hmm.

Dr. Matthew Hill 1:01:01 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.

Andrew Huberman 1:01:09 Mm-hmm.

Dr. Matthew Hill 1:01:09 I don't think there's anything compelling for that.

Andrew Huberman 1:01:11 Mm-hmm.

Dr. Matthew Hill 1:01:12 Um, 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, 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.

Andrew Huberman 1:01:39 Mm-hmm.

Dr. Matthew Hill 1:01:39 Um, it's still there, I mean, I think the effects that are more often seen in kind of, um, let's say, smaller laboratory studies where they're using people who've used cannabis but aren't regular users might be a little bit more profound because they may not be...... you know, 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. Um, and this is something people... I mean, I remember learning about this in undergrad through alcohol.

Andrew Huberman 1:02:03 Mm-hmm.

Dr. Matthew Hill 1:02:04 So like, you know, 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, you know, 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. And so-

Andrew Huberman 1:02:22 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, of a substance does not mean that you have higher proficiency-

Dr. Matthew Hill 1:02:35 Yeah. (laughs)

Andrew Huberman 1:02:36 ... at that particular task-

Dr. Matthew Hill 1:02:37 Yeah.

Andrew Huberman 1:02:37 ... while under the influence. In fact, the way it was presented to me when I was an undergraduate, um, uh, was incorrect. The, I remember, the lecturer said and later corrected himself, um, I won't call him out here 'cause that's unfair.

Dr. Matthew Hill 1:02:50 (laughs)

Andrew Huberman 1:02:50 He's not here to defend himself, but it happens in lectures, um, that people who studied drunk would be better off coming to the exam drunk.

Dr. Matthew Hill 1:02:58 Yeah.

Andrew Huberman 1:02:58 That is not true-

Dr. Matthew Hill 1:02:59 Yeah.

Andrew Huberman 1:02:59 ... from what I understand.

Dr. Matthew Hill 1:03:00 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.

Andrew Huberman 1:03:07 Correct.

Dr. Matthew Hill 1:03:07 Just because they had had some state dependent learning.

Andrew Huberman 1:03:09 Mm-hmm.

Dr. Matthew Hill 1:03:10 Uh, 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. And 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, uh, 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 'cause I'm not a memory researcher and I know there's very specific things of, like, episodic-

Andrew Huberman 1:03:44 Sure.

Dr. Matthew Hill 1:03:44 ... and declarative and whatnot. So, um, 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 con- consolidated that information as well. Um, 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

Dr. Matthew Hill 1:04:09 replicable or reliable or, or-

Andrew Huberman 1:04:10 Mm-hmm.

Dr. Matthew Hill 1:04:11 ... stable in any way. So yeah.

Andrew Huberman 1:04:13 Thanks for clarifying that. And also thank you for clarifying the, um, discrepancy between endogenous cannabinoid binding and affinity for CB1 versus THC.

Dr. Matthew Hill 1:04:23 Yeah.

Andrew Huberman 1:04:23 I really appreciate that because that's something that you and I discussed in light of the solo episode I did about cannabis and, uh, now you've made it clear, uh, that THC does not bind with much higher affinity. It's just as you, I think your words were, it... Assuming high THC levels in the cannabis carpet bombs all the networks as opposed to binding more, uh, with higher affinity at particular receptors.

Dr. Matthew Hill 1:04:44 Yeah.

Andrew Huberman 1:04:44 Okay.

Dr. Matthew Hill 1:04:44 I mean, I don't actually even think it matters if it's high THC in the cannabis. I think, like, some people can get very intoxicated off of very, very low doses of cannabis.

Andrew Huberman 1:04:51 Is that right?

Dr. Matthew Hill 1:04:52 I mean, you look at edibles, for example. I mean, this may be an interesting segue into route 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 is, like, a different game. Like-

Andrew Huberman 1:05:08 Yeah, let's talk about this 'cause I know that, um, you and I, um, arrived at different understanding of the fastest, typical, and slowest-

Dr. Matthew Hill 1:05:17 Yeah.

Andrew Huberman 1:05:17 ... um, routes of entry, um, for, uh, THC into the system, um, into, to get, to arrive at the brain.

Dr. Matthew Hill 1:05:25 Yeah.

Andrew Huberman 1:05:25 Right? Um, the numbers I gave you 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.

Dr. Matthew Hill 1:05:34 Yeah. Which is very fast, yes.

Andrew Huberman 1:05:35 Um... Right, which is very fast.

Dr. Matthew Hill 1:05:37 Yeah.

Andrew Huberman 1:05:37 Um-

Dr. Matthew Hill 1:05:37 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, I, I... It's very fast.

Andrew Huberman 1:05:43 Mm-hmm. Okay.

Dr. Matthew Hill 1:05:43 It's like-

Andrew Huberman 1:05:43 So, so there may be, um... It may be that it is the same as nicotine, it may be that it's faster, but, um, importantly, it can, it can be fast.

Dr. Matthew Hill 1:05:53 Yeah.

Andrew Huberman 1:05:53 But, but typically, how fast is the onset of the subjective experience of, okay, um, you know, somebody takes a hit off a joint or a bong hit and they start to experience the subjective effects of euphoria, et cetera. How quickly after?

Dr. Matthew Hill 1:06:10 Two to five minutes, I would say.

Andrew Huberman 1:06:11 Two to five minutes.

Dr. Matthew Hill 1:06:11 It's pretty fast. I mean, so this is one of the things with cannabis is... And again, this will kind of go into this idea of the change in potency of the plant as well. Um, it's pretty quick and people titrate cannabis pretty well. Like, at least people who've used it a couple times and understand this tend-

Andrew Huberman 1:06:29 I don't know, I've seen some people not titrate it very well. (laughs)

Dr. Matthew Hill 1:06:31 (laughs) Depending again on how you... So again, this can vary. So like, you know, cannabis from the '70s was like, I don't know, 5% THC, let's say. It was pretty low. Uh, and nowadays cannabis is, a lot of the commercial stuff is between 20 and 30. Although whether those are super accurate numbers, not entirely clear.

Andrew Huberman 1:06:49 Wow.

Dr. Matthew Hill 1:06:49 But, so it's gone up a fair amount.

Andrew Huberman 1:06:51 Oh, yeah.

Dr. Matthew Hill 1:06:51 Yeah.

Andrew Huberman 1:06:51 I mean, that's a... That's not just a fair amount, that's... I mean if we, if we were talking about alcohol concentration-

Dr. Matthew Hill 1:06:56 It's beer to vodka.

Andrew Huberman 1:06:57 Mm-hmm.

Dr. Matthew Hill 1:06:58 Yeah, basically you're talking about a, a beer or wine to a spirit.

Andrew Huberman 1:07:01 And there are aquavit, uh, varieties-

Dr. Matthew Hill 1:07:03 Yeah. (laughs)

Andrew Huberman 1:07:03 ... so to speak. Um, by the way, I think when people, um, hear me talk about any kind of, uh, drug that can be used recreationally or alcohol, I think some people assume that, you know, I'm a ult- ultra anti all these things. I'm actually not, right? I'm not an alcoholic so I can, um, drink a little bit and I have.

Dr. Matthew Hill 1:07:19 Yeah.

Andrew Huberman 1:07:19 I just don't tend to. And, um, we could discuss cannabis in a different venue.

Dr. Matthew Hill 1:07:23 Yeah. (laughs)

Andrew Huberman 1:07:23 Um, but the, uh, the point here is we're not trying to frame this as what people should or shouldn't do.

Dr. Matthew Hill 1:07:29 Yeah, yeah.

Andrew Huberman 1:07:29 We're just trying to inform people.

Dr. Matthew Hill 1:07:30 No, no. Exactly.

Andrew Huberman 1:07:30 I want to be very, very clear about that. So, um-

Dr. Matthew Hill 1:07:32 So I think-

Andrew Huberman 1:07:33 But when I hear about, you know, um, 20% to 30% concentration as opposed to, you know-

Dr. Matthew Hill 1:07:38 Five.

Andrew Huberman 1:07:38 ... 5% concentration, it's significant.

Dr. Matthew Hill 1:07:41 So I would say this is what's super interesting.And this was something that came out of the way that cannabis research is done, certainly in the States.

Andrew Huberman 1:07:50 Mm-hmm.

Dr. Matthew Hill 1:07:50 And Canada's been quite behind on this. Even with legalization, we haven't caught up. Um, but they have been doing lab-based studies of cannabis, you know, Meg Haney, Harriet de Wit, this cluster of researchers around the country, Ziva Cooper at UCLA here-

Andrew Huberman 1:08:03 Mm-hmm.

Dr. Matthew Hill 1:08:03 ... have all done this where, you know, you have people come into the lab, you give them cannabis, you measure subjective outcomes or neuroimaging outcomes or whatnot. So to do this, you can't use commercial cannabis and pre-, even like the state by state legalizations hasn't changed this. So if you are doing cannabis research in humans and you're funded by like NIDA, which is National Institute of Drug Abuse, um, you get all your cannabis sourced. I mean, this may be changing. I think there are some shifts that are happening, but historically and all the literature that we would talk about that's kind of pre the last couple years, all that cannabis came from one source, which was I believe a farm in like Mississippi that was essentially funded by NIDA to produce cannabis.

Andrew Huberman 1:08:44 Lucky farm.

Dr. Matthew Hill 1:08:45 And (laughs) well, the cannabis that came out of it though, and this is one of the reasons a lot of the clinical stuff people have kind of been like, "Oh, I don't know how representative this is," 'cause it reflects cannabis that I would say is more from like the '70s or '80s. So it would be like 5 to 9% kind of THC cannabis. Now when you put someone in a lab setting and you get them to smoke to level of intoxication, people would take, you know, whatever, eight tokes, let's say, something like that. Um, and that's where they would stop. And so, you know, a lot of the labs that use this have always been like, our people who are regular cannabis users are getting high off of it. It's not as potent as the stuff that's on the street, but they're clearly getting intoxicated from it and it's giving us reliable data. Um, so when they started looking at the blood levels of THC that you achieve, it was around 100 nanograms per mL of THC, give or take. That seemed to be where it was. Now because of the way that the, you can legally study Canada- cannabis in the States, you couldn't just go down to a dispensary and buy the products that everyone on the street are using, which is kind of like, it's been a weird thing for a lot of people 'cause they're like, "Why wouldn't you study what we're using?" But because of the legal aspects of this, you couldn't bring those products into the lab. They'd never been standardized. No one knew exactly what was in them, pesticides, all this other stuff that could influence it. So from a safety perspective, it was always like, no, you use the, the cannabis that's sourced from NIDA.

Andrew Huberman 1:10:08 Mm-hmm.

Dr. Matthew Hill 1:10:09 Um, so it was a group in Colorado, so Kent Hutchinson and Angela Bryan and Cinnamon Bidwell have kind of, I would say became very creative actually, to figure out how to study cannabis that's being used, uh, I call it in the wild, like, uh, in kind of an ecological setting, let's say. And so they created what was called the canna van (laughs) . And the canna van was a way to study people using products on the street, but not have them come into a laboratory setting where it was complicated. And so what they would do is they would drive the canna van to someone's house, but they'd be parked on the street, and someone would use the product, whatever it was on, in their own property, on their own time, and then come into the canna van to have blood taken, to look at what their THC levels are, and to undergo testing. And so it was actually like, I think this was a, a great advance in the field 'cause it was this-

Andrew Huberman 1:11:00 Mm-hmm.

Dr. Matthew Hill 1:11:00 ... huge innovative approach that allowed us to start comparing what we've learned from lab-based settings with this kind of old school weed that was coming from NIDA with what is being used on the street.

Andrew Huberman 1:11:10 I love this. I mean, as somebody whose lab has done a, in laboratory VR based experiment on human anxiety and fear, and then compared that to, uh, you know, a clinical study that we did sort of en masse where people were at home doing specific respiration practices, you have many more subjects, but of course they're reporting back-

Dr. Matthew Hill 1:11:30 Yeah.

Andrew Huberman 1:11:31 ... their effects. Um, well, you can monitor them by device, you know, look at HRV, look at heart rate-

Dr. Matthew Hill 1:11:35 Yeah. Yeah.

Andrew Huberman 1:11:35 ... et cetera. Um, I think having the ability to compare and contrast in laboratory and ex laboratory-

Dr. Matthew Hill 1:11:42 Yeah.

Andrew Huberman 1:11:42 ... data is extremely valuable.

Dr. Matthew Hill 1:11:43 Yeah, and I mean, my view is you need both because-

Andrew Huberman 1:11:45 Mm-hmm.

Dr. Matthew Hill 1:11:45 ... you need the in laboratory for the control because we all need control over various things, but you also need the ecological validity to see how it shakes out and make sure it looks the same.

Andrew Huberman 1:11:55 Yeah. For people that have never been to a laboratory or tried to find a parking spot at a university-

Dr. Matthew Hill 1:11:59 Yeah.

Andrew Huberman 1:11:59 ... that's an anxiety inducing experience in and of itself.

Dr. Matthew Hill 1:12:02 Well, I mean, and, a novel experience while someone's intoxicated with cannabis can also create a very different altered state. Like-

Andrew Huberman 1:12:07 I wouldn't wanna be stoned in a laboratory.

Dr. Matthew Hill 1:12:09 Yeah. So-

Andrew Huberman 1:12:09 I'll tell you that much.

Dr. Matthew Hill 1:12:09 ... I feel like there's pluses and minuses to both sides, but I think the data together is very compelling and that's where we get a lot of advance in the field. So what, uh, Kent and Angela and Cinnamon did with the canna van was kind of create this situation that allowed this research to occur. And what we found fascinating, I remember talking to Meg Haney about this because sure, all the people in her lab studies tended to always hit around 100 nanograms per mL using this relatively lower potency cannabis. When Kent and, and Angela and Cinnamon started studying this in the people and taking blood, despite the fact that these people are now using cannabis that's 20 to 30%, their blood levels are the same. So they're still coming in around 100 nanograms per mL because people are really good at self titrating.

Andrew Huberman 1:12:49 Mm-hmm.

Dr. Matthew Hill 1:12:50 Now, where things fall apart is with the concentrates. So then you go into things like dabs or these like high potency products that are now like... 'Cause cannabis itself, realistically, from what I understand from the botanists that I've talked to, you can't really grow