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

Andrew Huberman:
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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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/huberman. And now for my discussion with Dr. Matthew Hill. Dr. Matt Hill, welcome.

Dr. Matthew Hill:
Thanks for having me.

Andrew Huberman:
Delighted to have you here because you're an expert in the biology of cannabis, a topic that 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:
Mm-hmm

Andrew Huberman:
... 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:
Cannabis is a plant that has been around for some time. It's kind of got 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, in the West, it really wasn't a thing mainstream-wise until about the '60s. And then it became kind of introduced as 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 '90s and on, has become kind of a very heavily used drug by a large swath of people, ranging from teenagers on up. In terms of what it is inside it, it's a plant with a lot of very complex chemistry and biology behind it. So there are 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-9-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 going to get when they consume it. There are probably 70 to 100 and some odd other cannabinoids that are within cannabis. Most of them are pretty trace levels, and they vary from different types of cannabis from one another. But the other one that's had a lot of attention is cannabidiol, or what we call CBD. CBD 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 a 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 are those other things called terpenes-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... 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 an 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. 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 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. So-

Andrew Huberman:
Mm-hmm 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, right?

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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? I mean, that's my own business. I just want people to understand what you mean by psychoactive effects.

Dr. Matthew Hill:
So, the way that people would usually describe the intoxicating effects of cannabis is, 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. If there wasn't, people wouldn't be using it, if they didn't feel positive about it afterwards. There can be 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, you know, jacked up.

Andrew Huberman:
Possibility everywhere.

Dr. Matthew Hill:
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 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 where people get someone high, they just use what we call a visual analog scale, which is a one to 100 or something, or a 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 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 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.

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

Dr. Matthew Hill:
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 the drug-

Andrew Huberman:
And they pay you-

Dr. Matthew Hill:
... to be enrolled. Yeah.

Andrew Huberman:
So now pot smokers everywhere are running to look at studies.

Dr. Matthew Hill:
Yeah. I don't think you can use drug naive people. 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, 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, because I don't know how they would replicate that state-

Andrew Huberman:
Mm-hmm. Interesting

Dr. Matthew Hill:
... if they're not expecting it.

Andrew Huberman:
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-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... very little time has passed. Maybe it's sometimes even the reverse. Is the mechanism by which cannabis can adjust time perception known?

Dr. Matthew Hill:
I wouldn't say it's well worked out. There definitely seems to be some temporal dilation, like you're saying, where people think things of, 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, it might even be in pigeons, but it might be in rodents. It's looking at 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 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 in that context, it does still seem to produce some state where there's an altered perception of time passing.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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-- Anything I can think of is pretty old. I can't think of anything modern where people have actually looked at this.

Andrew Huberman:
Interesting. 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.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
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? Makes people hungrier, obviously, but we hear again in kind of recreational terms of people getting the munchies.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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?

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

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... before we go into that.

Andrew Huberman:
Great.

Dr. Matthew Hill:
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.

Andrew Huberman:
CB1.

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

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And I think, as 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. And so THC acts on these CB1 receptors, which 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:
Wow.

Dr. Matthew Hill:
So it's really important. And I think as you had alluded to previously, this didn't evolve in humans in the hopes that one day humans would find cannabis. This is just-

Andrew Huberman:
Although cannabis users everywhere use that argument.

Dr. Matthew Hill:
Yeah. I know people love to leverage things. If it's a plant, it's natural and safe. And there's obviously issues we'll talk about with that. But really, this is just biological redundancy. 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 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 some limited distribution in actual brain cell neurons.

Andrew Huberman:
Where in the body is it expressed?

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

Andrew Huberman:
Cells that gobble up debris.

Dr. Matthew Hill:
Yeah, and that basically regulate inflammatory processes. And so the main role of CB2 seems to be much more about 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 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 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, certainly in the brain, they don't behave like a normal neurotransmitter. So, 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. And so the way that we always 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.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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. So endocannabinoids are kind of this 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 kind of liken it to a thermostat model for the most part.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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 going to start releasing endocannabinoids to go back and tell neuron A to stop driving it. So-

Andrew Huberman:
So sort of a homeostatic scale-

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
Yeah. 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:
And that's probably why the CB1 receptor is so widely distributed-

Dr. Matthew Hill:
Exactly

Andrew Huberman:
... 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.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Because we're talking about retrograde signaling. But ultimately you don't want runaway excitation-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... because that looks like epilepsy.

Dr. Matthew Hill:
Exactly.

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

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
Exactly.

Andrew Huberman:
Okay.

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

Andrew Huberman:
Mm.

Dr. Matthew Hill:
Where they go back and gate how much is coming in. And they do this through various mechanisms, essentially turning off the electrical activity of that presynaptic neuron so that it stops releasing neurotransmitter.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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:
So inhibiting the inhibitor-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... leads to more excitation.

Dr. Matthew Hill:
Exactly. I usually liken it to basically taking the brakes off of a car while you're going downhill kind of thing.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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 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 CB1 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.

Andrew Huberman:
Interesting. If I may, earlier you mentioned one of the potential psychoactive effects of cannabis is euphoria.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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:
So, yeah, I wouldn't say that cannabinoids don't affect dopamine-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
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. Or at least-

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

Dr. Matthew Hill:
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. 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.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Whether or not that relates to the positive affect or the euphoria, I don't think anyone has cleanly demonstrated that. Obviously, dopamine's 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'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. Obviously, you can always just theoretically guess as to why somebody 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 then this one circuit is kind of free of it. But yeah, so 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 kind of roles that endocannabinoids play in that domain. But even within the endocannabinoids, 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, 15 receptors or 20 or something now. 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 bonafide endocannabinoids. There could be more. They're called anandamide, which is actually a kind of a funny name because it comes from the Sanskrit word anand for bliss. And so-

Andrew Huberman:
Mm

Dr. Matthew Hill:
... Rafi Mechoulam, 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. And so-

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

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... he took anandamide as a direct experience, and then-

Dr. Matthew Hill:
No, I mean he-

Andrew Huberman:
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 for a particular reason, you have to speculate that they had some familiarity with the compound.

Dr. Matthew Hill:
Rafi Mechoulam was also the guy who isolated and discovered THC. So, he's kind of the grandfather of the 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 20th, 1964 and so the joke is, is this where 4/20 came from? Because the original birth date of the first THC paper was 4/20, 1964.

Andrew Huberman:
Well, now that potential myth is definitely going to propagate.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Interesting.

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

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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 kind of caps out pretty fast. So it doesn't have a sledgehammer effect.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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 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 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 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.

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

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

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Whereas 2-AG is like, let's say, the pinch hitter who gets brought in to do the heavy lifting. And so 2-AG, during a situation like, let's say, something 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 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 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 all these forms of turning things up or down in a kind of rapid and on-demand manner, that's mostly 2-AG.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So most people who study neurophysiology and record activity in neurons and look at endocannabinoids, they're almost entirely talking about 2-AG when they play with stuff. So Yeah, that's one of the ways we do it. We say that anandamide may be more tonic, and 2-AG might be more phasic-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... and 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 resting conditions as well, and there certainly are some situations where anandamide might get brought into play to affect plasticity. But as 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 2-AG is activity dependent. So as that neuron becomes more active, it's going to make 2-AG to regulate its inputs.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So yeah, you have this very complex system, and it's really widely distributed, it's everywhere. The 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:
All over the brain.

Dr. Matthew Hill:
Except the one area where it's really interesting, actually, where you don't really see much receptor is in brain stem populations that regulate unconscious cardiac and respiratory function.

Andrew Huberman:
Hmm.

Dr. Matthew Hill:
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 cardiorespiratory parts of the brain stem, 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. There's always the saying, there's never been an account of someone actually dying from a cannabis overdose or a THC overdose. 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. And a lot of that is just because of the localization. For some reason, it's just not the receptors in that part of the brain.

Andrew Huberman:
Mm-hmm. Very interesting.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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 a phasic, so the ability to spike, forgive the pun-

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So very interesting, unique system-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... in a number of ways that raise a number of key questions.

Dr. Matthew Hill:
So yeah, if you go back to the munchies question you had. So if we tie into that, so there's a few ways. Cannabinoids and feeding are a really interesting thing because if you ask people 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, they are expressed in these feeding circuits in the hypothalamus. There's a lot of complex circuitry there that can regulate food-seeking behavior and-

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

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
Yeah, exactly

Andrew Huberman:
... 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-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... craving, and then eating.

Dr. Matthew Hill:
And so we know that cannabinoids, they regulate, again, those inhibitory inputs around AgRP neurons, for example, and so one thing they can do is disinhibit those AgRP 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. And so we know that you can also just dump anandamide, for example. Steve Muller and Kent Berridge 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 integrate with the reward circuitry. 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 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, or 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 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 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 of 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 what is it that... Because it's not just food seeking, and it's not just you 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 reinitiate 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 a picture of a pizza, or someone brings a pizza in front of you, it just looks delicious. And 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'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. And you get them high on a cannabis extract. We have these vape chambers that are like, I don't know how else to describe it outside of a little hot box. It's probably the best way to describe, because it's essentially a locked, airtight box that the rat goes in, and it gets 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 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 pre-satiate them, and they get them stoned, they will reinitiate eating again. And you make them work for it, where they have to lever press, and you get them stoned, and they will go to town on that, and they will work. And-

Andrew Huberman:
Proof that even under the influence of cannabis, animals will work hard.

Dr. Matthew Hill:
Yeah. For food. I don't know about other stuff, but for food, they certainly will. I mean, and Elise Wirtz 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.

Andrew Huberman:
It's like life.

Dr. Matthew Hill:
Yeah. Then you got to hit it 16, and it scales exponentially up. We've had this one female we joke about in the lab, this one female rat, and you get her high, and she'll do 300 lever presses to get one sugar pellet. She really wants it. So you can really 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 do another way of testing this question, which is you compare a food with something that will make the animal feel nauseous, like lithium chloride. This is the way that you would test 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 that's another way to 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 a negative associated flavor because the animal got nauseous before, you can 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 from the orbital 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 supports this idea that a lot of what the munchies is, is this ability to 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. And then similarly, we and others have also done work to show we 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 goosing up endocannabinoid activity.

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

Dr. Matthew Hill:
Mm-hmm.

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

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... 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?

Dr. Matthew Hill:
Yes. They dynamically change all the time.

Andrew Huberman:
But you're talking about experimentally or recreationally-

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
So, okay. A 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, not-

Andrew Huberman:
So it sort of mimics the-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... anandamide and 2-AG.

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

Andrew Huberman:
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.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So essentially what I was saying is that at very high THC concentrations, maybe not the binding affinity, but the amount of THC that is available to the CB1 receptors-

Dr. Matthew Hill:
Is high

Andrew Huberman:
... is going 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:
Yeah. 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 think the main way that most people in the cannabinoid theory field would look at this is that THC is not a very strong agonist. Even if you look at its ability to trigger an intracellular response, it's much lower than 2-AG.

Andrew Huberman:
So-

Dr. Matthew Hill:
It's actually more like anandamide.

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

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

Andrew Huberman:
But it is high affinity.

Dr. Matthew Hill:
It's high affinity, so it has the ability... But the tricky thing with that is it can outcompete 2-AG, but because it's a lower efficacy agonist than 2-AG, in that sense, it's almost blocking the effects, not amplifying them.

Andrew Huberman:
Blocking the effects of 2-AG-

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
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 would 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.

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

Dr. Matthew Hill:
Yeah.

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

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
Yeah, exactly.

Andrew Huberman:
And therefore, lead to more binding of the now elevated levels of anandamide that are available to CB1, and you see no psychoactive effects.

Dr. Matthew Hill:
No. No psychoactive.

Andrew Huberman:
People are not aware that they-

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

Andrew Huberman:
There's no euphoria.

Dr. Matthew Hill:
No one can guess. Yeah. No one can guess.

Andrew Huberman:
What is it used for?

Dr. Matthew Hill:
Well, 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 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 FAAH inhibitor, which is, take a step back, FAAH's 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 FAAH inhibitors. 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:
Aleve.

Dr. Matthew Hill:
Yeah. Essentially, yeah.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
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 going to work." So it kind of shelved for a while. A colleague of mine, Markus Heilig and Leah Mayo, Leah's now a colleague of mine in Calgary, but at the time she was a postdoc with Markus in Sweden, and they were able to get access to this molecule right before COVID, essentially. And they did a trial on 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 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 were interested in. And we did find that boosting anandamide with this drug over 10 days, was sufficiently capable of dampening stress-induced autonomic responses, so looking at heart rate or skin conductance. I think skin conductance was the measure we did in there, but it's a proxy for 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 conditioned fear memory that they had trained people to do. And so I worked with them on 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 help reduce fear. And so that is 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 one of the things. The drug has not really been used that widely yet. It's one of the frustrations I have as a scientist who does a lot of translational work and with clinical partners like Leah, is that getting access to these molecules is not easy when they're not 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. 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 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, 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. 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 a sleep study to show that it did have some effects on sleep cycle, the same way THC does. And then they also did an in vivo PET binding study to show that they could displace a radioactive molecule that would bind to the enzyme in the brain.

Andrew Huberman:
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-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... subjective experience than-

Dr. Matthew Hill:
THC

Andrew Huberman:
... ingesting or smoking THC.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Which brings us back to THC-

Dr. Matthew Hill:
So what's it doing?

Andrew Huberman:
... and cannabis.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... no munchies, et cetera. Then people smoke or take an edible of-

Dr. Matthew Hill:
Yeah

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

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And since we're here, we might as well talk about CBD-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and I think you're going to tell us the lack of interaction with CB1 receptor, right?

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And what is cannabis doing at the level of these receptors?

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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.

Dr. Matthew Hill:
Yeah. 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.

Andrew Huberman:
They evolve to do that.

Dr. Matthew Hill:
Yeah. And I think it's very clear that anandamide, for example, is not active at every synapse that 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:
Mm-hmm.

Dr. Matthew Hill:
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. And so-

Andrew Huberman:
You're introducing the ligand, the thing that binds-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... the receptor. This is far and away different than, say, the actions of amphetamines-

Dr. Matthew Hill:
Yes

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

Dr. Matthew Hill:
Yes.

Andrew Huberman:
Right? 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.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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.

Dr. Matthew Hill:
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 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, at its simplest form, what cannabinoid receptors do is they change the way that two neurons talk to each other.

Andrew Huberman:
So you're changing all the networks simultaneously.

Dr. Matthew Hill:
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 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:
Got it

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

Andrew Huberman:
That's very helpful.

Dr. Matthew Hill:
Yeah.

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

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... given as a therapy-

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

Andrew Huberman:
... is very different because that's-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... a levels issue.

Dr. Matthew Hill:
Yeah.

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

Dr. Matthew Hill:
Yeah. This is a lot more to do with just, yeah, 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 a 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 going up and up following 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 energy detecting its periphery and saying, "Oh, 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 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 a natural endogenous mechanism to regulate feeding based on nutritional state. THC, on the other hand, it hits the brain. Yeah, some of it's going to be the intoxication, but in tandem, you're going to hit the CB1 receptors that are in those feeding circuits as well. And the consequence of that is going to be, the way I 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 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 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 someone gets stoned, they're not going to eat lettuce. They want 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 theory that I have about what it is that it's doing is, and I think you can make this analogy for multiple different things. 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 tricking the brain into thinking you're in that state now.

Andrew Huberman:
Very interesting.

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

Andrew Huberman:
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.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
You used the word stoned.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Kind of out of it. And yet I've heard of some potential uses for enhancing focus.

Dr. Matthew Hill:
Honestly, this is a bit of a tricky one to speak to because I just don't think there's good evidence for it.

Andrew Huberman:
Either way, or?

Dr. Matthew Hill:
As far as I'm aware, it hasn't been studied in a lot of depth. There's some things, a lot of the stuff that's been done is usually more 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. So-

Andrew Huberman:
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:
I don't think I would say that. I don't think you could lump anything in that context. 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:
Negative effects or enhancements or decrements?

Dr. Matthew Hill:
I would say most of it has to do with recall or consolidation. So there does seem to be some, 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.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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:
Mm-hmm.

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

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
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.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
It's still there. I think the effects that are more often seen in, 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 ... used to that state, let's say. There's certainly something we call state-dependent learning, which I'm sure you're familiar with. And this is something people-- I remember learning about this in undergrad through alcohol.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So, 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. And so-

Andrew Huberman:
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-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... at that particular task-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... 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 it 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.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
That is not true-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... from what I understand.

Dr. Matthew Hill:
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:
Correct.

Dr. Matthew Hill:
Just because they had had some state-dependent learning.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And so I think 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 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 episodic-

Andrew Huberman:
Sure

Dr. Matthew Hill:
... and declarative and whatnot. So, I can't say that, but I'd say it's kind of generally, and 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. So, yeah.

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

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
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, I think your words were it, assuming high THC levels in the cannabis, carpet bombs all the networks as opposed to binding more with higher affinity at particular receptors.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Okay.

Dr. Matthew Hill:
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.

Andrew Huberman:
Is that right?

Dr. Matthew Hill:
You look at edibles, for example. This may be an interesting segue into route of administration stuff because 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 a different game.

Andrew Huberman:
Yeah. Let's talk about this because I know that you and I arrived at different understanding of the fastest, typical, and slowest-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... routes of entry for THC into the system to arrive at the brain.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Right? 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.

Dr. Matthew Hill:
Yeah. Which is very fast. Yeah.

Andrew Huberman:
Right. Which is very fast.

Dr. Matthew Hill:
Yeah. 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.

Andrew Huberman:
Okay. So it may be that it is the same as nicotine, it may be that it's faster, but importantly, it can be fast.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
But typically, how fast is the onset of the subjective experience of, okay, 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:
Two to five minutes, I would say.

Andrew Huberman:
Two to five minutes.

Dr. Matthew Hill:
It's pretty fast. 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. It's pretty quick, and people titrate cannabis pretty well, at least people who've used it a couple of times and understand this tend-

Andrew Huberman:
I know. I've seen some people not titrate it very well.

Dr. Matthew Hill:
Depending again on how you-- So again, this can vary. So, cannabis from the '70s was like, I don't know, 5% THC, let's say. It was pretty low. 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:
Wow.

Dr. Matthew Hill:
But so it's gone up a fair amount.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
That's not just a fair amount. If we were talking about alcohol concentration-

Dr. Matthew Hill:
It's a beer to vodka.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Yeah. Basically, you're talking about a beer or a wine to a spirit.

Andrew Huberman:
And there are aquavit varieties-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... so to speak. By the way, I think when people hear me talk about any kind of drug that can be used recreationally or alcohol, I think some people assume that I'm ultra anti all these things. I'm actually not. Right? I'm non-alcoholic, so I can drink a little bit, and I have.

Dr. Matthew Hill:
Yeah.

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

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
But the point here is we're not trying to frame this as what people should or shouldn't do.

Dr. Matthew Hill:
Yeah.

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

Dr. Matthew Hill:
No, exactly.

Andrew Huberman:
I want to be very, very clear about that.

Dr. Matthew Hill:
So I think-

Andrew Huberman:
But when I hear about 20% to 30% concentration as opposed to-

Dr. Matthew Hill:
Five

Andrew Huberman:
... 5% concentration, that's significant.

Dr. Matthew Hill:
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:
Mm-hmm.

Dr. Matthew Hill:
And Canada's been quite behind on this. Even with legalization, we haven't caught up. But they have been doing lab-based studies of cannabis. Meg Haney, Harriet de Wit, this cluster of researchers around the country, Ziva Cooper at UCLA here, have all done this where 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 even the state-by-state legalizations hasn't changed this. So if you are doing cannabis research in humans and you're funded by NIDA, which is National Institute of Drug Abuse, you get all your cannabis sourced. This may be changing. I think there are some shifts that are happening. But historically, in all the literature that we would talk about that's pre the last couple of years, all that cannabis came from one source, which was, I believe, a farm in Mississippi that was essentially funded by NIDA to produce cannabis.

Andrew Huberman:
Lucky farm.

Dr. Matthew Hill:
And well, the cannabis that came out of it, though, and this is one of the reasons a lot of the clinical stuff people have been like, "Oh, I don't know how representative this is," because it reflects cannabis that I would say is more from the '70s or '80s. So it would be five 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, whatever, eight tokes, let's say, something like that, and that's where they would stop. And so 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. 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 you can legally study 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 like, it's been a weird thing for a lot of people because 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 cannabis that's sourced from NIDA.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So it was a group in Colorado, so Kent Hutchison 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, I call it, in the wild, in kind of an ecological setting, let's say. And so they created what was called the Canavan. And the Canavan 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 Canavan to someone's house, but they'd be parked on the street, and someone would use the product, whatever it was, in their own property, on their own time, and then come into the Canavan 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 great advance in the field because it was this 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:
I love this. As somebody whose lab has done a in-laboratory, VR-based experiment on human anxiety and fear, and then compared that to 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 their effects.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Well, you can monitor them by device, look at HRV, look at heart rate, et cetera.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I think having the ability to compare and contrast in-laboratory and ex-laboratory data is extremely valuable.

Dr. Matthew Hill:
Yeah. And my view is you need both because 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:
Yeah. For people that have never been to a laboratory or tried to find a parking spot at a university-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... that's an anxiety-inducing experience in and of itself.

Dr. Matthew Hill:
Well, and a novel experience while someone's intoxicated with cannabis can also create a very different altered state.

Andrew Huberman:
I wouldn't want to be stoned in a laboratory.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I'll tell you that much.

Dr. Matthew Hill:
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 Kent, Angela, and Cinnamon did with the Canavan 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 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 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:
Mm-hmm.

Dr. Matthew Hill:
Now, where things fall apart is with the concentrates. So then you go into things like dabs or these high potency products that are now like... Because cannabis itself, realistically, from what I understand from the botanist that I've talked to, you can't really grow a plant that's going to exceed more than 25% to 30% THC just by sheer biology. So it taps out there. That's about as high as it's going to go. Concentrates can go up to like 90%, 98%. So you can get really, really-

Andrew Huberman:
These are tinctures?

Dr. Matthew Hill:
Distillates, yeah. Various just in oil-based forms that are very, very high potency products. Those are incredibly challenging to titrate. They cannot be titrated because the sheer volume of THC that hits the system, even from a single hit, is so overwhelming. And so when the Colorado group looked at those, their blood levels were closer to 200, 300 nanograms per ml. So With cannabis plant, there does seem to be this ability for people to relatively self-titrate. And then my buddy Ryan McLaughlin, who's also at Washington State, he was really one of the ones that pioneered these vape chambers in rats and created this really cool model of self-administration, which was a very important thing to actually establish because it was very challenging to get rodents to self-administer cannabis if you were doing an IV approach or something else, because they found it quite aversive. But when you let rodents actually titer their ability to get vape hits, they will work for this, the same way they will other reinforcing drugs. So it was a really important finding that you could do this. And what Ryan found was he actually did one study where he gave them access to a low-potency product, we'll call it medium, and then a high. And what you ended up, if you look at the data, is the one the rats liked the best was the medium-potency product.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
And if you gave them the high-potency product, they would actually take less vape hits off of that than they would off the lower ones. And again, all their blood levels tended to cluster in the same range because they titrated. Even at the rodent level, they're able to titrate because of the lag between inhalation and feeling the effects is only on the order of a couple of minutes, people can titrate better. Not just people, it seems like the rodents can as well. So the higher potency cannabis, where it becomes a problem is if someone's highly inexperienced and they consume a whole bunch of it without allowing that time lag to occur, and then they can probably exceed the levels they intended to and consume too much and then have probably an adverse response.

Andrew Huberman:
So does that mean that cannabis use rarely leads to tolerance of cannabis use?

Dr. Matthew Hill:
I wouldn't say that. There's definitely some degree of tolerance. The tolerance is definitely more prominent when people start using concentrates. There's no question about that. We can talk about the concentrates, I guess, separately after. Because I would say if we're talking about a harm reduction thing, that's more where we need to focus a lot more, is this idea of these high-potency products.

Andrew Huberman:
Yeah. It sounds like those are precarious.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
That somebody who thinks they have a lot of experience or, God forbid, no experience, takes a concentrate and is, what? No longer getting the euphoric experience that they anticipated, but instead are getting, what, a paranoid anxiety attack?

Dr. Matthew Hill:
Yeah. I think you're far more likely to go overboard and have an adverse response. But also, I think the problem is if you're using a product of that potency and that much THC floods your system on a regular basis, the biological changes from that are going to be very different than what you get if, again, you're titrating your THC from inhaling plant at roughly the same level, whether that's a 10%, 5%, or 25%, people generally tend to scale.

Andrew Huberman:
All right. This is a very important point, and I'm going to highlight it because I think it's very, very important, although you're making it very clearly already, which is these days we hear a lot about the quote, unquote "problems" with high-THC containing cannabis as relative to what was present in the '70s and '80s, and presumably '90s as well.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I was a teen in the '90s, so maybe I'm alluding to something there. But what you're saying is that unless one is talking about concentrates, that people and animals in the laboratory will self-regulate the amount of intake in a way that leads to approximately the same blood levels of THC. So it may not be as much of a concern, at least in light of-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... the concerns about, oh, these levels are so high that people are overwhelming their system with THC. Basically, this could be stated in real-world terms as people are taking fewer tokes of the higher concentration stuff that allow them to match blood levels that were present in the person taking many more tokes-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... in the '70s.

Dr. Matthew Hill:
So the joke I always make to people is I say, "Go watch a Cheech and Chong movie from the late '70s. Look at the size of the joints that they smoke in movies like that relative to what you would see someone on the street consuming nowadays." So the advantage that existed from a titration perspective was with '70s weed, there's a large window to titrate. So people could take small amounts and not over-consume, let's say, because there was a much lower concentration of THC in the plant, so they were able to consume, even if they were doing it relatively fast, because of how little THC was coming into the system, it was a little easier to scale that.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So there certainly is the propensity for people to over-consume higher potency cannabis, even independent of concentrates, if they're not allowing that titration to occur. Also, if you have someone who's just exquisitely sensitive to THC for various reasons, even one or two tokes could be too much for them because at the higher potency, they may not have that ability to titrate quite as well.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And so a lot of people, anecdotally, you talk to people about cannabis, and a lot of people who don't like cannabis have said, "Oh, I've tried the new stuff, it's too strong." And if there's someone who's more in our age range who grew up in an earlier decade where things were a bit different, they may be referencing their own experience from when they were younger and what they were able to consume, and now they try doing the same and it hits them like a sledgehammer.

Andrew Huberman:
Got it.

Dr. Matthew Hill:
So it's a little different in that sense.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And I don't think it's to say it's not concerning that cannabis is as high as THC as it is. I just think if I'm going to put my efforts into public health perspectives of this, I would be digging my feet in much more about the access to concentrates and the issues and the potential harms that are going to come with them than I would about the cannabis flower myself.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
That's just my opinion based on what I see with the concerns and what we've seen from the data in humans. And I think the real world ecological studies that the Colorado group have done have been very informative in this sense because, yeah, if the blood levels of THC you achieve from concentrates are double to triple of what you get even from higher potency flower, that's a concern. I think that's where problems start arising, because then you're going to start seeing a lot higher degree of tolerance. There used to be more of a debate in the field as to whether people develop tolerance, because one of the things with cannabis that I do find very interesting is with a lot of chronic users, they don't escalate the way you would see with cocaine or alcohol, where there's very profound tolerance that develops. And so, people definitely see this in cocaine, where people can become tolerant almost immediately. And so dosing starts scaling up very fast.

Andrew Huberman:
Yeah. Usually, it's the life destruction that thwarts their-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... progressive increase. Seriously.

Dr. Matthew Hill:
Or the cost.

Andrew Huberman:
Right.

Dr. Matthew Hill:
The sheer cost.

Andrew Huberman:
Another form of life-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... deterioration.

Dr. Matthew Hill:
Yeah, that is required to be able to maintain that. But with cannabis- It seems like there is some degree of tolerance that people exhibit. It varies from person to person. But as Meg has said to me many times, the guys that come in her studies, these are very heavy users, and then they will use this relatively low potency product and still get high off of it.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And so it's not to say that there's no tolerance, it's just not as profound as I think we see with a lot of other drugs. And this is probably due to the fact of just, we definitely see, if we look at some PET imaging studies, chronic cannabis users do have some downregulation-

Andrew Huberman:
Sorry, I have to interrupt. PET, positron emission tomography-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... not pets. Although people get their pets high, and we don't know what those pets think about that.

Dr. Matthew Hill:
Not good.

Andrew Huberman:
Although-

Dr. Matthew Hill:
Don't get dogs high.

Andrew Huberman:
Although if also high, one can assume a lot of things about what your pet is thinking-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... while also high. Sort of half joke there. But yes, positron emission tomography is one way to assess the binding of drugs within the brain, as well as activity of endogenous neurotransmitters, neuromodulators, such as anandamide, dopamine, et cetera.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
So a typical PET study in a human looking at this, they'd give a molecule that's radiolabeled that will bind to CB1 receptors. You can scan them, and then look at the emission rates of the radiation to get an idea of the density of receptors that are in the brain. Chronic cannabis users tend to have less. What that means in terms of the functional outcome is unclear. There's a lot of evidence that there's some degree of a reservoir of CB1 receptors that there might be a lot more receptors there than we necessarily always need or are always using, let's say. So we might be down-regulating a component of this, but maybe not all of the ones that are required to produce the psychoactive effects, because there's clearly some maintenance of the system that allows someone to continue to get intoxicated. And so with cannabis users, we do see that. But you do see much more profound tolerance with people using high potency extracts and concentrates and things like this. And again, surely I think as a response to the biology of hitting the system that heavily with that much THC as it comes in because they can't titrate it the same way.

Andrew Huberman:
It makes sense. Yeah, these concentrates sound like something to at least pay attention to as a potential problem. I'd like to take a quick break and acknowledge our sponsor, InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. Now, I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long-term health can only be analyzed from a quality blood test. Now, a major problem with a lot of blood tests out there is that you get information back about metabolic factors and hormones and lipids and so forth, but you don't know what to do with that information. With InsideTracker, they make it very easy to know what to do with those numbers because they have a personalized platform that allows you to see the levels of those metabolic factors, lipids, hormones, et cetera. And they give you specific directives that you can follow related to nutrition, behavioral modification, supplementation, and more, that can help you bring those numbers into the ranges that are optimal for you. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 10% off their new membership program. InsideTracker membership offers significantly reduced prices on InsideTracker's comprehensive blood panels. Again, that's insidetracker.com/huberman to get 10% off. Along the lines of use tolerance, et cetera, is cannabis addictive and/or habit-forming? And I think it's probably important that we distinguish between the two. I may have made this joke in the previous episode I did on cannabis. I've known a lot of chronic cannabis users, and none of them admit to being addicted. It's not my place to challenge them on that. But they do seem, in my experience, this is not an experiment, but in my experience, more irritable when they don't have access to what they call their "medicine."

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So, that speaks to a dependence or something. But then we need to be careful because in the classic sense, addiction, I've defined, and others in the field of addiction have defined it as a progressive narrowing of the things that bring you pleasure, such that it causes disruption to other areas of life, and your life becomes maladaptive.

Dr. Matthew Hill:
Yeah. I'm not going to play with the definition of addiction. I feel like I have enough friends in the addiction space that it's a very contentious-

Andrew Huberman:
Sure

Dr. Matthew Hill:
... field. So, I will try and not use that word, although I understand talking to the general public, if you say someone has a use disorder versus an addiction, that may not make sense to them.

Andrew Huberman:
Right. But that's the nomenclature now that people are using.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Alcohol use disorder.

Dr. Matthew Hill:
Yeah, exactly. So-

Andrew Huberman:
Cannabis use disorder.

Dr. Matthew Hill:
Yes.

Andrew Huberman:
This is what you start to see now instead of saying being addicted to pot or being addicted to alcohol.

Dr. Matthew Hill:
Yeah. And so an addiction is obviously a very complex thing that, again, I don't want to touch it simply because it's not my space. But that being said, there's no question that people can develop cannabis use disorder. It's definitely a thing. So if we say, is cannabis addictive in kind of a normal lay speak, I would say yes, it is addictive. What does that look like? How does that relate to other substances of abuse? Certainly, the outcomes associated with it are going to be slightly different than something like opiates or alcohol because that's a totally different beast because you have fatality potential. There's a whole bunch of other health consequences. But if we look at how we would define a use disorder, the criteria for someone hitting cannabis use disorder is really no different than how someone would hit alcohol use disorder or opiate use disorder in the sense that it can consume their life, it can shift the way that they behave. They can put themselves in risky positions to get access to a drug. It can consume their time and their energy to have it. Like you said, if they don't have access to it, it can trigger ... an assembly of behaviors that looks like irritability, anger, frustration, things like that. So, the numbers in terms of the conversion rate of use to developing use disorder, I would say, are not entirely clear. The old numbers that used to get tossed around were 9 to 11% of people that would start initiating cannabis use would probably transition to develop use disorder. The more modern numbers, I would say, if we're looking at people who are already using weekly, we're talking probably closer to 30%.

Andrew Huberman:
30%.

Dr. Matthew Hill:
So it's a much higher-- When you're using that frequently, then the rates of people who would qualify as having cannabis use disorder probably go higher.

Andrew Huberman:
So I just want to make sure I'm understanding clearly. For people that use cannabis weekly, the propensity for developing cannabis use disorder is on the order of about 30%?

Dr. Matthew Hill:
Yeah, I'd say in that neighborhood, they would probably qualify as meeting criteria for a cannabis use disorder.

Andrew Huberman:
Because weekly doesn't seem like that often.

Dr. Matthew Hill:
No. It depends, again, on how you vary this. I've had a lot of conversations with the public, and I think depending on someone's experience in their own or in their own inner circle's life with cannabis, the way they would view it is very differently, because I think a lot of people, again, regardless of anyone's opinion of alcohol, if someone told you they had a glass of wine with dinner every night, I don't think people would say you have an alcohol use disorder.

Andrew Huberman:
No.

Dr. Matthew Hill:
I think that's not uncommon.

Andrew Huberman:
No, I don't think they would.

Dr. Matthew Hill:
Similarly, if someone had a brandy at the end of the night, or a nightcap to go to bed, and they did it on a nightly basis, I don't think anyone would say that they have a use disorder. And I think with cannabis, there are a lot of people that fall into that bracket, that would use it even daily, but relatively infrequently and as an end of the day thing. I think some of them certainly would fall under the criteria of cannabis use disorder, because if you start looking and say, well, if you travel to Egypt, are you going to go put yourself at risk of going to jail to get access to cannabis because you can't function without it? If you do, then yeah, you've got cannabis use disorder. Are you going to burn relationships? Are you going to start failing at meeting responsibilities or getting things done on time because you're preoccupied with cannabis? Yes, you're going to hit the criteria for cannabis use disorder. If it's someone who's just intermittently using it, the same way that a lot of people casually use alcohol, I would say a lot of them probably wouldn't hit criteria. But I think to someone who has never had cannabis in their inner circle or in their life, they look at it like a drug like cocaine, whereas they're like, "Wow, if you were using cocaine on a daily basis, we'd be super concerned about you." Mm-hmm. It's just as you go, cannabis is in this really weird transitionary period, I would say, of going from illicit to not, just because of the changes in the legal regulatory framework. In Canada now, we're five and a half years into legalization, so in many ways, I would say the transition has happened where a lot of people view cannabis very similarly to alcohol, whereas you go to some states and the perspective is still very different. And certainly, if you're still in one of the states where there's no legal access, people still look at cannabis the same way they look at a lot of other illicit drugs like cocaine or amphetamines or things. And I think-

Andrew Huberman:
That's interesting. I was under the impression this had really changed over the last five, 10 years. Growing up, I think there are still people in jail now-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... because of possession and sale of cannabis. And then of course, there are stores not far from here where people are selling cannabis.

Dr. Matthew Hill:
Ironic, yeah.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
Sadly. Obviously, a big push for legalization is not endorsement of the safety of cannabis. It's more the harms associated with prohibition outweigh the harms associated with legalization. I think that's generally the public health perspective. That's certainly what motivated it in Canada.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And there was some attempts, let's say, at restorative justice in terms of removing criminal records and things. May not have been entirely as successful as people had hoped it would be, but it certainly has changed things. We can look at our federal data and see that arrest rates related to cannabis are obviously very low compared to what they were. That obviously becomes very important because there are clearly minoritized communities, they get hit more with this than other communities. And so the perpetual disenfranchisement that happens with a prohibition model in communities that are already suffering from various other things that affect them, just potentiates all that. So-

Andrew Huberman:
Got it

Dr. Matthew Hill:
... I can understand the legal framework behind why there would be a move to a legalization state over a prohibition state. Which again, a lot of people confuse legality with safety, which is a weird-- Alcohol is the perfect example of this. You look at the scale of harms on a public health level, alcohol stacks at the top. Across the board, in terms of harms to the individual, harms to society, it's a lot. Cannabis has harms, there's no question on that. It just would fall lower than alcohol. But the way that people view it, a lot of people are like, alcohol is legal, therefore it's safe and it's not something to judge people on. Cannabis, at least historically, was illegal and in some states still is. So people view it very differently, and I think it's an interesting thing, because I feel like, despite the fact that some people hate the government and hate the way that it regulates their life, there's this weird passive belief that if the government dictates something is legal, that means it's safe.

Andrew Huberman:
Mm-hmm. Is the legalization of cannabis leading to more cannabis users or fewer, and/or incidents of people going into the emergency room suffering from cannabis-induced psychosis, something that I hope we can also talk about.

Dr. Matthew Hill:
Yeah. So it depends on how you break this down. So what we've seen in Canada is, I would say there's demographic differences. Proportionately, when we look at the biggest change in use, it's actually elderly communities. It's like 55 plus. Especially women over 55 tend to be the-

Andrew Huberman:
More cannabis use.

Dr. Matthew Hill:
More cannabis use. Now, granted, their baseline was quite low pre-legalization, so if you look at a fold change, it looks like a very dramatic ... increase. Raw numbers, it's probably not that high, but it was one to 2% or something before, and now it's gone up to 8% or something. So it's a fourfold increase kind of thing. So we do see the magnitude of that seems to be the biggest in terms of where the use has come from. Definitely the young adult population, like 20, 24, that group has definitely seen increased use as well.

Andrew Huberman:
Does it split male, female?

Dr. Matthew Hill:
Historically, cannabis tended to be more male-biased. I'd say the gender separation there has narrowed quite a bit, where you do see a lot more females use than historically had.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
There is a little bit of difference. Females tend to prefer edibles over males.

Andrew Huberman:
Mm.

Dr. Matthew Hill:
So, males tend to like inhalation over females. So, roots of administration vary a little bit based on who someone is, but yeah. Interestingly, we don't have a lot of actual indication that teenagers have used more. So you look at 14 to 18-year-olds, now granted, our baseline going in was pretty high, as is down here in the States. Canada and the States both hover, you look at grade 12ers, and it's somewhere between 35% and 40% of them have used cannabis. Now, you even have some that are probably around 5% are probably almost daily users. So, you do have a pretty high baseline to begin with in that group, but that has remained relatively unchanged. If anything, some of the states, when they legalized, saw slight dips in teenage use of cannabis. So, I think that's obviously an important demographic to have tracked. This was one of the concerns with legalization was you'd increase access. Teenagers would get it from their parents and whatnot, or had just other siblings and stuff, and so you get this big boost in consumption. But we don't seem to see that in terms of raw numbers of teenagers who are using cannabis. So that's good. ER visits. So we did an interesting roll out in Canada. We legalized flower for a year before edibles came online. So we have a before and after. Once edibles became available, there was a notable increase in unintentional pediatric consumption that resulted in ER visits because a lot of these look like gummies and candies. People are buying them, not storing them properly.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Kids would find them and eat them and become very intoxicated.

Andrew Huberman:
I want to make mention of something along those lines. I actually know somebody whose child accidentally ate THC-containing gummies. Fortunately, the child was fine. But there are actually pretty serious ramifications for this. The parents actually are quite susceptible to legal action-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... if this happens. Right? So this is something to really keep in mind. There are a million other health-related reasons why this is probably-

Dr. Matthew Hill:
Yeah. I don't know if that's true in Canada the same way.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
But in the States, yeah.

Andrew Huberman:
Yeah. If your kid gets into a stash of THC-containing gummies and ends up in the emergency room, there will also be, most likely, there'll be a police visit to that emergency room also.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And it doesn't bode well for the parents.

Dr. Matthew Hill:
So this is-

Andrew Huberman:
It's a very serious issue.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And again, this was highlighted to me by someone that I know who didn't anticipate any of this, but kids are good at finding candy.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And if that candy contains THC and they end up in the emergency room, serious issues.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Nonetheless, if your kid is acting strange because you think they ingested THC-containing anything, take them to the emergency room anyway.

Dr. Matthew Hill:
Well, so this was one of the things that also was influenced by legalization is in Canada, some of the increase in the ER visits was because of the shift in legalization and the change in policy. And so, if your kid ends up drunk underage, it's not the same ramifications as if your kid used an illegal substance underage. And so once cannabis was legal, people were more likely to actually go into the ER because the consequences were different.

Andrew Huberman:
I see.

Dr. Matthew Hill:
And so sure, some of this is availability, and some of it is just like, "Okay, I'm not as concerned now about something happening because I've taken my kid in. I'm not going to have my kid taken away from me," or whatnot. So, both those factors I think have contributed to it, but we definitely see the majority, at least, of kids ending up in the ER is almost all based on edibles. I can't imagine a situation where that would happen from inhalation. It would be very rare if it would. It's almost always edibles because kids find them.

Andrew Huberman:
So as long as we're talking about edibles, is there any fundamental difference between the dose regulation that you talked about earlier of-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... inhalants versus edibles? Meaning earlier you said that even if it's high-THC containing cannabis, people will self-regulate to achieve approximately the same blood concentrations.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
But with edibles, I imagine you eat half a cookie, a quarter of a cookie-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and you can end up in a vastly different place than you expected.

Dr. Matthew Hill:
So edibles, so this throws a wrench in the whole system, and I'll say this in the context of blood levels, and then what that means from a regulatory capacity as well because of the impact this has. So edibles are very low doses, for the most part. In Canada at least, you cannot buy a pack of edibles, and I think this law might be changing, at least when they first brought it in. No pack could have more than 10 milligrams of THC in it. So that either meant one 10mg gummy or two five mg gummies, or four 2.5mg gummies. You get it. So you couldn't, in one package, have more than 10 milligrams of THC. Now, for people who are, I would say, relatively naive to cannabis or THC, even people who might use it intermittently, most people will feel five milligrams. They'll feel some form of intoxication. Some will even feel it at 2.5 mgs. Most people will feel it at five. Virtually everyone will feel it at 10. Now, if you look at the blood levels these produce, we're now talking blood levels of two to five nanograms per mil. So ... folds lower than what you get from inhalation.

Andrew Huberman:
Right. Before you said 100.

Dr. Matthew Hill:
Yeah. So this is dramatically lower. And so, also the time course of this is fundamentally different. So in oral consumption, you're looking at a minimum of 30 to 45 minutes for onset of intoxication, for some people, up to 90 minutes after they've eaten. Now, this is also the reason why the majority of adverse events that happen with cannabis happen with edibles, because people don't understand this, and so they eat a cookie or a gummy, they wait half an hour, like, "I'm not feeling anything. I clearly didn't take enough." And then they'll double their dose, and then 15 minutes later it starts hitting them, and then once it fully kicks in, it's just like a steamroller.

Andrew Huberman:
Yeah. I've heard of this happening.

Dr. Matthew Hill:
Yeah. There was that New York, I think it was Maureen Dowd or someone, went down to Colorado and she ate an insane amount of THC in a chocolate bar, something like 50 or 100 milligrams, and spent the weekend on the floor of a hotel room being like, "This was the most aversive experience. Why would anyone do this?" And again, I think people just don't understand the dosing around this. And so this is one of the things we're trying to do in Canada, and that was create this idea of standardized dosing units so that people have an-- like we with alcohol, we always say one beer is the equivalent to one glass of wine versus a shot of tequila or something, so that there's some comparator that people understand how many drinks are, say two drinks you do, you're going to hit legal limit kind of thing.

Andrew Huberman:
Yeah, it seems very important.

Dr. Matthew Hill:
Yeah. And so this is very difficult to do with cannabis because the dosing with oral consumption is just a different ballgame than it is with inhalation. But what happens with oral consumption is it very slowly leaks out of the GI tract. And it also goes through first pass metabolism in the liver. And what happens there is you get a metabolite called 11-hydroxyTHC, which seems to be a bit more potent than THC is in terms of its ability to activate the receptor. So, and its efficacy, at least, at driving a response through CB1 receptors seems to be higher than what you would get with just the parent molecule of THC itself.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And it seems to accumulate a lot more as well. So at any given time, you've got THC kind of leaking out of the gut, going through the liver, making 11-hydroxy, and it progressively accumulates in the brain, and that's one of the reasons why it takes 45 to 90 minutes to kick in, but then the high itself also lasts six hours, four to six, sometimes eight, depending on the person, what they've eaten. Versus inhalation is just this spike, so you get this very rapid, because it goes right through the lungs into the blood, goes into the brain, but it also clears out. And so, yeah, people will start feeling intoxicated two to five minutes. Their peak high is 15 to 30 minutes maybe from consumption, and then they'll start to come back down. And you will still see some indications of intoxication that can go on for three to four hours.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
But the bulk of the intoxication from inhalation is done by two hours-

Andrew Huberman:
Got it

Dr. Matthew Hill:
... for the most part.

Andrew Huberman:
As long as we're on the topic of time course, based on what I was able to find, I believed, and tell me if I was wrong, that cannabis can stay in one's system for as long as 80 days. The reason I brought this up-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... previously was there are a number of people who have used cannabis, are going to take a drug test, and want to know how fast it can clear from their system. But based on conversations we had offline, sounds like that 80 days might be a bit too long.

Dr. Matthew Hill:
You could still fail a drug test at 80 days. I would say, I feel like, I think the way it was worded more it was like that you made it sound like that was the standard.

Andrew Huberman:
Got it.

Dr. Matthew Hill:
I wouldn't say that was the standard at all.

Andrew Huberman:
Okay.

Dr. Matthew Hill:
I would say for the majority of people, 30 days probably after that-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... they would not pass, or they would be able to pass a drug test. But that being-

Andrew Huberman:
So abstinence for 30 days.

Dr. Matthew Hill:
Yeah. After abstaining for 30 days. And it's going to be highly variable depending on how much you consume. If you're talking about someone who's used it once, I don't imagine it would be in your system that long. That'd be surprising.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
The thing is, THC is a lipophilic molecule.

Andrew Huberman:
It's fat soluble.

Dr. Matthew Hill:
Yeah. So it's fat soluble. It likes to store. It doesn't like the blood. The blood is aqueous and watery. It likes fat. So it goes into the brain, it goes into the fat, and it kind of resides there. And it can essentially slowly leak back. As THC concentrations in the blood would reduce, THC that's in the fat will start leaking back into the blood still. So detectably, you will still have THC for quite some time. Some of this, again, it's going to be dependent on how much cannabis someone's used, how much THC they've consumed, how long it's been in their system for. I would've thought this was going to be somewhat reflective of people's body fat content, although talking to colleagues who do this, they say not always. But we do know certain things like exercise, for example. Anything that's going to trigger adrenaline, because adrenaline is lipolytic, so adrenaline causes fat to metabolize and release stuff that's inside it. So there are plenty of cases I've heard from people where they were testing themselves and were negative and then went for a run or went to the gym, and then tested positive.

Andrew Huberman:
Or lost weight.

Dr. Matthew Hill:
Yeah. Or they've lost weight. And anything that's going to cause the lipolysis to occur so that it releases that THC, you can certainly all of a sudden test positive again when someone had tested negative previously, just because of the fact that there still is some in the fat. And so this is where something like, and this is what I mean by standardization of regulatory issues become very complicated, was I remember right when legalization happened in Canada, all these kind of chemists were talking to me about they're going to create a breathalyzer for cannabis because this way they'll be able to do roadside detection the same way they could do with alcohol. And I kept trying to say to them, I'm like, "The rate-limiting step here is not the science of detection thresholds. It's the biology of how the body processes cannabis."

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And you're never going to get a test that works because you can take someone who has eaten an edible and is profoundly intoxicated, and they will Have possibly under five nanograms per ml of THC in their blood.

Andrew Huberman:
But you were talking about this metabolite that can come from the edibles that doesn't come from inhalants, that can have a much more potent effect.

Dr. Matthew Hill:
You get a bit of it from inhalant, but not nearly as much as you get from edibles. But that's-

Andrew Huberman:
So it's sort of a different situation altogether.

Dr. Matthew Hill:
It is, but it's also the timeline. Because of the fact that with inhalation, it's like a bolus that hits you at once, so you get a high blood level.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
With edibles, it's like the time course. So, it's going to be like five nanograms per ml, let's say, but it would be like that for a long time. Whereas the 100 nanogram per ml from smoking is, like, for 20 minutes, and then it starts dropping. But the problem is with the way that you detect it, is you can take someone who's a chronic cannabis user and is completely sober and hasn't consumed in a day or two, and their basal levels of THC in their blood may be higher than someone who's profoundly intoxicated by an edible.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Just by the sheer nature of the fact that it would reside in their fat tissue or their brain, it would leak back into the blood. And so you have this issue where, let's say your cutoff was five nanograms per ml, which is for some of the stuff detection thresholds would hover around that area. So you could have someone who's dead sober that tests positive and someone who's profoundly intoxicated who tests negative. So it's like, what's the value in this?

Andrew Huberman:
Right.

Dr. Matthew Hill:
It's not telling us anything.

Andrew Huberman:
Well, I guess it sounds like the drug tests either have to be revised or discarded, and it also sounds like if somebody is going to take a drug test for cannabis and they have used cannabis in any form in the previous 90 days, let's say, going for a run right before your test-

Dr. Matthew Hill:
Yeah, probably not a good idea

Andrew Huberman:
... is going to liberate whatever THC resides in the fat stores.

Dr. Matthew Hill:
Potentially, yeah.

Andrew Huberman:
Okay.

Dr. Matthew Hill:
So, it is complicated.

Andrew Huberman:
A lot of people are writing this down.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Along the lines of what's known and not known, I'm curious what is known and not known about the effects of cannabis, THC in particular, on hormones. I've seen studies that cite increases in testosterone from cannabis use. I've seen studies that cite increases in estrogen from cannabis use, and they argue for increased aromatization of testosterone into estrogen as the mechanism.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
I've also seen studies that say the exact opposite.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So, is there any global takeaway message yet, or is it just highly variable, or it depends too much on dose and individual age, et cetera, that we just really can't say?

Dr. Matthew Hill:
I would say there's nothing that's super clean cut. I know in the previous podcast you talked about a prolactin thing.

Andrew Huberman:
Right. And this is where I think it's important that people understand that on this podcast, we cover science and studies, but we also pull from common experience that people want explained-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... if we can. And one of the experiences that is talked about a lot in certain, let's just say online communities, is the experience of people who had no preexisting gynecomastia, male breast development-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... will smoke marijuana. Do we call it marijuana these days?

Dr. Matthew Hill:
No. We'll go with cannabis.

Andrew Huberman:
I got a lot of comments that said marijuana is an inappropriate term.

Dr. Matthew Hill:
It is. Yeah.

Andrew Huberman:
Okay. We'll go back to that.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
That was new to me. I didn't know.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So forgive me if I-

Dr. Matthew Hill:
No. I understand it, but yeah, a lot of people don't know that.

Andrew Huberman:
Okay. So will smoke cannabis and experience gynecomastia, or in females... So males and females both have breast tissue, but in males it's not hypertrophied. But they'll smoke cannabis and get a gynecomastia, a growth of the male breast tissue, that's sometimes reversible, sometimes not, presumably through the aromatization of testosterone into estrogen, which then acts on the tissue, makes it grow. As well as reports of breast tissue tenderness after cannabis use in females. So, that was sort of the origin of that discussion around does cannabis impact aromatization of testosterone into estrogen? And you can find a little bit of evidence for that, but you can also find evidence to the contrary in the scientific literature.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So I'm just curious your thoughts on this.

Dr. Matthew Hill:
It's super mixed. So you're talking about something like prolactin, for example. That is another one that's obviously involved in this whole cascade stuff. Generally, I would say the bulk of the literature actually says that cannabis would suppress prolactin, not increase it. That's the majority of the literature that's out there.

Andrew Huberman:
Interesting, because dopamine is one of the main ways that prolactin is suppressed.

Dr. Matthew Hill:
Turned off, yeah.

Andrew Huberman:
They're kind of in a seesaw.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
They work in somewhat seesaw fashion.

Dr. Matthew Hill:
And it probably, the rodent work, would suggest it's through dopamine that it's turning off prolactin, because you can reverse some of these effects by playing with dopamine signaling.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
So I don't doubt that's the mechanism. So typically, I would say more often, there's studies with inhalation and IV that have generally found reduced prolactin, and in chronic cannabis users, they find somewhat lower resting states of prolactin. That's been found in one study that came out of Yale.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
Testosterone gets a little bit more complicated because there are a lot of studies that find, A, to begin with, cannabis users may have higher levels of testosterone just at rest. Now, whether that's a preexisting thing-

Andrew Huberman:
Is there any reason to think that would be the case?

Dr. Matthew Hill:
I don't know. Yeah. That being said, a lot of the stuff, now granted, this was mostly done in the '70s, and this is from my previous life because my undergrad and graduate supervisor, he was a neuroendocrinologist, focused much more on sex hormones and reproductive hormones. So we've written a few reviews, so I've done reviews on this area, and I know the literature somewhat. It's mixed, but generally, from the '70s studies, what they would often see is that if they would serially look at testosterone after someone consumed, they would have little dips. That wasn't uncommon for them to find it. Not every study found it. That being said, the kind of range that testosterone stayed in was always the normative range. It was never that it went so low that someone would've classified as being hypogonadal or would lead to something like gynecomastia, at least from a testosterone deficiency side, in terms of the balance between testosterone and estradiol. I don't know as much about the aromatization side of it. Again, I'd say it's pretty mixed. I don't think the gynecomastia stuff is-- Certainly, people online might be talking about it, and there might be some other components to this. I've also heard, and again, this isn't science, this is just the same kind of stuff you see on random internet communities, people talking about, "Oh, well, it has plant estrogen," so maybe they're subbing in and having estrogenic effects. I don't know how valid any of this is.

Andrew Huberman:
Yeah. There are phytoestrogens in tons of different plants.

Dr. Matthew Hill:
Yeah. So I don't-

Andrew Huberman:
The sort of attacks on soy and the attacks on-- This, I think, grew out of the soy versus meat communities-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and plant-based versus carnivore. This podcast has always been agnostic with respect to nutrition, and if we encourage anything, it's that people consume unprocessed and minimally processed foods as the bulk of their food intake. There seems to be enough data on that. But whether or not people choose to be vegan and-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... eat a lot of plants or carnivore and eat just meat, we've essentially stepped out of that debate because, let's just say, it's as futile as about any other debate.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
It's completely circular. You end up right back in Twitter.

Dr. Matthew Hill:
Yeah. And I think that when it comes to something like this, I've not seen any compelling evidence for it. I certainly wouldn't say that it's a typical side effect that men would experience, is developing breast tissue in response to cannabis. I feel like if that was the case, it would be very known in the scientific community as something that comes out.

Andrew Huberman:
So this seems to be something that purportedly occurs on a backdrop of elevated androgens, meaning in puberty, or a backdrop of some other form of androgen increase.

Dr. Matthew Hill:
Like someone who's on steroids or something. Yeah.

Andrew Huberman:
Yeah, but that's not the community I'm referring to.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Because transient gynecomastia during puberty is actually fairly common, because there's just so much androgen being produced-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... in puberty that some gets aromatized and that the idea, I'm not stating this as fact, is that it may exacerbate that. In any case, it sounds like the takeaway from this is that there aren't a lot of conclusive studies about the effects of cannabis on testosterone or estrogen or aromatization in any direction.

Dr. Matthew Hill:
Yeah. I'd say, yeah, enough studies to suggest that you might see transient drops in testosterone from cannabis, and it seems to be relatively short-lived. But again, a lot of these studies also find that the basal testosterone is already high to begin with. So you're staying in a normal dynamic range.

Andrew Huberman:
There it is again. It's homeostatic.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Just like the endocannabinoids.

Dr. Matthew Hill:
Yeah. And that's the thing, testosterone fluctuates across the day-

Andrew Huberman:
Sure

Dr. Matthew Hill:
... anyways, so there's other things that fluctuate. It's like cortisol. These hormones have cycles, so as long as you're in this normal range, there really shouldn't be any kind of behavioral, in terms of sex drive, for testosterone, or physiological, like gynecomastia or some change in-- Now, there are potentially effects of THC directly on the testes that could affect sperm.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
That could happen independent of changes in testosterone.

Andrew Huberman:
Are those positive or negative changes? I'm assuming that the studies you're referring to saw disrupted what they call sperm quality, which has to do with motility, et cetera.

Dr. Matthew Hill:
Yeah. A lot of the in vitro stuff definitely would suggest that. Some of the animal stuff as well. The human stuff is definitely a bit mixed. But again, if anything, it would be like, yeah, could have some effect on sperm. So I have like a-

Andrew Huberman:
As we say this, I'm just chuckling to myself because anytime this conversation comes up about a substance and sperm quality or egg quality, I always get a barrage of comments of people telling me how many children they conceived-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... while under the influence. No one is saying that you're going to be infertile. But if people are having challenges conceiving, it might be something to think about.

Dr. Matthew Hill:
I would say that. I would agree on that. So I would say if someone was asking me this and they were trying to get pregnant and struggling, I would say, well, definitely cut cannabis because some people may be more impacted by it than others. So for some various biological reasons that we don't have a biomarker for, there may be some men that use cannabis, and it has a profound effect on their sperm quality, their sperm capacitance, their ability to maintain fertility. And for the bulk majority of men, I'd say it's probably not the case. But again, if you're someone who is struggling and you use cannabis, male or female, I would say cut that out and see if that has an effect for you.

Andrew Huberman:
Along those lines, I saw a jaw-dropping statistic, and I'm not sure I still believe it, but you tell me what you know about this, which is that up to 15% of pregnant women in the US have used cannabis during pregnancy. That number just seems too high, and yet, it exists out there.

Dr. Matthew Hill:
Yeah. I've heard higher numbers than that.

Andrew Huberman:
In the research literature.

Dr. Matthew Hill:
No, I've heard higher numbers than that as well.

Andrew Huberman:
Okay. So I'm on the low end of this.

Dr. Matthew Hill:
Well, so I've heard as low as two, and I've heard as high as 20.

Andrew Huberman:
Okay. Two sounds like, okay, that I could imagine. But as high as 20. And do we know what the effects on the developing fetus are?

Dr. Matthew Hill:
There's a lot to unpack there. So first thing, going back to the levels. That's challenging because, again, this depends on are you talking about self-report, or are you talking about verified blood levels, because those have varied. So some of the higher numbers actually come from blood levels, where they've taken blood samples and found THC, but the women have reported not using cannabis. And so the idea that it's like the self-report numbers tend to come in around 2% or 3%. My guess is the real number is probably somewhere around 10%, but that also is going to vary depending on what you're talking about. Because there are a proportion of people who are using cannabis and become pregnant and are unaware they're pregnant and are still using cannabis, and that would still qualify under the way that it's defined that someone used cannabis while pregnant. So the majority, I would say the overwhelming majority of people, once they learn they're pregnant, now that can be all the way up to almost the end of the first trimester, typically stop using cannabis. That seems to be ... the norm, I would say.

Andrew Huberman:
Yeah. Important point there.

Dr. Matthew Hill:
Yeah. And I think also the number that carry on through the entire gestational period is going to be a lot less, I would guess. Now, the motivations for this, quite often, are more in the capacity of the kind of anti-nauseant, qualities that cannabis can have for some people, and for women struggling with morning sickness. Now, anecdotally, I have heard women say, with a history of things like thalidomide and other anti-nauseant drugs that had profound teratogenic effects on the fetuses. Women have said that they would rather use cannabis than one of these other compounds because they're less concerned about the impacts of cannabis than they are because of the thalidomide effects that happened and caused-

Andrew Huberman:
Thalidomide effects are malformation of the limbs and other bodily structures in fetuses. It was a absolute tragedy of medicine that this occurred in-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... even one birth. But, yeah, it's the reason why thalidomide is now, I believe, banned as a drug for use during pregnancy.

Dr. Matthew Hill:
Yeah. I actually have no idea, but I would imagine. I think it would be one of those hard things to sell, given its history, especially. So I think there's a reticence of a lot of people to consider using pharmaceuticals to regulate nausea because they're uncertain of the consequences of it, and they feel that cannabis may be safer. Now, that in and of itself could present some problems, in terms of that thought process. Now, there was also a study that I thought was like... Some of these things just frustrate you. It's where they actually decided to call, this was done in Colorado, where they called dispensaries and just acted naive and asked what their recommendations were, and it was something like 80 to 85% of them were actually recommending that people would use cannabis to manage morning sickness. And I thought that was, it's just one of these disappointing things where you're like, "Why are you being so wildly irresponsible to kind of promote these things?" And this is-

Andrew Huberman:
You're talking about the irresponsible that the dispensaries would say that?

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Or irresponsible that the study was carried out that way? Because it's a little bit of-

Dr. Matthew Hill:
Entrapment?

Andrew Huberman:
You said it, not me.

Dr. Matthew Hill:
Could be. You can balk at either side of this. I have a lot of frustration in general with the information that budtenders put out into the world.

Andrew Huberman:
Is that what they're called, budtenders?

Dr. Matthew Hill:
Yeah, budtenders. That's kind of the colloquial term that people will use for someone who sells cannabis at a dispensary. We say this in Canada, and I've heard this throughout the States as well. I personally have been a huge advocate for the fact that I think... So, I worked in restaurants and bars and stuff when I was younger, and for me to serve alcohol, I had to undergo, I don't know if you do this in the States. In Canada, you have to do a weekend course essentially, called Serving It Right or some other terminology, where you learn the basics of alcohol, harms, blah, blah, blah, how to tell if someone's intoxicated, when you have to cut them off, all these things that you have to do to be able to serve alcohol. I have no idea if this exists in the States, but-

Andrew Huberman:
I don't know

Dr. Matthew Hill:
... it was a thing in Canada.

Andrew Huberman:
Bartenders in the US, put in the comments on YouTube. Do you have to undergo training about alcohol to be a bartender?

Dr. Matthew Hill:
Like anything, even if it's just an online quiz. So my perspective is because pre-legalization, at least in Canada, there was somewhat of a misguided thought that people would leverage their physicians for knowledge about cannabis. And what's become very apparent is that the overwhelming majority of people talk to the people selling them the cannabis. And yet, those people selling cannabis don't need to have undergone any form of education. And so, this kind of kills me because we've worked very hard to try and create educational platforms that are agnostic in terms of our position on cannabis, that are just based on the science. I'm an executive director of an organization called the Canadian Consortium for the Investigation of Cannabinoids, the CCIC, and we've done CME courses for physicians to try and train them about cannabis because I think it's important that physicians understand this. But I've tried suggesting that I think that anyone selling cannabis should undergo a course like this, just so that there's some consensus in the informed level that someone who comes in, because a lot of people going to buy cannabis are quite naive about it, and they just... Even when we're talking about dosing and what we've talked about with edibles or smoking or how people consume it, you need to have a reliable source of information at the frontline that is able to relay that to people. And it becomes very frustrating to me that they have become the main source of information that people go, and I'm uncertain of what their level of training is.

Andrew Huberman:
You're certainly doing your part to provide the public education about cannabis now, so we all appreciate your highly informed and broad distribution of this information.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Because this is also an issue with psychedelics-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... which currently don't have legal status in the US. This is an ongoing process of whether or not it will. Right now, things are really on the teeter-totter-

Dr. Matthew Hill:
Little dicey, yeah

Andrew Huberman:
... with MDMA, where we await the decision from the FDA, but the early recommendation to the FDA was to not approve MDMA as a treatment for PTSD. That's as of today and mid to late June 2024. We'll see what happens. But this is also the case for ketamine, which has legal status, but many people are accessing ketamine not through a physician-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... but through online sources. So what you're speaking to here is a much larger issue, and I absolutely agree with you.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I think most people are probably not aware, except by experience, positive or negative in some cases, about the differences in blood concentration as it relates to number of tokes versus concentration versus edible. These are critical themes, especially for where we're going to go next, which is all the discussion about high THC and psychosis.

Dr. Matthew Hill:
Yeah. Exactly. So I think that I just wish, again, even if this was just an online course that wasn't that much, but at least had some consensus of information that was the basics about how to have conversations. And our system, at least, is somewhat provincially regulated. So our organization has worked with the Ontario group that deals with cannabis distribution, like the OCS, which is Ontario Cannabis Stores, and helped to create some information pamphlets and stuff. Again, it's not the same as a teaching course But at least it's like these little infographic stuff that kind of gives people rough breakdowns of things.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And kind of gives you a little bit of information about dosing and understanding things, especially with something like edibles, how long you should wait, just stuff like this. And then-

Andrew Huberman:
It sounds like the take-home message is, proceed with caution, low and slow, right?

Dr. Matthew Hill:
That's the, yeah. I mean, we have-

Andrew Huberman:
Don't ingest too much too quickly. Really, if one is going to explore this, legally of course, take a little bit, wait, take a little bit, wait. Because otherwise you're going to get the... What, who was the reporter?

Dr. Matthew Hill:
Oh, I think it was Maureen Dowd, but I-

Andrew Huberman:
Right. You're going to hit-

Dr. Matthew Hill:
I don't know, actually, when I say that. Maybe it was-

Andrew Huberman:
Is she still on the floor in a Colorado hotel?

Dr. Matthew Hill:
She may have recovered by now.

Andrew Huberman:
Reporting from the floor in Colorado.

Dr. Matthew Hill:
But it can become very frustrating. It's just the kind of lack of understanding that exists-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... in this space. And so I think this is one of the reasons why we've really kind of tried to push the public health side of this a lot more.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And we have, there was the Center for Addiction and Mental Health in Canada, which does a lot of the organization of these things. They did kind of put together what I found to be really useful, which again, could be leveraged in the States. These are all accessible online. It's called the Lower Risk Cannabis Use Guidelines. They kind of tried to create a framework that is similar to how people have done stuff with alcohol.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
That just kind of goes through, and a lot of it is this low and slow approach, but it's like, obviously you want no risk, you abstain. If you're going to use, these are the different ways to engage in harm reduction.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Obviously, oral consumption has, you avoid the issue of lung damage that you could get from smoking. But then, with oral consumption, you have to be aware of dosing and timing and all these other considerations, but-

Andrew Huberman:
What about vaping? Can people self-regulate their THC concentration in the blood by vaping as well as they can by joint or bong or other form of smoking?

Dr. Matthew Hill:
I think that would depend on exactly what you're vaping. So, in the States, I've noticed when people say vaping, they almost exclusively refer to some kind of oil-based product that's in a pen.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So, in those situations, that's going to really heavily depend on what the concentration of THC in that product is. Now, the other form of vaping that I think is a little bit more common in Canada maybe, is vaping of the plant matter itself. And so this is where they have a vaporizer device that heats the cannabis to a point that will essentially hit the lift point-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... to vaporize THC and the cannabinoids.

Andrew Huberman:
Yeah, the big bag.

Dr. Matthew Hill:
Yeah, yeah.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
Like a volcano.

Andrew Huberman:
I've seen it.

Dr. Matthew Hill:
Yeah. But it doesn't create any plant combustion. And so there are studies that have been run on that, that have shown that you avoid the combustion byproducts. So people don't exhale carbon monoxide or these other things that we know can be damaging, if they're vaping plant matter. That was actually somewhat approved as a medical device. Pre-legalization when cannabis in Canada was only under medical authorization. Because of the reduced harm associated with vaporizing the plant matter versus smoking it, that is, I would say, a safe guideline for harm reduction, that if you're going to try and avoid... There's still going to be some issues that happen with vaporization of plant matter, but it's not the same as combustion.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So you avoid some of the other issues that come out. When we're talking about oil-based vapor products or whatever they're in, they're usually in some kind of oil-based solution. Who knows? We don't have the research on this. We just don't know. We certainly know there have been some pretty big errors of the things that happened in the States. There was that problem where all those people developed, I don't know, popcorn lung or that lung inflammation where several people died from vaping products, which seemed to be a byproduct, I believe, of them adding vitamin E acetate or something into the... Because again, everyone just assumes it's inert.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
But then when it combusts through the vaporization process, it creates a massive irritant on lung tissue. And so that was just, again, in my mind, this is a problem with a lack of a federal regulatory framework because stuff like this happens. You would not see that on a federal landscape because you would have to go through testing. It's kind of the Wild West you get down here. Every state has its own rules. There's not really a lot of-

Andrew Huberman:
Well

Dr. Matthew Hill:
... regulation of things.

Andrew Huberman:
Well, and if you go overseas, it's even more wild. I mean-

Dr. Matthew Hill:
Then you have no idea what you're consuming anywhere, I would say. Just because outside, again, Netherlands is a little bit of a different situation. They're not legal, they're decriminalized. I don't know how well the regulation over there of the product is.

Andrew Huberman:
No, we're going to be doing episodes on stem cells, and you've got people flying out of country to do stem cell injections. People were getting them down in Florida who went blind from the injections of stem cells into the eye-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... in an attempt to save what little vision they already had. Probably don't want to get me started on that one.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I'm in total agreement with you, by the way. I want to make sure that I ask about psychosis and paranoia.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I've previously said, and I wasn't joking, but I have observed in my history that when people started to experience some degree of anxiety or paranoia when smoking cannabis, that sometimes the message they would receive back is to take more to just adjust the subjective experience.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I think that's a terrible idea. Terrible idea.

Dr. Matthew Hill:
I'm baffled that you heard that. I have no idea who on earth-

Andrew Huberman:
Let's just say I did more than hear it.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
See, I've observed it many times over.

Dr. Matthew Hill:
I cannot even understand that. That is the strangest thing I've ever heard, but okay, yeah.

Andrew Huberman:
Well, usually the advice of people in terms of, that was recreational drug taking, is rarely excellent advice.

Dr. Matthew Hill:
Yeah. No, no. That's-

Andrew Huberman:
So, I didn't-

Dr. Matthew Hill:
Yeah. I mean, I agree with you on that point, for sure, that you should not be consuming more if you're having a bad reaction to it, because that will just grease the wheels going downhill, for sure.

Andrew Huberman:
Yeah. I also am aware that there are some very high-profile papers that have been published in the last really five years or so, pointing to potential increased risk for psychosis of lasting duration-

Dr. Matthew Hill:
Mm-hmm

Andrew Huberman:
... even after the effects of cannabis have worn off, in high-THC cannabis users. In particular high THC cannabis users that initiate that cannabis use young, and this might be preferentially impacting males. I want to make clear that what I just said is not a statement of absolute fact. It's my understanding of the conclusions of these papers. There are other conclusions in these papers also, but that particular conclusion seems to be important enough that they place it in the abstract, and it's reached major press headlines. So I guess the simple question, which probably doesn't have a simple answer, is does THC cause psychosis?

Dr. Matthew Hill:
So yeah, there's not a simple answer to that, and I think that also is a question over whether you're talking about acute drug-induced psychotic episode versus the development of a chronic psychotic disease like schizophrenia. So the first arm of that is just can people acutely have a psychotic episode to THC or cannabis? And the answer to that is yes. It's not common. I would say in terms of adverse events that happen with people consuming cannabis, it's on the rarer side, but it definitely can happen.

Andrew Huberman:
So less than 5% of people that-

Dr. Matthew Hill:
Oh, much less than that.

Andrew Huberman:
Okay.

Dr. Matthew Hill:
And certainly, if something like this was happening at a regular frequency, it would be very well-known.

Andrew Huberman:
What about anxiety attack?

Dr. Matthew Hill:
Yeah. Anxiety attack is, I'd say, more of a standard indication that someone's kind of gone overboard.

Andrew Huberman:
Dosage overboard, or does it carry the same set and setting considerations that psychedelics like psilocybin have?

Dr. Matthew Hill:
Both.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So I think there's some contextual component to it. Back in the '70s when they did more, let's say, interesting studies, there's one where basically they dosed people on THC and then had them undergo oral surgery, which seems like, in hindsight, a very bad idea, and I think virtually everyone in that study had a panic attack. So it really potentiated the stress of what they were undergoing, and had they been given that same dose in a different setting, I'm not sure it would've evoked that kind of response. But there is definitely a dose effect to this in terms of the kind of classic low-dose aspects of THC or cannabis that are usually considered more the positive, pleasurable responses that are why people use. It reduces anxiety, it relaxes, blah, blah, blah. That is more of a low to normal-ish dose, let's say, of what someone consumes to produce those responses. If they start going upwards, though, it's not like it's graded. It's like a full flip. It's not linear at all. It's almost like it goes in the opposite direction. So someone can use cannabis to reduce anxiety, but then cannabis can also trigger anxiety in other people, and even in the same person if they consume too much. And a lot of this, at least we think, has to do with the ability of it to regulate both excitatory neurotransmission and inhibitory. And so for reasons that we don't totally understand, there's way more cannabinoid receptors on inhibitory neurons than there is on excitatory neurons. But in the early days of creating the genetic lines, Giovanni Marsicano and Beat Lutz were over in Europe, created deletion of CB1 only from excitatory neurons or only from inhibitory neurons.

Andrew Huberman:
Okay. So to just clarify for people, these are laboratory mice that are genetically modified so that they contain or lack specific receptors on particular neuron types so that researchers can parse the effects of THC on what we're referring to as inhibitory neurons, which quiet other neurons, versus excitatory neurons, which excite other neurons and so forth. And in doing so, to understand some of the network biology.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Which is basically impossible to do in a typical mouse-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... what's called a wild-type mouse, or a human, because when one ingests the drug or when the mouse is given the drug, it affects potentially any site in the brain where the CB1 receptor is expressed.

Dr. Matthew Hill:
Yeah. So if you do a full body deletion of CB1 and you give a mouse THC, doesn't respond to it at all. Not surprisingly.

Andrew Huberman:
That's a comforting experiment.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
You want to see that result.

Dr. Matthew Hill:
Yeah. Exactly. So that's how we know CB1 drives all the kind of psychoactive effects of THC. So if you delete CB1 off of inhibitory GABA neurons, even though that removes like 70% of the CB1 receptors in the brain, those animals look just like wild type. They still exhibit all the classic signs of intoxication in terms of how they would respond to pain sensitivity or locomotion or these other assays we use in mice to tell if they're high. If you delete the CB1 only off of excitatory neurons, the glutamate neurons, then you see what looks like the full knockout. So now the animals don't seem to get high. So even though the majority of CB1 receptors seem to be on these inhibitory GABA neurons, it's the CB1 on the glutamatergic excitatory neurons that mediate most of the classic signs of what we would consider intoxication from THC or cannabis. But what's interesting is Beat worked with a Spanish group 10, 12 years ago. Then they showed they're looking at anxiety, that if you delete CB1 only off of excitatory neurons, you lose the anti-anxiety, anxiolytic effects of THC, but you still have the panicky, anxiogenic effects of high dose. If you delete CB1 off of only the inhibitory GABA neurons, you still have the low-dose anti-anxiety effect, but now you don't have the high-dose anxiogenic panicky effect.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
So what that was suggesting was that for some reason, THC will initially hit CB1 on kind of glutamatergic neurons, and essentially the thought is this will reduce excitatory transmission and probably quiet down circuits, and if we're talking about something like the amygdala, this is probably how it's reducing anxiety. Whereas as dosing starts to increase and you start to saturate the CB1 on the GABA neurons and turn off inhibition, then the network effect is more of an amplification, and that seems to result in the development of kind of an anxiogenic-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... pro-anxiety response that's obviously undesirable. Why there's this differential shift, it's not exactly clear. It's probably either due to some of the biology of exactly where the CB1 receptors sit on excitatory or inhibitory neurons relative to all the machinery that regulates transmitter release. Beat Lutz has definitely done some stuff looking at the ability of cannabinoid receptors to evoke signaling responses in a cell, and on glutamate neurons, they're much more sensitive than they are in GABA neurons, so there's probably a dose threshold. So it does look like this kind of low dosing, what most people are trying to achieve, I would assume, when they consume cannabis, is probably these effects mediated by quieting down excitatory transmission. And then the adverse effects when someone consumes too much and they have a negative response, that's probably due to the higher dose starting to saturate on the inhibitory neurons. Now, we obviously can never test something like that in humans, because we can't know. But based on what we've seen in animals, that's my theory of how this is working and why we see these classic biphasic effects. So, yeah, too much THC, not a good thing, because then you start maybe disinhibiting things like the amygdala and producing these kind of panicky, anxiogenic-like outcomes. On that scale, though, paranoia, obviously, that's a hard-- I don't know how you study that in a rodent. That's just a strange thing. But, that's the precedent of when you start going into the psychosis, because obviously paranoia would be a big component of that. Someone once asked me a question about what happens in the brain, imaging-wise, when someone's having a psychotic episode from cannabis, and I was thinking, like, how would that study get done?

Andrew Huberman:
Probably on accident because somebody takes cannabis, is in the scanner, and then starts-

Dr. Matthew Hill:
Having-

Andrew Huberman:
... having a psychotic episode. But chances are they're going to try and get it out.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
For those that don't know, I don't want to scare people out of doing MRI or fMRI, but you're typically told to stay extremely still. There's sometimes even a bite bar.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
This is a very controlled environment, not an environment that you would want to be in during a psychotic episode.

Dr. Matthew Hill:
No. I can't actually even imagine how that would go down, so this is something I don't think we're ever going to have an answer to because I don't think you can actually ever test it. But in terms of people having this kind of psychotic response, it is pretty rare. And I say this because I can think of, in Canada, whenever it's happened and someone has actually done something wildly unpredictable because they've had a psychotic response to cannabis, it tends to make headlines, so it's not common. I could not give you an actual number, but it's certainly not a frequent thing because we would hear about this a lot more if we did.

Andrew Huberman:
And there's also the issue of polypharmacology, which is simply when people take one drug, then there's often the tendency to take another drug, either because it's available in those conditions or because their threshold to saying yes is a little bit lower. Do most people who take cannabis and achieve the high have a tendency to do other drugs? It doesn't seem like a drug that people combine with a lot of other drugs.

Dr. Matthew Hill:
Cannabis is used in tandem with other drugs, alcohol, psychedelics, at times, for sure. But that being said, there is clearly a population of people that use cannabis as their only drug that they use. I don't think that's that uncommon. But in the context of the psychosis stuff, I would definitely say, sure, if someone mixed it with amphetamine or something, you could have a very unpredictable response there.

Andrew Huberman:
Yikes.

Dr. Matthew Hill:
But I think the psychotic responses that have been documented there are usually purely due to cannabis. It's not necessarily due to some kind of drug interaction there. There is something about the way that cannabis is changing the way the brain functions in a way that for people who seem to be prone to this, they can have a psychotic response. Again, I don't think that's a very typical thing. But when we're talking about what that means in the context of an actual disorder, like a chronic disorder like schizophrenia, which is characterized by psychosis, I think we're talking about a whole different ballgame here. And this is an area that is an important thing to discuss in the context of science because you can't establish causality. In my view, it's virtually impossible because there's just no way to control all the variables that play into this. What we can say definitively is individuals who have schizophrenia, first of all, they use cannabis at a higher rate than the general population.

Andrew Huberman:
Oh, right.

Dr. Matthew Hill:
That's very clear, yeah. They definitely use cannabis at a higher rate than the general population. There is definitely a relationship between using cannabis and having the initiation of the development of schizophrenia. And this is where a lot of the statistics that have been used to develop the risk assessment, essentially, so that you have a greater risk if, like you were saying, if you've used cannabis as a teenager, you use high potency, as a lot of the research has shown, though they've done these studies and they say it relates to a greater risk of schizophrenia. Essentially, this is just a statistical association that they've found, that people who use cannabis, the conversion into schizophrenia happens at a higher rate, and there's more people with schizophrenia who are using cannabis.

Andrew Huberman:
Is there a bias towards males developing psychosis? I know there may be a bias initially toward males in schizophrenia that could confound this, so we want to be careful.

Dr. Matthew Hill:
To be honest, in all the research I've, in all the literature I've read on this, I don't ever remember there being clear sex descriptions of the differences of males and females. Again, historically, cannabis was more used by males than females, so that could-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... lean towards any bias that may be out there in the media or just in general, what people talk about. I can't think of any study that I've ever read that explicitly said this was male-biased per se. They usually just report numbers or proportions of people. The issue is So yes, there's this relationship that exists, and yes, we know that cannabis can trigger psychotic episodes. So if there's an individual who has schizophrenia, we know for certain that cannabis can lead to the onset of increases in positive symptoms like hallucinations and delusions, and a full-blown psychotic episode. So I think the first thing to say, which is very clear, is, in my view, if someone has schizophrenia, cannabis is contraindicated. You shouldn't be using cannabis if you have schizophrenia. I think that's a risk across the board.

Andrew Huberman:
What about a first relative who has schizophrenia?

Dr. Matthew Hill:
So-

Andrew Huberman:
Because there's a strong genetic-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... component to schizophrenia.

Dr. Matthew Hill:
So I was going to say, then the next question is, knowing who's going to develop schizophrenia, obviously we don't know this. And as you say, the only real predictive variable that we know of is a first-degree family member that has schizophrenia, means that you have a higher risk of developing schizophrenia. So again, same with bipolar. I would say if there's bipolar or schizophrenia in a family, to me those are the people who should avoid cannabis. Just in terms of the likelihood, there's a much greater likelihood that they'd have-- It would relate to the onset of a disease or could accelerate its presentation in some capacity.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
I think where things get really complicated in this whole cannabis schizophrenia story is the causality. And there is a camp of people who have looked at this literature and definitively believe that cannabis causes schizophrenia. And they attribute a proportion of people who have schizophrenia to only having that schizophrenia because of the fact that they used cannabis. And I think you'd had some discussion about this in the last podcast. I can't remember exactly the way that you described it.

Andrew Huberman:
Yeah, I was looking toward some of the recent studies in Lancet, JAMA Psychiatry.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I believe we can provide links to these again. And now more recently, there's been a lot of, let's just call it mainstream media coverage of this potential-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... I think is the right way to refer to it, potential linkage between adolescent, teen, and young adult use of high-THC cannabis and lasting psychosis. But the more I hear you talk about this, the more I'm wondering if that idea is being amplified more than perhaps we ought to let it be amplified.

Dr. Matthew Hill:
Yeah. I think this is what happens when you have-- Obviously, you're familiar with this. In science, there's different... There's some things that we can be a little bit more definitive about, and then there's some things that we just can't know for certain. It's just the way it is. Because of the way that we gather data and because of the way humans are, and this isn't a question I believe we can ask from an animal model perspective in the same capacity. So I don't think anyone would deny, at least anyone who's read the literature, that there's this relationship between cannabis use, especially in adolescents, and the development of schizophrenia. Now, my perspective on this is, and I'll explain why I have this perspective and how I justify it, is to me, cannabis is fuel on a fire. So if someone is prone to developing schizophrenia, adding cannabis into the mix, I think, will make it kick in faster and harder. So if there is a genetic vulnerability for developing schizophrenia or some biological predisposition that's there, I would say in that situation, cannabis can trigger an initial onset of the first episode, and it can make the prognosis of the disease in the long term a lot worse, let's say.

Andrew Huberman:
As I recall, and I may have this incorrectly, but as I recall from my undergraduate years, what you just said is also true for military service, for people that have a predisposition to develop schizophrenia, that active military duty can exacerbate it as well.

Dr. Matthew Hill:
Oh. I've never heard that, but that would be a stressor, and stressors are other ways. There's situations where some of it's the age, but for example, if someone is prone to develop schizophrenia, they move away to college. Even that stressor can be something that brings on an episode. But cannabis very specifically, different than any other drugs, like alcohol or cigarettes, as far as I understand it at least, the temporal relationship between cannabis use and the development of a first episode can be pretty linked.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
But the arguments that I've always had with people in this area who are very definitive on their end of the spectrum that this is a causal relationship is, first of all, we have a few things that I would leverage as real-world evidence that makes this questionable. So the first one is, like I was saying earlier in the episode, we really didn't have cannabis use in the West as a normal thing, as one of the drugs that was part of the repertoire of what people use recreationally, until the '60s. So unlike alcohol, which has been there for centuries, we have a little bit of a before and after, what we can look at. Now-

Andrew Huberman:
The Grateful Dead.

Dr. Matthew Hill:
Yeah. So now granted, we don't have really good prevalence data of what schizophrenia was in the era prior. Even nowadays, our prevalence data's not perfect. But if cannabis as a solitary variable was driving the genesis of schizophrenia de novo, in the absence of any kind of biological predisposition or genetic predisposition, I find it very hard to believe that we wouldn't have seen a shift in the prevalence of the disease as cannabis became more mainstream and more widely used. And generally, schizophrenia rates have remained largely stable. People can make arguments about that, better care, other things to challenge that argument, sure. So another modern perspective would be, okay, well, let's look at Canada and the States, let's say, where we have, as I said earlier, teenagers in Canada and the States, by grade 12, 35% to 40% of teenagers have at least used cannabis somewhat sporadically, and somewhere around 5%-ish are probably using almost daily. So we have a concentrated group of what would be the high-risk population here that are using at a pretty high rate. And then we compare that to somewhere like, let's say, Norway or Sweden or any of the Scandinavian countries where cannabis is not a thing.

Andrew Huberman:
Hmm.

Dr. Matthew Hill:
Certainly not at a recreational level and not in teenagers. And the use rates there are probably under 5%, globally, for teenagers. Probably closer to 2% or 3%.

Andrew Huberman:
Wow.

Dr. Matthew Hill:
So you have two countries that have pretty similar Social structures and other capacities of things. We're both Western countries, and yet our schizophrenia rates, prevalence-wise, are relatively comparable, and yet in Canada and the States, our cannabis use rates in adolescents are wildly amplified compared to those countries. So again, if this was causing schizophrenia to develop as a disease out of nowhere, how would that not track? How would that not be seen when you just look at individual variances across countries and prevalence rates?

Andrew Huberman:
Yeah, I hear your point loud and clear. I seem to recall that there is a higher incidence of schizophrenia independent of cannabis use closer to the poles and less so at the equator. I don't know if those statistics still hold up, but-

Dr. Matthew Hill:
I have no idea.

Andrew Huberman:
Okay.

Dr. Matthew Hill:
Yeah. I don't know the data.

Andrew Huberman:
It'd be interesting for us to look into that because then it would argue that since we're comparing very northern locations to less northern locations, that perhaps cannabis was sort of exacerbating the-

Dr. Matthew Hill:
Yeah. You could probably use Greece or Italy. They're going to have cannabis use higher than Scandinavian countries, but it's going to be way lower than North America still. Because it's just-

Andrew Huberman:
What is it about North Americans and cannabis use?

Dr. Matthew Hill:
I have no idea. I think it's just part of the culture here. It's just evolved totally differently.

Andrew Huberman:
The Grateful Dead. No, I'm just kidding. I'm not picking on the Grateful Dead.

Dr. Matthew Hill:
No, no.

Andrew Huberman:
I like the Grateful Dead. Rick Rubin convinced me to start listening to them again because my sister used to listen to them and there's some great songs, and they're from Menlo Park, Palo Alto, so I've done my duty to listen. There's some great songs, so I'm not picking on them, but-

Dr. Matthew Hill:
But you also have in Europe, though, alcohol is also much more normalized in general. Kids will drink. It's not abnormal for kids who are teenagers to drink out. Alcohol is just much more of a cultural thing as well, and there are just differences. It's the same thing. You look at the opioid crisis that we're going through. Sure, it's there to some degree in Europe, but it's nothing like it is in North America. We are just a different beast for a lot of drug use.

Andrew Huberman:
Do you see differences between United States and Canada with respect to either cannabis or opioid use?

Dr. Matthew Hill:
I don't think dramatically. I think we're pretty comparable. For cannabis rates, I would say they're almost the same. Sure, you might get some regional differences. I think Quebec has much lower rates of cannabis use than some other parts of Canada, and you guys probably in some southern states maybe are a bit different than other states. So, I don't know about that. But again, overall, at a federal level, which is where most of the data aggregates, I would say that they're pretty comparable with each other. So they're not wildly different at all. And again, even if you talk about climate, a lot of the US is a lot warmer than Canada, and you guys are certainly closer to the equator than we are. So, we know you do see higher rates of schizophrenia in urban settings than you do in rural settings, and so-

Andrew Huberman:
It's the stressor argument.

Dr. Matthew Hill:
Yeah. There's a lot of transitory populations that come in and out of cities that you don't see as much in rural communities. There's a lot more mental health services. There's other variables that can influence that. No one's really, I think, sussed out a mechanism to explain why you see that. But, so there are things that shift across places, but I don't think it has anything to do with the rates of cannabis use.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And the other thing that became very interesting in this whole debate over the last 15 odd years, that people have really been talking about this a lot more, is the fact that there's also been several studies now that have done genetics, either at the GWAS level or just even just looking at polygenic risk scores. And there's at least three papers that I can think of off the top of my head that I could put the citations down for sure after this, that do look at this from a somewhat, let's say, unbiased perspective, where they see there's certainly some genetic architecture that relates to people either initiating cannabis use or people developing cannabis use disorder, and there's clearly some genetic architecture that relates to risk for schizophrenia. And what these studies have found across the three of them was quite similar, which was from their analysis, the directionality suggested much more that having genetic risk for schizophrenia predicted cannabis use, more so than cannabis use predicted the development of schizophrenia.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
So what that would mean is that there is some underlying biology that might be shared between a biological vulnerability to develop schizophrenia and some factor that relates to people using and/or liking and/or excessively using cannabis.

Andrew Huberman:
I've spoken to many psychiatrists in an effort to find someone expert in ADHD. We've done two episodes on ADHD, focusing on everything from behavioral to nutritional, but also prescription drug treatments for ADHD. And what's interesting is that all of them have relayed the fact that many people, not just young people, but adults with ADHD, will often use, not necessarily abuse, but will use stimulants-

Dr. Matthew Hill:
Mm-hmm

Andrew Huberman:
... like coffee and other forms of stimulants to a high degree. And then, of course, you can say, well, perhaps the stimulants are causing-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... ADHD. But they actually argue for the opposite, which is that people are attempting to self-medicate.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And then it's perhaps no surprise that most, not all, but most of the medications that are approved for the treatment of ADHD are variants of an amphetamine or similar.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So it's another case where depending on whether or not you look through the lens of the drug leading to the condition or the-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... or through the lens of the condition leading to the use of the drug, you can end up in two very different places.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
But it looks exactly the same through each lens, so to speak.

Dr. Matthew Hill:
Yeah. And I've debated with other researchers in the area in print and in person about the different interpretations of this, and one of the possibilities is, again, this idea of self-medication. Independent of there being some underlying biological thing that just is a third variable that explains the relationship between cannabis and schizophrenia, the other possibility is self-medication, and there are some studies that suggest this and others that don't support it. Anecdotally, from having done work in the community and talked to individuals who have schizophrenia who use cannabis, what their perspective on it is, what I've heard from a few of them is the medications that they're provided to manage the disease are relatively effective at managing, let's say, the positive symptoms, like hallucinations, delusions. That aspect of the disease is somewhat well-managed. But then there's another component, which is the negative symptoms, which is things like avolitions. They don't like engaging in stuff.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
There's some anxiety, some depression, some social withdrawal, and a lot of the medications don't manage that component of the disease, and they have said that they find cannabis helps that side of it, or it helps them de-arouse a little bit. Even though a lot of them recognize it may trigger the development of some of the positive symptoms, they feel that they don't have any tool in their kit to manage the negative symptoms. And so It could be, in my mind, when I look at that, it could be a bit of a vicious cycle where someone's using it to band-aid one aspect, but making other aspects of the disease worse at the same time. So-

Andrew Huberman:
Mm

Dr. Matthew Hill:
... it can get very complicated. There are various ways of looking at this. So it's either you could say there's a causal argument, which is made by many, saying cannabis causes schizophrenia, and therefore if we eradicated it, and I think you had alluded to something like that in the last podcast. That if you removed it, it would have this big effect in terms of reducing schizophrenia rates. And that's similar to the argument that a lot of the researchers in Britain have made, and I'm not personally convinced of that. And I say that simply because I look at the data from Scandinavia, and I'm like, well, there you have a population that barely uses any cannabis, and yet their schizophrenia rates are the same. So the only way, in my mind, if I look at this scientifically from a data perspective, that cannabis could be causing schizophrenia de novo in a subset of people, is that there must be an equal proportion of people for whom, for some reason and somehow, cannabis is preventing them from developing schizophrenia, so that it's a zero-sum game at the end of the day, and there's no change in rates. I can't actually understand any other model that could explain this.

Andrew Huberman:
Yeah. No, the way you're explaining it now makes perfect sense. I do want to make sure that we distinguish between schizophrenia, like psychosis or schizophrenia itself induced by cannabis-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and manic bipolar episodes. So people who have a predisposition or full-blown manic bipolar, sometimes called manic depression.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
There's still a lot of nuance there. We did an episode about this that people can also find linked in the show note captions. But in any case, is there any evidence for the fact that people who suffer from or have a predisposition to manic bipolar conditions like bipolar depression, for instance, should avoid high-THC cannabis?

Dr. Matthew Hill:
So first of all, in heritability family trees, for example, where you look at something like bipolar schizophrenia, the two do track together.

Andrew Huberman:
Sure.

Dr. Matthew Hill:
I think it's hard to separate these in some capacity because I remember years ago at Society for Neuroscience, Glenn Close was one of the-- I don't know if you were at that meeting, but Glenn Close was one of the-

Andrew Huberman:
The actress Glenn Close?

Dr. Matthew Hill:
Yeah. She was one of the public speakers, and she had talked about schizophrenia in her family tree, and she put up this family tree of her family and the previous relatives in her family and showed the individuals who had schizophrenia and bipolar as well. And this is something I think that's been seen a fair amount is there is some co-relationship in the way that these track at a heritability level. And so I don't know that area really well enough to be able to comment on it. And from the cannabis perspective, bipolar is definitely much less studied and focused on than schizophrenia is. But I think also to the comment about the high-THC thing, I think this is the other part of the argument that's emerged out of this, and this is the other part where I see a lot of the causality arguments crumble onto themself to some degree. And there's been others who've made these very similar arguments to what I'm making here, which is the push that came out of this, out of the UK at least, was much more that it's this high-potency skunk cannabis they referred to. Which first of all, was based on a smell, which they really hadn't done a lot of analytics on. So people make the assumption if it smells stronger, it's more potent cannabis. That's not really true because THC doesn't dictate the odor. That's, as I was saying, more of a terpene thing. But certainly, I'm sure some of the skunk cannabis they were referring to is high-potency cannabis. And so the analysis on this, if you actually go back to those papers and read, is they often use hash or low-potency cannabis as their control, where they show no association with cannabis. And so that's what's used as this argument that it's the high-potency cannabis that has driven this. So now the problem with this argument, in my view, again, I look for what is the answer that fits in with the data. What's the most parsimonious explanation here that everything can be explained by? And so the problem with that argument is if you look at the cannabis schizophrenia literature, everything goes back to this one 1987 Lancet paper out of Sweden, where in that paper, they essentially looked at, they have really detailed life records and health records, and this was Swedish conscripts. And they essentially found that if someone had used cannabis, the risk of developing schizophrenia had gone up and up. And so this was based on a cohort of people, when it was published in '87, that the data would've been collected through the '60s, '70s, early '80s. So we're talking about Sweden and cannabis, where it's not a country that has high cannabis use rates, and in an era when cannabis was hovering in a 2% to 5% THC range. That was the initial finding that provided this association between it. And yet the cannabis in that study that they would've been referring to would've been incredibly low potency compared to what has happened, or what it is today. So if the argument is that it's only related to high potency, how would that initial finding have ever been found? Because it doesn't make any sense. Whereas the alternate explanation that others have put forward, which I agree with and is far more sound, is that there is some biological reason why individuals who are either prone to develop or who have schizophrenia like cannabis, and they will tend to seek out the highest potency product they can get access to. So in the '70s in Sweden, that would've been 2% to 5% THC cannabis. Nowadays, it's higher potency cannabis.

Andrew Huberman:
Mm. Or maybe they seek out lots of different forms of recreational drugs, and cannabis just happens to be one that they land on. Which raises the other question, which is it's hard to imagine that these people who develop psychosis, who happen to be using cannabis, are only using cannabis.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
It could be, but presumably-

Dr. Matthew Hill:
There's no question there's a lot of nicotine consumption. Individuals with schizophrenia, they smoke a lot of cigarettes. That's also-

Andrew Huberman:
That's well established

Dr. Matthew Hill:
... much higher than the general population rates as well.

Andrew Huberman:
Which is known to stimulate dopaminergic-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and other pathways.

Dr. Matthew Hill:
And there could be other reasons. Again, there may be some reason why they like it. And I think this is Something that I think we just don't understand. It's a very challenging thing to figure out why it is that individuals that have certain diseases may like certain substances. Is it helping them? Some people have argued that perhaps nicotine, for example, might enhance cognition in individuals with schizophrenia, and that may be why they like it.

Andrew Huberman:
I think it enhances cognition in everybody. It just carries certain health concerns.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And by the way, it doesn't enhance all forms of cognition, but there is a nice body of work to support the idea that nicotine delivered in any number of different forms can improve cognitive function to some extent. But I don't suggest people run out and do it. And in fact, it's one of the more quickly abused drugs nowadays because of the non-smoking delivery routes that are becoming really popular, pouches and-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and things. In fact, I was chewing a little bit of Nicorette gum to do an experiment. I liked it a lot, and then I decided to stop completely recently because it wasn't having the same effect, and I found myself reaching for more, and that's the time when I usually back out.

Dr. Matthew Hill:
Well, yeah.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
Nicotine's a whole other thing.

Andrew Huberman:
Sure.

Dr. Matthew Hill:
Which I, yeah.

Andrew Huberman:
We'll have you back to talk about nicotine.

Dr. Matthew Hill:
No, I definitely do not know enough about that to have any kind of informed conversation. So I don't know. I would say, to me, at the end of the day, if I put all the data together, the perspective that I have on this is, for some reason, be it genetic architecture or biological predisposition, individuals who are prone to develop schizophrenia also seem to be prone to use cannabis, and use it possibly at excessive levels or possibly at higher potency products they seek out. Using cannabis, if someone is prone to develop it, may initiate or trigger the onset of the disease. And I think in the long term, it will likely make the prognosis of the disease worse. So if you were a psychiatrist in a clinic and you consistently see patients presenting saying, "I didn't have psychosis, I used cannabis, now I have psychosis," and it converts into schizophrenia, I can understand why the association would be made regularly that there's kind of a domino effect here and causality becomes attributed. But I think when we take a step back and look at the larger data in its entirety, to me, it's a very tricky argument to make because there's a lot of things that you just can't explain from that perspective.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And this is also one of the things that I find absolutely bizarre about cannabis in general is it's a wildly polarizing topic of conversation. And people have incredibly deep-rooted opinions on both sides of the spectrum. And for some reason, if I don't say cannabis is the devil and causes disease, that means I'm an advocate. And then on the other side of the coin, if I don't say cannabis cures everything, I'm a prohibitionist. So I'm in this fun position where I get hate mail from both sides, and everyone just generally, depending on their perspective, thinks that I have a bias going in one way or the other, and I'm very want it this way, or want it this way, when at the end of the day, I'm just like, "No, I just like data." So I'm like, "I'm going to try and answer things as best as I can with data." And to me, that's the perspective I've maintained. And I do think that these aren't trivial questions, because when we went through the legalization process in Canada, this was something that came up again and again and again. Was this association with schizophrenia. And in the UK, this is something that comes up again and again and again, because whenever there's any discussion about the UK moving forward to legalization, these ideas come back. And so the public health consequence of this is not intangible. And so for people to be making these very strong causality arguments and having this kind of opinion that a lot of people just take up, I think can have a lot of influence. And so that's why there's literally no reason I should have a dog in this fight. I don't study schizophrenia in any capacity. And it's not my area of research, but because I am in the cannabis field, I always feel very strongly that we need to maintain clarity over what the data says and not get caught in these opinion-based arguments. And I feel like this is one of these areas that has just kind of-- The amount of people I talk to that regularly tell me that they know that cannabis causes schizophrenia, and they're terrified if someone uses it because it's going to cause them to become schizophrenic, I am just kind of shocked by. So this has clearly permeated the general population, that there's a widespread belief of this.

Andrew Huberman:
I think it's because of these very high-profile papers and the way those were picked up by traditional media.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And this seems to be something that every couple of years, there's a resurgence of this idea.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Clearly, people are curious about it. And so I just want to say thank you for clarifying what is now, to me, obvious that it could be that there's a relationship there. It's clearly not the case yet.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And it may never be the case that there's a causal relationship there, and it could just as well be that people who have a predisposition to schizophrenia are seeking out cannabis use and engaging in cannabis use.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And I think that's a very important principle for our listeners and viewers to just hear and understand anytime we're talking about a substance and a condition.

Dr. Matthew Hill:
Yeah. And I think, again, this is no endorsement. That doesn't mean that it's safe and that it's without harm. I'm just strong of the opinion that I don't think individuals with schizophrenia or who have first-degree relatives should use cannabis because I think there's a high degree of risk there. But that's a very different argument than making saying cannabis causes schizophrenia, and if we remove it from society, we'll see drops in rates of schizophrenia. I don't believe there's any evidence that actually could support that. So it's just a nuanced argument, and this is a good thing about more of a long-form podcast is it allows for nuance.

Andrew Huberman:
Yeah. Absolutely. Let's talk about strains of cannabis. I've spoken before about the sativa versus the indica strains, and certainly there is a lot, a lot of Subjective anecdotal descriptions about differences in the "effects" of those-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... as reported by users. When I talked about this before in the cannabis episode, I leaned on a paper that took those subjective reports of arguably many, many people, pushed those subjective reports through what was known about the strains they claimed to have used. So this is people are reporting their use.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
We assume honestly, but you always have to assume that, I guess people could be lying about which strains, or misinformed.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And then using machine learning to couple their subjective experiences, as they report them, to indica versus sativa strains, and then by looking at the chemical composition of those different products, because these were products that they had consumed, trying to tack chemical composition to strain, in this case, mainly the indica/sativa discrepancy, to subjective experience. And I know that you, and presumably others in the field of cannabis research, take real issue to that sort of approach, and perhaps, I have the feeling this is what you're going to say, rest on the idea that we, at least at this point in time, really can't say anything about the different biological effects of sativas versus indicas. And yet at the beginning of the episode, you said that there are many, many different cannabinoid compounds in cannabis. So three questions, and I'll keep these very short. One, do you think that there are different subjective effects of different strains of cannabis that can be attributed to the different strains, right, not just to individual differences in experience? And then the second is, do you think that there will ever be a time in which we can understand this plant flower, right, to the extent that we can engineer it to provide specific subjective experiences, perhaps more positive than negative, et cetera? And then there's a third question, but I'll hold off.

Dr. Matthew Hill:
Okay. So, yes. So going back to just the idea with the indica/sativa thing. So the indica and sativa names, at least from everything I've understood from everyone that I talk to and being in this field, is those are botanical terms that largely refer to shape of the plant, the way the bud grows, blah, blah, blah. They do not track with chemical composition in any way. In fact, Nick Jacomus has done a lot of analysis of thousands and thousands of different kinds of cannabis that have been submitted for biochemical analysis to understand THC, CBD, terpenes, minor cannabinoid content. And essentially, his work, as well as from all the people who have done the genetics on this, is the variability that exists within what someone calls an indica or a sativa is greater than the variability that there is between them.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And there is no such thing as a chemical profile that exists in something that's a sativa versus something that's an indica.

Andrew Huberman:
Is it possible that there's a chemical profile that relates to the most common indicas or most common sativas?

Dr. Matthew Hill:
I think in Nick's analysis, there was a couple of terpenes that may have loaded on a little bit onto things that were sativas, but there was tons of sativas that didn't fall into that bracket.

Andrew Huberman:
Okay. Well, then that immediately, to me, negates the premise of this paper that I was referring to that divides according to indica/sativa, and yet the paper is also trying to distinguish among all the different types or products of cannabis.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Meaning, is there some other feature of the cannabis plant that does relate to these different subjective effects? Because people do seem to get different subjective effects from different products that relate in some way to things other than the concentration of THC.

Dr. Matthew Hill:
Yeah. My honest opinion is this is expectancy bias. This is all expectancy bias.

Andrew Huberman:
I see. So they purchase something that they think is going to make them calm, and it makes them feel calm.

Dr. Matthew Hill:
If 20 people tell you that taking this makes you calm, you cannot remove your expectation bias from the fact that when you consume it, you feel calm. And this has been, I think, one of the most common things with cannabis, is this whole area is so ripe with these expectancy biases that people have about what they assume. If someone goes in, and a budtender tells them, "This is a sativa, it's going to energize you," there's no way to remove that expectancy bias from what you get. And from talking to a lot of people that study this more explicitly, they always say the biggest predictor of what someone feels when they consume cannabis is what they're told on the label it's going to do to them. And a lot of this-

Andrew Huberman:
That's pretty wild. I did an episode on the placebo effect.

Dr. Matthew Hill:
Yeah. It's similar, yeah.

Andrew Huberman:
And a lot of people hear placebo effect, and they go, "Okay, well, then everything's a..." Placebo effect is amazing. There's dose response-

Dr. Matthew Hill:
Yes

Andrew Huberman:
... in the placebo effect of nicotine on cognition.

Dr. Matthew Hill:
Interesting.

Andrew Huberman:
Dose response. If you're told you got a high dose when you actually got a low dose, you will exhibit the high dose neurocognitive enhancement effect.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And by brain imaging, it shows a high dose-like enhancement of the relevant brain areas.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
In other words, the expectancy drives changes in brain activity.

Dr. Matthew Hill:
It's across the board. Again, this is not unique to cannabis in any way. It's just cannabis is so ripe for this because of the lore that it just exists. People say this. The issue has been, and I just asked Ryan Vandrey this, as far as I know, I don't believe there's actually ever been a clinical trial that has blinded people and given them sativas or indicas and actually had them predict what they are or been able to characterize any kind of phenotypical description of what that intoxicated state feels like. And because the paper that you were referring to where it was users who had got the product, they can't remove their own inherent biases from their own experience. It's going to influence it. There's no way around it. And so People kind of lean into this and probably not consciously, but the amount of people I've talked to that really genuinely believe this to their core, that sativa does this and indica does this is fascinating to me because, again, you have these two... THC is what drives the high. That's very clear. And you can take a sativa and an indica that have virtually identical levels of THC, and yet people will report very different intoxicating states that come out of that.

Andrew Huberman:
Do you think this also explains the lore, or perhaps it's real, that different alcohols produce different drunks?

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I've got friends who will swear that whiskey makes them feel aggressive-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and vodka is mellow, and that white tequilas feel different than the other tequilas. And, for people listening to this thinking, "Okay, well, that's not science," I agree. That's not science. That's just anecdote.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And yet, the chemical composition of these different drinks is different, but ultimately, we're talking about alcohol, right?

Dr. Matthew Hill:
Alcohol. Yeah.

Andrew Huberman:
Different sugar contents.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Different hangover propensity.

Dr. Matthew Hill:
I have to believe the majority of that's an expectancy bias.

Andrew Huberman:
Wow, okay.

Dr. Matthew Hill:
I have a hard time believing that these things are really driven by fundamental biological differences within. Because anything else, that's the thing. Sure, some of the labs now, there is a movement to start looking at can certain compositions of other things in cannabis start to maybe modulate or influence? This is called, I think I've said this before, the entourage effect. This idea that THC alone might do one thing, but then layering in other terpenes or minor cannabinoids may influence that effect. That is a theory. That's not a thing that we know definitively in any way, and in fact, there's virtually no research that's ever been done to test this. There's some stuff that's starting to come out now. Like Ryan Vandrey at Hopkins recently published a paper where they, in a dose-dependent manner, added limonene, which is one of these terpenes, like I said, I think gives it a citrusy odor, into the THC. And did find at a really high dose, probably a dose that I don't think you could actually find in cannabis, it's a little bit higher than what you would've gotten there, but limonene did seem to be able to curb the ability of high-dose THC to make someone feel anxious. And this was done in a blinded manner, so there's, I think, some validity to the interaction. Whether that's occurring in cannabis naturally because of the levels of THC to limonene, I don't know. But it really was one of the first demonstrations that adding in a terpene could actually influence a component of the intoxicated state in a blinded manner. I think is interesting. And Ziva Cooper, who's here at UCLA, is doing some work with beta-caryophyllene, which is probably the second most abundant terpene, I think, from Nick Jakomis's work. I think myrcene may have been the highest prevalent terpene across all types of cannabis. Beta-caryophyllene is probably the second, and limonene, I think, is probably the third. And so they're looking at, I think Ziva's work is in the context of pain, so they're trying to look at if a fixed dose of THC, if you add in varying levels of beta-caryophyllene, does this influence this? Because again, you do see this in patient communities where they say, "Well, this strain helps my pain better than that strain."

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And so it's like, okay, is there actual legitimacy to this? Or again, is this just an expectancy bias because someone who sold this to you told you that this strain is better for pain? And the problem is these are all subjective endpoints. This is pain, sleep, anxiety. These are all how someone personally experiences it. And we know from all the clinical trials that study pain, sleep, and anxiety, there's massive placebo effects that happen in all these conditions. And so it's very difficult to actually make any kind of sound statements about this in the absence of there being clinical trials that have clearly started to do this. But it's like, as you can imagine when you start doing the math, given the amount of terpenes, the amount of combinations at different levels, how overwhelming this could become. Because maybe there's a few that you need in there that interact with THC, not just one. There is a lot of work that's happened in the last few years that has really started to try and look at if these terpenes or minor cannabinoids act at the cannabinoid receptor, which none of them seem to. So this isn't like you've got things that modulate how THC is binding to CB1. If they're doing something else, it's probably through an interaction with another neurochemical system that's influencing what THC is doing. So I'm not against the idea that different chemovars, or what people call strains of cannabis, could do different things subjectively. I just am remiss to believe this until I see some blinded data because I think outside of that, we know how powerful an expectancy bias is, so it makes it very, very challenging to make any kind of firm statements.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And so in the context of how you introduced this, that was, again, I think one of the issues that I took with the other podcast was because, as you've said, I understand the thought process you went through. You had this paper where people were reporting subjective effects. There's some neuroimaging data that's been done with cannabis, so you said, "Okay, this is what that was, and that was what sativa did versus this is what indica did." So I think it's important that you explain that because I do think that-

Andrew Huberman:
Well, that's what the data pointed to. But now what I'm realizing is that any time we're talking about cannabis, because of the 70 plus cannabinoids present that could modify or join, so work in parallel with the effects of THC, we're really talking about polypharmacology.

Dr. Matthew Hill:
Possibly.

Andrew Huberman:
It's not a pure substance. It's not like giving anandamide.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Or it's not like adjusting levels of endogenous anandamide.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
This raises, I think, an equally important issue for us to resolve, which is CBD-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... which we didn't talk about earlier. When Nolan Williams, who's a psychiatrist, he's one of these phenoms, triple board certified psychiatry, neurology, colleague of mine from Stanford School of Medicine who mainly works on ibogaine and transcranial magnetic stimulation. But we talked about cannabis a bit when he was on the podcast, and he mentioned a strain of cannabis that is available in Colorado, which is pure CBD. I think it's called Charlotte's Web. And the parents of Children who have epilepsy-

Dr. Matthew Hill:
Mm-hmm

Andrew Huberman:
... will move there or go there just to get this strain because it seems to help their epileptic seizures.

Dr. Matthew Hill:
Yeah. I would say that's definitely not true nowadays. Pre-legalization anywhere outside of Colorado, that was true. People were gravitating there towards it.

Andrew Huberman:
Yeah. So the questions are, could you tell us a little bit about the biology of the CBD receptor, mainly as it relates to CB1 or not? Does it bind CB1 as well? If not, how is it working? And you mentioned that people will not report any subjective effect of taking a pure CBD compound, so lacking THC, but it sounds like it may have some usefulness for treatment of epilepsy. And what are some other established, meaning clinical trials and/or lab data to support the use of CBD for any type of either psychiatric condition, pain, et cetera?

Dr. Matthew Hill:
So, the first thing that's interesting that I think a lot of people don't understand about CBD is CBD doesn't really exist in any form of street cannabis, and it hasn't for a very long time.

Andrew Huberman:
You mean there's no CBD in there?

Dr. Matthew Hill:
There's some. There's very low levels of CBD. And the reason that is, is because THC and CBD are both made from the same precursor molecule, and which direction it goes in is based purely on which synthetic enzyme converts it to either THC or CBD. And so as people have clearly chased THC and wanted cannabis that's rich in THC, and so cannabis has been bred to become higher content in THC, by default, CBD has been bred out of the plant, and it has largely been bred out of the plant for quite some time. I always find it interesting that there's this community that's like, "Oh, well, THC is the recreational cannabis and CBD is the medical cannabis." I'm always like, that's bizarre, because historically, THC has been what people have bred cannabis for. And so any medical benefits that people have reported from cannabis per se usually are THC and CB1 driven. CBD is this other molecule that we can go into the pharmacology in a second, but again, I think in the analysis that Nick Jacoma did of all these strains and types of cannabis that exist in the United States when they went through their thing of thousands and thousands of kinds of cannabis, it was like 3% of them maybe had more than 1% CBD. It's very low. There's almost none. And in Canada, to get a CBD-rich strain, you have to basically explicitly buy it because it has to be bred to make CBD. And so this is the kind of chemo of our distinction, I think you did allude to this last time, which is the type one, type two, type three. So type one is high THC, type two is somewhat balanced, and type three is high CBD. And now, I think like 90 to 90 something low percent of all cannabises that are out there are type one. They're all high THC because that's what's been bred. There's a few that have been mixed, and so are equal proportions, but you're never going to get high equal proportions. So a high THC cannabis is like 20 to 30%. If you go for type two, which is mixed, they're both going to fall around 12%. Maybe a little more, but in that range, and then same if you've got a type three, it's high CBD, it's going to be 20-ish percent CBD and very low THC. And so no one has ever grown CBD-rich cannabis outside of this recent boom in the last decade that's happened about people wanting CBD because of the Charlotte's Web, which was popularized by, I think, Sanjay Gupta on CNN in like 2012 or something. It was a while ago. But that was what got a huge movement going around this idea of CBD. And yeah, so the Charlotte's Web was, I believe that was what they had named that kind of cannabis that they'd extracted it from. And so it was a tincture that they were using that was very high CBD content that they were finding was controlling pediatric seizures in kids. Now, this has actually been studied pretty effectively. Most of it's come out of Boston. Elizabeth Thiele has been one of the main leads on this, and she's a neurologist there that has done a lot of the work on this. And so they have, I think, very clearly, and the data is incredibly compelling. Their research is one of the reasons why CBD has been descheduled or changed in its scheduling down to a, what is it? A five? What is a class?

Andrew Huberman:
CBD?

Dr. Matthew Hill:
Yeah, like CBD.

Andrew Huberman:
Oh, CBD. Given the availability of CBD everywhere-

Dr. Matthew Hill:
Yeah, it's-

Andrew Huberman:
... in gummies and drinks and you can get it in a convenience store.

Dr. Matthew Hill:
Yeah. So a lot of it's been shifted in its classification status, because it actually has been shown very clearly to have medical benefit. And it was a very specific form of pediatric epilepsy called Dravet syndrome. Now, there's other forms of pediatric epilepsy I know Elizabeth has studied in addition that has found comparable levels of efficacy. But essentially what they have shown is that very high doses of CBD are relatively effective at calming down the seizures. In some kids, it's profound. In some kids, you're talking about kids that were having dozens of seizures a day to essentially none. And so, and I can understand.

Andrew Huberman:
That's impressive. Yeah, that's super impressive.

Dr. Matthew Hill:
From a grassroots perspective, I can understand if you were a parent who had a child with a disease like this that was largely intractable and not that well-controlled from the medications they were on, and then something came around that showed this level of efficacy, you would gravitate towards it. That makes sense to me. And I think the work that Elizabeth and her colleagues have done has been really important to establish the efficacy of CBD in these disease states. And so I don't think at this point there's a lot of controversy around that. The question that comes out, though, is so how is it working? And we don't have a mechanism. So as you had said, CBD receptor, there's no receptor that CBD binds to.

Andrew Huberman:
I was under the impression that CBD also bound to the CB1 receptor.

Dr. Matthew Hill:
No. Certainly not-

Andrew Huberman:
Or that under some conditions it can modulate ... the shape of the receptor to adjust THC binding. But now you're telling me that these two things-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... rarely coexist together. So I guess the question then would be-

Dr. Matthew Hill:
You can dose them. You can have products that are made that are oil-based products at least, that have a certain amount of CBD and a certain amount of THC, and people do go for those. One of the arguments people make is they say, "Oh, introducing CBD reduces the adverse effects to THC." Well, if you're using it in a strain, that's simply because the strain of cannabis has less THC now.

Andrew Huberman:
Right. So it's impossible to separate.

Dr. Matthew Hill:
So you've bred it out. But a lot of this was based on some work that came out a long time ago from Brazil, where they showed that giving CBD with a relatively high dose of THC could curb some anxiety that came out from high-dose THC.

Andrew Huberman:
I thought the explanation for that was that CBD can modify the CB1 receptor in some way that makes THC less able to engage with the THC receptor.

Dr. Matthew Hill:
There is some evidence to support that, that we would call these allosteric modulators.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
There's some evidence to suggest that CBD may interact with a allosteric site on the cannabinoid receptor that makes THC bind less.

Andrew Huberman:
Doesn't sound like you're particularly convinced by that evidence.

Dr. Matthew Hill:
I think that, I mean, like the paper-

Andrew Huberman:
I'm looking at the look on your face. For those listening, I'm looking at Matt, and I think he's being generous here. Let me ask it a little differently.

Dr. Matthew Hill:
It's definitely more complex than that.

Andrew Huberman:
Does anyone know what CBD binds to?

Dr. Matthew Hill:
So, the most convincing thing that I've seen that CBD binds to is the work that C.C. Hilliard has done, looking at its ability to essentially block adenosine uptake. And so it can inhibit the adenosine transporter, so it causes-

Andrew Huberman:
So that should make people feel more alert.

Dr. Matthew Hill:
No, because you're getting more adenosine, so you get an accumulation. It blocks the adenosine transport mechanism.

Andrew Huberman:
I see. Oh, so, okay.

Dr. Matthew Hill:
So you get an accumulation of adenosine-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... which is more sedative.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And that, in the PNAS paper that C.C.'s lab had from 2006, they showed that that also mediated, it was the adenosine, I think 2A receptor, that drove the anti-inflammatory effects of CBD. So it was this secondary effect by-

Andrew Huberman:
Sort of the opposite of-

Dr. Matthew Hill:
Caffeine

Andrew Huberman:
... of caffeine.

Dr. Matthew Hill:
Yeah. No, if I'm ever doing like-

Andrew Huberman:
Now, the way you're describing this, it sounds like the anti-caffeine.

Dr. Matthew Hill:
That's kind of how I describe to people if they ever ask me for what the pharmacology of CBD is.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
I'm like, that's not the only mechanism, but the thing that was important in C.C.'s studies that I think is relevant is that it was not super high concentrations of CBD that caused that. So you could get this adenosine accumulation at, you're not talking like micromolar levels of CBD, which is what a lot of studies have done. And so even when we're talking about the allosteric modulatory site, yes, there's evidence for it, and it is convincing evidence, it's just the dose range in there, you're kind of like-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... who's getting hit with CBD at that level where you're getting these effects? And more so when they've done the blinded work, like when Ryan Vandrey at Hopkins again, who is one of the main people who's done a lot of this work, has actually blindly given people CBD dosing with THC, finds the opposite, that it actually amplifies some of the effects of THC. And this was something we learned from the pediatric epilepsy world, was that when you start giving CBD at relatively high doses, one of the things it does is saturate a lot of liver enzymes. And so some of the efficacy in the pediatric epilepsy space may be a secondary effect due to an accumulation of some of the antiepileptics as well, because they're not being metabolized the same way. And this has now been very well replicated. We know that once you start taking CBD, when they hit doses that are at the clinical level, you're going to start having hepatic effects. So it's going to affect the liver, and it's going to affect the ability of the liver to chew up other drugs.

Andrew Huberman:
Not good.

Dr. Matthew Hill:
And there's very specific CYP enzymes, like the cluster of enzymes that metabolize things. There's very specific ones that CBD hits. And so as a consequence, one of them is what chews THC up. So you can get a potentiation of THC by inhibiting its metabolism if you have high enough CBD on board.

Andrew Huberman:
Given the effects on adenosine that you described before, that it's sort of the, what we're calling, just for sake of discussion, the anti-caffeine, how do we explain the preponderance of CBD added to energy drinks that also contain caffeine? There's no logic there.

Dr. Matthew Hill:
Expectancy bias.

Andrew Huberman:
There you go.

Dr. Matthew Hill:
I mean, yeah.

Andrew Huberman:
Everything can't be expectancy bias.

Dr. Matthew Hill:
I mean-

Andrew Huberman:
I have a feeling it's going to be interesting to see in the comment section on YouTube. Presumably there's some regular pot smokers listening to this, and the expectancy bias is so strong, as-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... I allude to in the placebo episode, and we've been talking about here. And yet it's so strong that I think people will also be convinced that there are real differences between different strains because they've maybe done the non-formal blind, someone gave them their weed and someone else-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and then they got a completely different effect, right? They're not expecting something different necessarily-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... or in a particular direction, but they get a very different effect. But that to me just speaks to the idea that, again, cannabis sounds like polypharmacology. 70 different cannabinoids.

Dr. Matthew Hill:
In some ways, yeah.

Andrew Huberman:
THC being among the more powerful components, but it's yoked in the sense that, as you said, people self-regulate their intake, provided they're smoking, not ingesting it by edible. And so it's almost like THC is being held constant, and then there's this constellation of other things around it that are modified, and people eventually veer towards what they like, what they can afford, what works with their-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... lifestyle, and then they come up with a bunch of theories based on packaging, what they're told, but presumably also some real effects of these terpenes, the CBD component, et cetera.

Dr. Matthew Hill:
It's possible. I mean-

Andrew Huberman:
It can't all be just psychological expectation.

Dr. Matthew Hill:
Yeah. So what you're saying is like what we said is the entourage effect, and I think that is a theory that is held by a lot of people that this exists.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
The reality is these terpenes and minor cannabinoids exist at such low levels that there's a couple of kinds of cannabis that might have a high enough level where you're seeing something, but yeah. I agree to the extent that it would be a little wild if everyone's subjective experience across different kinds of cannabis was entirely driven by some kind of expectancy, which I can't imagine is accounting for all of it. But I think when we talk about sativa versus indica, I think there's a huge bias that's going into there.

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
But one of the things with CBD that's interesting, unlike THC, is you can actually do pretty clean blinded studies, because it's really hard to give someone THC and them not know they're on THC.

Andrew Huberman:
Right. This was the big problem with the MDMA trial-

Dr. Matthew Hill:
Yes

Andrew Huberman:
... that happened recently, is that people who got the placebo knew they got placebo.

Dr. Matthew Hill:
Yes.

Andrew Huberman:
People who got the drug-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... knew they got the drug. It's very hard. You could do a dose response-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... but it's very difficult.

Dr. Matthew Hill:
It's very challenging to give someone a psychoactive drug and a placebo and them not know which one they have. Whereas because CBD doesn't produce an intoxicating state, and it's not really perceptible from the person who's taken it that it's doing anything, that actually does make it far more amenable to do blinded trials with. And so, the interesting thing with CBD, and this is where I get a lot of people that get angry at me as well, is that I would argue that the overwhelming majority of the effects of CBD that people report are all placebo effects. And I say that because people leverage the epilepsy stuff and some of the clinical work and say, "But we know it does things." And my response to them is, "Do you know what dose those people are getting?" Because this is something that for some reason has not made the transition from science into pop culture. So-

Andrew Huberman:
This is a similar phenomenon with GLP-1. I and other people have pointed to the fact that certain food products or certain drinks or certain activities can increase GLP-1, glucagon-like peptide, which is now becoming more commonplace knowledge because of Ozempic, Mounjaro, et cetera, as very powerful weight loss tools, although there's questions about muscle loss, et cetera. And then we had Dr. Zachary Knight on, who explained that even a fourfold increase in GLP-1 brought about through a prescription drug or ingestion of a particular food or drink does not lead to any appreciable weight loss.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
However, when one achieves thousandfold increases in GLP-1 through the use of things like Ozempic, Mounjaro, you see profound weight loss.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Meaning that you need enormous effects in order to see-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... the clinically relevant changes in that case, weight loss. So it sounds like a similar thing with CBD.

Dr. Matthew Hill:
Yeah. It's-

Andrew Huberman:
So if somebody takes a CBD gummy, and they feel that they sleep better, you would argue that that's entirely expectation bias.

Dr. Matthew Hill:
I think that's a placebo effect. And I say that because the majority of gummies are what? Like two mgs, five mgs, 20 mgs maybe?

Andrew Huberman:
I don't know. I've never taken a CBD product.

Dr. Matthew Hill:
So-

Andrew Huberman:
I know a few years ago they were all the rage.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I was never tempted to do it. And I'm aware, and we'll talk about this a little bit more, that there is evidence, according to Matt Walker, who did a six-episode series with us on sleep, that THC does help certain people fall asleep, but it can dramatically alter the architecture of sleep-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... in ways that are probably not great.

Dr. Matthew Hill:
Yeah. THC and sleep is definitely a whole other thing.

Andrew Huberman:
Sure.

Dr. Matthew Hill:
But sure, a lot of people report this with CBD. But again, so most CBD edibles or things that people take that are sold through commercial markets are in the range of two to 25 mgs of CBD.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So then I say to them, "So you're aware that in the pediatric epilepsy studies, the dose ranges are like 1,500 to 2,000 mgs?"

Andrew Huberman:
Yeah. There we go. Yeah.

Dr. Matthew Hill:
And then you're talking about a child who weighs on the order of what? 20 kilos, maybe?

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Like 40, 60 pounds, somewhere in that range. So if you start dosing by weight, which is how most of these things are done, where they'll say 20 mgs per kg or whatnot. So someone my size, so I weigh a bit over 200 pounds, for me to take that dose of CBD at let's say 20 mgs per kg at like 90 odd kilos, you're talking about me taking an-

Andrew Huberman:
A liver damaging dosage

Dr. Matthew Hill:
... an insane... Or maybe I wouldn't say damaging.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
It's definitely influencing how the liver metabolizes other things because it's going to saturate those enzymes. But you're taking a very high dose.

Andrew Huberman:
So if, for instance, you were to take a high dose of CBD and then maybe have a couple alcohol-containing drinks, that could be problematic, right? Because now you're talking about the two-hit model.

Dr. Matthew Hill:
Yeah. I can't speak to that because I actually do not know the metabolism of alcohol well enough. I don't believe so, because that's alcohol dehydrogenase. So that would probably be a separate enzyme pathway than the CYP. This is more like-

Andrew Huberman:
Separate enzyme pathway, but you're challenging the liver.

Dr. Matthew Hill:
Yeah, but I don't know if it would have an effect in that capacity. They've definitely seen this, they know the list of medications-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... that this is a problem for. So it's things like warfarin-

Andrew Huberman:
Mm-hmm

Dr. Matthew Hill:
... and like blood thinners.

Andrew Huberman:
Blood thinner. Yeah.

Dr. Matthew Hill:
And the antiepileptics funnel into the same metabolic pathway as this THC. So there's certain things that this would influence. I don't know if I would say this would in the context of alcohol, but I think more so, what I try and point out to people repeatedly is, I have yet to see a blinded clinical study that has found any effective CBD that's efficacious that's under 300 to 500 milligrams. And yet, in the wild, in people who are using it on their own, were using doses of 10 to 20 milligrams and reporting these effects. And the thing is that I think a lot of people don't also realize is CBD has absolutely horrific bioavailability. So if you take it orally in an oil or in a gummy or whatever you consume it in, now this might be different with some of these beverages that are out there. I don't know if anyone's actually ever done the pharmacokinetics on them. At least I've never seen it. But standard routes, we're talking 4%, like very little.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Actually leaves your gut into your bloodstream.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Now, we do know from the studies from GW, who created the pharmaceutical version of CBD that was used for a lot of the pediatric epilepsy studies, that they did, I don't know if it was random or intentional find, that opposite to something like alcohol, if you had just eaten a fatty meal, that actually enhanced the bioavailability of CBD dramatically. So then it went up to maybe 20% got into the blood. But that's probably because, again, CBD is a fatty molecule. It likes fatty environments, and for some reason, having fat in the stomach and in the gut seems to promote its ability to get into the bloodstream.

Andrew Huberman:
I can see it now. It's the steak and CBD-

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
... or the CBD with omelet protocol.

Dr. Matthew Hill:
But it's-

Andrew Huberman:
I'm just kidding, folks. I'm not suggesting that protocol.

Dr. Matthew Hill:
But yeah. And so because of this, it's like you're taking very low doses of CBD that have very poor bioavailability, and then people really stand by the effects of these. And so I'm like, what I would always say is if it works for you, there's no reason to stop it. But Because you're having benefit from it. But would I ever recommend someone do this? No, I wouldn't, because I can't say that I think that this has any biological activity. Because even when we start looking at these potential targets of what CBD could interact with, there's a couple of receptors people have said it might interact with the serotonin receptor. There's some of these random orphan receptors that we don't know a lot of what they do that CBD might interact with, but the concentrations you need to hit those are reasonable, and you're not getting that in the blood and certainly not in the brain of people from consuming incredibly low doses of CBD. So the whole market that exists for CBD, to me, is a little bizarre. And I think for a lot of us in the cannabis field, this has been one of the most bizarre social experiments we've ever watched because if you asked me in 2010 to walk into a room and ask how many people knew what CBD is, maybe one out of 100. No one knew what CBD was. And now it's like 80 to 90% would know what it is because you can't walk down a street in any city in North America and not see CBD products, whether it's some kind of cream, or a shake, or some random concoction that people have added CBD because now you're seeing the energy drinks. It's bizarre to me how much this has taken off, because it seems to have somehow migrated into being a health product in some capacity, so.

Andrew Huberman:
Yeah, I've never tried any of these CBD-containing products. I think a lot of what you're describing speaks to the fact that people are eager for things that can help them adjust their anxiety and sleep better.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Which is a large reason why a lot of this podcast has focused on respiration-based tools and other base tools that can help people with anxiety. I think that many people suffer from just too much activation in their autonomic nervous system.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And I would argue there are much better things that are not of a ingestible type, things that one can do that are science supported, right? There are clinical studies, meditation, breathwork. Not so much breathwork, I would argue, but certain patterns of breathing, meditation, cognitive behavioral therapy. There are a whole bunch of different things, as you know. So I don't know what explains the CBD craze, but you certainly have shed light on what is and mainly what is not known about CBD.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And I think it's really important for people to hear.

Dr. Matthew Hill:
Yeah. Again, I think from my point of view, it's an ethical thing as well, because this isn't covered by insurance. People are spending their own money on this. And so I find it really challenging to recommend someone to be spending what can... Especially if we're talking about an actual clinical dose. For someone to take CBD at the level where it could actually be shown to have some benefit and some condition, of which currently it really is just pediatric epilepsy. This idea with sleep, pain, anxiety, there's not a lot of super conclusive data, and I'd say most of the trials that have been done have not found really good evidence of benefit in any capacity. So it makes it very challenging to recommend this in any capacity. Especially, if finances aren't an issue, sure, go for it. But I understand people are, like you say, looking for solutions, so it makes-

Andrew Huberman:
It doesn't sound like CBD is the solution.

Dr. Matthew Hill:
I am not convinced by the data that exists that it's really doing what a lot of people claim it's doing.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Except supporting the placebo effect, perhaps.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Perhaps.

Dr. Matthew Hill:
It's a great study of the placebo effect.

Andrew Huberman:
I want to make sure before we close that we touch on some of the potential harms or asserted harms of THC, because I think there's a lot of misunderstanding about this. We talked about psychosis and the lack of evidence for a direct causal effect. You give a beautiful description as to how we should think about all of that based on the current literature. But cannabis and driving is a potential hazard.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Right? And some people will laugh. They'll be like, "Oh, driving too slow," as opposed to driving drunk or driving too fast. Okay. We can talk about that. We talked about the potential for addiction-

Dr. Matthew Hill:
Mm-hmm

Andrew Huberman:
... and the evidence potentially for and against that, right? There's also the big black or gray box of all the things we don't know about what regular cannabis use could do. And yet I know a lot of people who've used cannabis for years, mainly as a replacement for alcohol, at least that's how they describe it. "Well, it's not as bad as alcohol."

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
You hear that a lot. Okay? But what are some actual, if any, what are some actual harms of cannabis use that people need to take into account and just weigh against the fact that every compound, caffeine, even water, can kill you if you drink too much of it?

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And then let's make sure that we touch on this issue of cannabis and driving or operating machinery, but I think the machine most people are thinking about these days is driving.

Dr. Matthew Hill:
Yeah. So health harms, someone's smoking, obviously there's risks for lung damage. I would say the evidence for things like lung cancer certainly don't hold the way they do with cigarette smoke.

Andrew Huberman:
Because people are smoking less of it, or there are just fewer carcinogens in there?

Dr. Matthew Hill:
I don't think you could make the argument about fewer carcinogens per se. I think probably it relates more to the frequency. Donald Tashkin, who's in California here, I think he was at UCLA, I'm not 100% sure, but I know he was in California. He did very long-term studies tracking cannabis smokers and basically did not find associations with lung cancer the way that you do with cigarette smoking. Why that's the case, I don't think anyone has... People have theories. Some suggest because a lot of this in vitro animal work with really high dosing suggests it could have anti-proliferative effects for tumors. Whether that's real or not, I don't know, but I think more likely it's because most people who smoke cigarettes, at least the relationship with lung cancer, were people who were smoking regularly throughout the day, and it's very rare someone smokes cannabis at that frequency. Maybe if they isolated that population, they would see relationships with lung cancer. I just don't think it's been borne out by the data the same way. Certainly lung damage, emphysema, things like that are on par. If you have any combustion product, you're going to have damage there. There's no question about that. So again, harm reduction perspective would be oral routes of administration bypass lung damage. They come with their own issues with dosing and whatnot, but if you're talking about physical harms, that's one thing to avoid that you could bypass that aspect of it with. I don't think we are at a point where we can say the state of it. There is something with cardiovascular function in cannabis that relates to higher frequency of strokes perhaps, or cardiac events in some capacity. The data's not entirely clear in this sense yet. Again, it's not super clean relationships like we're seeing that were there when they established cigarette smoking and lung cancer kind of thing. I think that effect was so profound, and the population of smokers used to be so high.

Andrew Huberman:
Can this potential, I want to highlight potential, relationship between cannabis use and cardiovascular issues be bypassed, no pun intended, by using edibles, not inhalants, or is it related to THC itself?

Dr. Matthew Hill:
I would probably guess, and this is a guess, that anything, again, combustion smoke-wise, maybe not vaping plant matter, but at least the combustion from smoking probably exacerbates this, just because any kind of combustion product is going to have some vascular effects to some degree on the system. So I imagine it would make it worse. But THC itself has a very complex effect on cardiovascular function because it tends to cause, typically, vasodilation, so you get widening of the blood vessels. Which is why it relates to a lot of people will experience postural hypotension. So sometimes what that is, is if you stand up and your blood pressure doesn't catch up with you, so you get really lightheaded and people will collapse. And so this is not uncommon to happen to people, and with edibles as well, so it's not just from smoking. But when they've consumed cannabis in some capacity, there are some people that seem to be very sensitive to the vasodilating effects. And so when they stand up, their blood pressure can't match the shift in gravity that happens, and so not enough blood perfuses the brain, and they go down.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And that can be transient. They'll come to a minute or two later, but it happens. But as a consequence of the vasodilation is it triggers tachycardia, which is an accelerated heart rate. And so that's a very reliable physiological response for a lot of people who use cannabis. And so it's a bit of a tricky thing because obviously if there is some underlying heart or a cardiac sensitivity or issue, the tachycardia itself can be a problem. So if someone has an underlying heart condition where at rest it may not present itself, but the shifts into that kind of beating faster to compensate for the fact that you've got a drop in blood pressure, can put strain on the heart in a way that could unmask a vulnerability or an event. And again, this is me theorizing what I think it could be based on what we understand to some degree about how it affects cardiovascular function.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
There are occasionally people who have reported having elevated blood pressure. Some of that also could be from an anxiety state or whatnot coming around. But the typical response, and this is usually driven by cannabinoid receptors that are in the vascular beds themselves, that it causes a vasodilatory response. And so that is usually the first step. The second is the uptick in the heart rate. So you get these kind of effects over time. There's some work looking at vascular stiffness that can evolve over time in cannabis users. There's some evidence to suggest that you might get more of that emerging.

Andrew Huberman:
Mm.

Dr. Matthew Hill:
And so again, that could relate to a vulnerability to have strokes or other kind of cardiovascular events in that sense. So I think the issue in terms of why it is more difficult for us to say anything definitively at this point is just obviously the timeline of this. Cigarette smoking was an easier thing to establish in that context because once antibiotics and medicine advanced in the '40s and the '30s and stuff and people started living longer, you started seeing a lot of these effects of cigarette smoking emerge because-

Andrew Huberman:
And yet, it took a while for the-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... medical community to adopt the idea-

Dr. Matthew Hill:
Exactly

Andrew Huberman:
... that cigarette smoking was bad.

Dr. Matthew Hill:
Oh, I know. It's wild to look back on it.

Andrew Huberman:
Physicians would smoke in clinic.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
There were ashtrays in the doctor's office.

Dr. Matthew Hill:
My grandparents grew up in Belfast. They had smoked for years, and they had even said when they were younger, doctors would say, "Oh, have a cigarette after a meal. It promotes digestion." So it's kind of wild to hear that stuff when you think of how cigarettes are viewed nowadays. But I don't think we've been able to track this long enough to be able to say with certainty what we're seeing. If people ask me about risks and harms of cannabis, the first thing I always say is schizophrenia and bipolar. Those are the main concern areas, I think, where you want to avoid cannabis. And I would also say if anyone has cardiovascular issues, they should avoid cannabis. Just because that's more of, I would say, a being safe, because I don't know how to actually explicitly say what I would say the harms associated with it are. But I think there is something there. I've seen enough evidence that's starting to coalesce into a story that's like, there's something here.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So that's where I would say that I think there's risk. There's also things like this bizarre cyclic vomiting syndrome, which is this really strange thing that has become really apparent. We've seen this in Canada a bit more now with legalization, again, because people are going into ERs more. Where it's this somewhat strange phenomenon where it's usually people who are pretty excess cannabis users. They just start puking, and they can't stop it. And it's like this intractable vomiting that they get into. And then bizarrely, one of the things that seems to cure it is a hot shower, which I can't even begin to understand this. There's also-

Andrew Huberman:
I'm chuckling at the example because you are so very clearly rooted in science, but that just came out of nowhere. Like, okay, cool. Hot shower. Deliberate heat exposure, folks. There it is.

Dr. Matthew Hill:
I have been trying to understand how this was-

Andrew Huberman:
I'm not enjoying it because it's deliberate heat exposure, but it just speaks to the fact that we're talking about smoking being a ... a regular part of the medical community's behaviors up until a few decades ago. And then, a hot shower being the treatment for this chronic vomiting. And it speaks to the fact that with science and medicine, we do know a ton. It's amazing how much we've progressed, especially in the last 100 years, the last 25 years even. But it's also astounding how these seemingly surprising antidotes to uncomfortable conditions can hold up over time in the absence of any randomized control trials-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... or mechanistic data.

Dr. Matthew Hill:
I really struggle to understand, because certainly, I don't think it was doctors that figured this out. This was people, I think, who were experiencing this, and then they started telling doctors this. And I could only imagine, I'm like, "Maybe they're going in the shower because they're vomiting on themselves?"

Andrew Huberman:
Probably.

Dr. Matthew Hill:
And then inadvertently realized that being in a hot shower somehow seemed to calm this down. I have seen a study where they actually applied capsaicin cream, and that also seemed to provide benefit.

Andrew Huberman:
So something about activation of the heat, thermal-

Dr. Matthew Hill:
It's something with thermoregulation, because the other thing that seems to have shown some benefit is propranolol, which again would suggest some kind of sympathetic.

Andrew Huberman:
Which is a beta blocker.

Dr. Matthew Hill:
It's a beta blocker, so yeah, it's your effect. So there's something with autonomic. It must be messing up some kind of autonomic balance or something with thermoregulation.

Andrew Huberman:
Wild.

Dr. Matthew Hill:
Why that results in this bizarre vomiting syndrome, I have no idea. But I remember when I first started hearing the stories of this years ago, and I was just like, "How?" Because it is, again, surprisingly counterintuitive because one of the medical uses that people have used cannabis for is as an anti-nauseant, especially in the context of chemotherapy.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
And so something that typically has anti-nauseant qualities suddenly triggering a vomiting syndrome is kind of paradoxical.

Andrew Huberman:
And yet, we started off today's conversation with you explaining beautifully how activation of these CB1 receptors are homeostatic in some sense, the thermostat analogy.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And maybe after chronic use, the seesaw-

Dr. Matthew Hill:
They've messed it up

Andrew Huberman:
... sort of gets flipped to one side-

Dr. Matthew Hill:
I think, yeah

Andrew Huberman:
... and gets stuck there.

Dr. Matthew Hill:
I think that's how most people have tried to conceptualize what's going on, is maybe, and it seems to involve the insular cortex. At least the anti-nauseant effects of cannabinoids are involved through the insular cortex. And so maybe you have burned out those receptors from chronic use, and so that endogenous mechanism isn't working, or it's somehow flipped in the other direction, now and that circuit becomes sensitized. But it is a very bizarre but very real thing that seems to happen. Again, this isn't common. I've heard a couple of people I've met describe it, but it's not like it's happening to every 10th or 20th person or something. It's a little more infrequent, but it's certainly happening enough that we've now captured it at a federal data level, that this is a thing that people are showing up in the ER for.

Andrew Huberman:
Interesting.

Dr. Matthew Hill:
It is, yeah.

Andrew Huberman:
So a hot shower.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
So apparently, if it happens, a hot shower is what people claim.

Andrew Huberman:
Shower yourself in the shower.

Dr. Matthew Hill:
So yeah. So for me, I would say the main harms that people need to be aware of are the schizophrenia, bipolar, possible cardiovascular effects, and then this is one of these syndromes that can come out of it, as well as possible lung damage from smoking. Those are the main, I think, genuine, bona fide health issues associated with cannabis that people should be aware of.

Andrew Huberman:
Yeah.

Dr. Matthew Hill:
I know we're not going to probably go into depth with it. On the other side, with the medical stuff, it's a little bit more challenging. A lot of this is just because we really don't have good studies that have been done in any capacity that have really definitively told us if cannabis has really bona fide medical benefit.

Andrew Huberman:
Yeah, I was going to ask you about that. It's always nice to end on a positive side, and we don't want to demonize cannabis, nor do we want to glorify it. But the examples that I've heard of medical uses for cannabis include appetite stimulation.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
We talked about that. For glaucoma, lowering eye pressure-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... and glaucoma, the age and age-related increase in eye pressure are two of the major risk factors for glaucoma, which is the most common blinding disease second to cataract. More than 70 million people suffer from it. Everybody, regardless of age, get your eye pressures checked. There are drops for this, but okay, cannabis can reduce eye pressure in glaucoma. Nausea, you mentioned.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
And then anxiety. It sounds like if people get the-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... dose right and it's right for them, that in some cases, it can help them with their anxiety. And the reason I raise that one is because it seems that most people who decide to use cannabis regularly are using it perhaps for its euphoric effects, but as a kind of a mild sedative, a way to relax in the same way that they would use a glass or two of wine.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
What are your thoughts on that? Because I think this is the most common use case.

Dr. Matthew Hill:
Yeah. The other one that wasn't on there, but you've mentioned this before, and I have as well, is pain. So chronic pain is-

Andrew Huberman:
Oh, pain. Thank you

Dr. Matthew Hill:
... pain is, I would say, the number one. So pain is certainly the one that there's the most amount of evidence for, and-

Andrew Huberman:
Thank you

Dr. Matthew Hill:
... I would say when you talked about this in the previous podcast, you were mostly correct about this component of it in the sense that it's not that cannabis is a profound analgesic. It's that cannabis, it has some analgesic properties, but it's not super sledgehammer in that sense. But what it does seem to do is, it seems to strip away the affective component of pain to some degree. And so what I have consistently heard from chronic pain patients when they use cannabis is they say, "Yeah, my pain's still there, but now the pain's background noise. So I can sleep at night." And just being able to sleep, I think, is actually providing a huge amount of the benefit to that community. But it's the day-to-day. They're able to function with the pain because they don't become focused on it the same way because they're able to kind of push it to the background. That seems to be the main ability of cannabis. Yes, there's some mild analgesic properties to it to some degree, but it really seems to be much more that component of it. And I think you'd alluded to something like that in the previous podcast. You'd said something about how it's changing the emotional state of pain.

Andrew Huberman:
Mm-hmm. And we know from the biopsychosocial model of pain that Emotions and interpretation of-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... the sensation of pain is a huge component of what people refer to as chronic and acute pain.

Dr. Matthew Hill:
Yeah. So, the pain thing, I think, is a central one, and that's one of the only ones that there's a little bit of actual research on. Most of it's either with isolated THC, I think there's one or two studies that have actually looked at smoked cannabis and found small signals of benefit. But so, anxiety is an interesting one. And so, obviously this is more near and dear to my heart because I study stress and anxiety as my primary area, and cannabinoids and endocannabinoids in that space. And yeah, you look at questionnaire-based studies about why people smoke cannabis, and 85% of them will say, "Because it reduces stress and it makes me feel less anxious." That was a big impetus as to why we started studying endocannabinoid regulation of it, because similar to feeding and pain, where we know endocannabinoids are involved in regulating feeding circuits and endocannabinoids are also integrated into pain circuitry and can provide some endogenous analgesic signals, we figured the same was going to be true for stress and anxiety, which to some degree it is. But it's very complicated because it can be, like I said before, biphasic, where some lower doses are anxiolytic, higher doses can promote anxiety. But for the majority of people who use cannabis regularly, it's because it helps reduce anxiety. Now, whether that would hold weight in a clinical trial is a different story. There is some old evidence from, I'd say the '70s or early '80s, where they were using synthetic forms of THC, like nabilone, which is something you can get in Canada, or Marinol or dronabinol, which I think is what's accessible in the States, where they did find some evidence to suggest it was on par with a benzodiazepine, like diazepam or something. I can't remember exactly what the comparator they'd used there, but there was some evidence for there being some anti-anxiety properties of THC. And that tracks generally well with the self-reported literature that's out there. Now, whether that's the same as an ability to have benefit in something like PTSD is a different question. It gets a little bit more complicated because obviously PTSD has an anxiety component to it, but there's a lot more to it as well. And again, there's very little research in this space. There was one really, really small study done by the Canadian military. First, they did one version of it that was an open label. Open label trials, for people who don't know, is just basically everyone knows what they're getting. It's not blinded in any way. But because of the self-reported data from the veteran population about cannabis helping, especially with sleep, and the big thing that they reported was that it suppressed their nightmares. And so, post-traumatic stress disorder is a very complex disease for many reasons, and one component of it is the re-experiencing events that happen during sleep, where there's a lot of nightmares and individuals will kind of re-experience the trauma that led to the development of the PTSD. And there does seem to be some suggestion that because they're remembering it and maybe changing the details because they're in a dreamscape space, that they reconsolidate it a little bit more, and there's often a high degree of sympathetic activation and arousal that goes on with these nightmares. And some of the belief is that this is part of the sensitization process that can happen in PTSD, where the disease can worsen over time because the re-experiencing and the reconsolidation and the sensitization of the disease that happens over time in this kind of sleep state can make it worse. And so the majority of veterans who have used cannabis and report benefit, if you actually talk to them about it, as I've done in a few different situations, and also just look at the anecdotal data, almost all of it talks explicitly about sleep. And they say, "Oh, we use cannabis or THC before bed. We find we don't have the nightmares." And just the simple trickle-down effect of that is hugely beneficial for them. And so the Canadian military did an open label trial on this. Again, not blinded, it was small numbers, but they basically found as soon as they put people on nabilone, this synthetic version of THC, in a large proportion, I think like 85% of them almost stopped having these nightmares. And this was a treatment-resistant population that was pretty severe, so this was a big benefit. So they then took the open label and did what you should and moved forward to do a double-blind placebo-controlled. Now, it was a very small sampled studies, and that is obviously always a problem with human work, is this was like 15 or 17 people. So not powered enough to really make any kind of firm conclusions, but interesting in the sense that at least it was done in a proper crossover design, where they got placebo at one point, they got nabilone at one point, it was switched. They didn't know which one they were on. Because they're taking it right before bed, maybe that will remove some of the subjective bias. Again, you can't totally remove it, but if someone's taking it within an hour or so of going to sleep, they may not feel the high the same way. But even under the double-blinded conditions, they found a very effective suppression of the nightmares and the re-experiencing. And then they also, at the same time, found this increase in quality of life measures, which tracked with the fact that they were probably sleeping better. I don't think they actually reported any change or even looked at maybe the overall PTSD score. They only reported or really focused on the nightmare component of it, because that was the primary outcome of the study. So I thought that was interesting because if you look at the anecdotal data in PTSD, that's where a lot of it is focused on, is using it as kind of, I wouldn't maybe call it a sleep aid because it's really more of a modulator of the dream state. And I think this is-

Andrew Huberman:
Right. Presumably because it's reducing the amount of rapid eye movement sleep you're getting, which most people will probably hear and interpret as bad. But REM deprivation is actually one treatment for depression.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
So there are certain case conditions where dreaming and REM is not advantageous, and you're describing one.

Dr. Matthew Hill:
I mean, and depression and PTSD are both two disorders that are characterized by changes in REM. Like, they have earlier onset to REM, so they go into REM faster. They tend to have some altered architecture of the REM component of their sleep. So in those states, maybe suppressing REM isn't actually a bad thing.

Andrew Huberman:
Right.

Dr. Matthew Hill:
At least, certainly for PTSD, I would imagine in terms of the context of the nightmares, that's providing some benefit. Whether or not it globally is changing the disease severity or improving the disease, I don't think we really have any evidence to say. But again, I can understand the ... the desire for people to self-medicate, let's say, by using this as an approach to try and reduce that component of their sleep so that they sleep better, they feel better. Maybe down the road, it would help the prognosis of the disease long term if it's not sensitizing the same way. But I don't think we have any strong data that we can leverage in that capacity to be able to say it. But to me, it's one of the more interesting areas. I think anxiety disorders in general, there's definitely some potential. So as I'd mentioned earlier, the FAAH inhibitor that elevates anandamide levels. So Johnson & Johnson did do a trial on social anxiety disorder. It's published, I think, from a few years ago, in '21 or something, I can pull up the reference for that, where they did find some benefit. It wasn't huge, and some of this had to do with the design of the study because they kind of underdosed the patients a bit. And so not everyone actually showed the elevation in anandamide when they went back and looked. But when they actually isolated the group of people that had higher anandamide, in that proportion of the patients, they did see some symptom improvement. So it did support it. And this is very similar, for us, this is a big thing because all of the work that we focused on is looking at how stress and stress hormones regulate largely anandamide signaling. And one of the main things that we've demonstrated that's been replicated relatively well over the years is that stress exposure can actually cause a rapid loss of anandamide signaling, and it's that loss of anandamide signaling that seems to facilitate some synaptic strengthening in the amygdala and promote activity in areas that are involved in these anxiety circuits.

Andrew Huberman:
Mm.

Dr. Matthew Hill:
And so, the thought has always been, well, if anandamide, it's that job as its kind of tonic housekeeper, keeping things in that homeostatic range, let's say we're talking about explicitly an anxiety circuit. There's individual variation that exists in humans across everything. So one of our predictions has been maybe people who are on the high end of the anxiety spectrum might be on the low end of their tonic anandamide signaling spectrum. And we've gotten a little bit of support from that from animal work where we've screened animals based on anxiety and looked at endocannabinoid levels in the amygdala and found lower anandamide.

Andrew Huberman:
That's extremely interesting because it squares with my, again, non-laboratory observation that a lot of people use cannabis to deal with their anxiety.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
Right? So what you're saying is that there's a range of, let's just say baseline circuit activation within the amygdala and related structures in mice and humans, presumably in other animals also. If people take a compound that adjusts the homeostatic level of what's considered low, moderate, and high activation of those circuits that include the amygdala, then perhaps they're bringing their anxiety into range-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... in a way that perhaps is different than with alcohol, which is more acute. People have a couple drinks, they'll feel relaxed, but then there's this phenomenon of hangxiety-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... the next day, feeling a little anxious when they're not drinking. Whereas, it's interesting that many people who use cannabis for this purpose are not using it all day long. They are perfectly able to wait until the nighttime or evening.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And of course, people can wait for happy hour for a drink as well.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
But it's far and away different than the way we envision something like alcohol use disorder, where somebody discovers that alcohol really helps with their anxiety, and then they're drinking maybe one at lunch, maybe a couple at dinner, and then in the evening to fall asleep at night.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
I'm describing extremes here, but I find your hypothesis to square really well with the real-world observations.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And it's an interesting one.

Dr. Matthew Hill:
There is some evidence to actually support. So my buddy Sachin Patel, who's at Northwestern now, but he was at Vanderbilt when he did this study. They basically played with these drugs that you can use to prevent endocannabinoid synthesis. So you can create a state of impaired endocannabinoid function. And-

Andrew Huberman:
In humans

Dr. Matthew Hill:
... and they did this in rodents.

Andrew Huberman:
Okay.

Dr. Matthew Hill:
So this was done in mice. One of the questions was is, so A, does reductions in endocannabinoid function produce states of anxiety? And they did demonstrate that. So you could deplete endocannabinoid levels, and you got the emergence of an anxiety state. So then you could give drugs that would boost the endocannabinoids to normalize this.

Andrew Huberman:
Mm-hmm.

Dr. Matthew Hill:
So again, it kind of fit with the idea. But then they did one key study where then they gave THC and saw could THC fill in the gap. And they found that like boosting endocannabinoids, giving THC on a background of low endocannabinoids was able to reverse that anxiety phenotype and bring it back into more of the normal range. So again, maybe for some people, again, this is theoretical, so I don't know how much of a spectrum there is, if there are people that are at this low end. But certainly, I think from the animal literature, there's some foundation for making a theory that's similar to what you're saying, which is maybe some people are trying to fill in a gap of something that's deficient in them, and therefore, that can help them feel less anxious. And that, again, may be very different than someone who is very anxious for different reasons or has normal endocannabinoid function, or something else might be at play there. So-

Andrew Huberman:
Very interesting

Dr. Matthew Hill:
... yeah, I think it could explain some of the heterogeneity that exists out there for sure, yeah.

Andrew Huberman:
So perhaps genetic differences in baseline levels of anxiety perhaps map to endogenous levels of anandamide and might predict propensity for THC use.

Dr. Matthew Hill:
Yeah. We have definitely found in human populations through work I've done with a lot of clinical collaborators and others, we look at endocannabinoids in the blood, and it's not in the brain, but they are lipids that can move pretty easily back and forth. And we have found relationships between peripheral endocannabinoid levels and mood states, both anxiety and kind of depressive measures, which does somewhat relate to the possibility that this could be real. We don't know. It's been hard, obviously, for various reasons, to really track this. But we've never looked at an anxiety disorder population. We've done some work with post-traumatic stress disorder populations. There's been work in depression populations that have found some relationships that are pretty similar. So it's certainly a possibility. But again, this is all our theory at this point. So we'll see as things move forward if they pan out. But yeah.

Andrew Huberman:
Fantastic. And I really appreciate that you're able to share some of what your laboratory is working directly on now and looking into the future. And I want to thank you for what has been an incredibly clear, precise, and in many cases actionable, whether or not it leads to a yes or a no, actionable information here, because cannabis and CBD, as you pointed out, are kind of everywhere around us.

Dr. Matthew Hill:
Yeah.

Andrew Huberman:
And people are making decisions about cannabis and CBD. And I also want to thank you because what initially started off as a bit of a confrontation online- ... which I alluded to in the introduction that I gave, has now evolved into a collaboration that I'm certain, based on the exquisitely clear and generous information that you've provided, has led to better education, more clarity, and therefore better informed choices for all the people listening and watching. So I really truly appreciate you coming out here, sitting down with me, discussing these issues, clarifying points that were unclear before, and also pointing to the fact that this is a complex system-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... a complex biology. There are a lot of things about psychosis, about negative effects, about potential positive uses of cannabis that just are not yet clear, and thanks to excellent researchers like you, are likely going to be clarified in the years to come. So thank you ever so much for your time, for your research, and for your attention to the public health education effort-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... around cannabis. Thank you.

Dr. Matthew Hill:
Thanks, and I think it's also important, I think it's good, as you had said, that for people to see that scientists can have disagreements.

Andrew Huberman:
Absolutely.

Dr. Matthew Hill:
I think it's important. I think it's good that you provided me an opportunity to correct the record and did so in a very appropriate manner. I think this was a great discussion for people to understand different perspectives. Also good to highlight where it was that I had had issue with your previous podcast, and I think the discussions that came out of that were for the better. So that's all the best. And hopefully, if there's other contentious issues that happen down the road, similar things move forward, and you chat with people in that area as well. Yeah.

Andrew Huberman:
Yeah, if somebody who is expert in a particular area takes issue with something specific and can substantiate it with something that can foster better understanding, without fail, I'll reach out to them. Now, how quickly we're able to get them here, et cetera, is always an issue. Sometimes we can put an addendum to a podcast. Nowadays that's easier using what's called dynamic insertion, where we can go back and actually make a correction.

Dr. Matthew Hill:
Mm-hmm.

Andrew Huberman:
But listen, the best situation is always when this podcast can mimic the real world of research science as you and I both know it to exist, where if we had been in a meeting and you presented data, I presented data, and we disagreed, what we would probably do would be to head, well, traditionally it would be to the bar, but we'd grab a cup-

Dr. Matthew Hill:
Yeah

Andrew Huberman:
... of coffee or go for a walk, and we would talk about it, hash it out, and then potentially bring it up again at the next meeting. So in some sense, what we've done here over the last month or so, and certainly during today's podcast, is to do something to that effect. So yeah.

Dr. Matthew Hill:
And I think it's really good for people in the public to know this is how science progresses. Someone says something, someone disagrees with it. You get an opportunity to clarify things, and I think that that's really good just to move things forward. So I think that was a good process that we've gone through.

Andrew Huberman:
Yeah. Likewise, and it's certainly within the spirit of the podcast. In no way, shape, or form do I purport to get everything right, and where I've made mistakes, I really strive to correct them. And listen, it's been a real honor and privilege to have you out here. Thanks for coming all the way from Canada, and I do hope to have you back again as the research evolves and we can learn more about these topics and more. So thank you so much, Matt. Appreciate you.

Dr. Matthew Hill:
Great.

Andrew Huberman:
Thank you for joining me for today's discussion about cannabis with Dr. Matthew Hill. I hope you found the discussion to be as informative as I did. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel. Please also subscribe to the podcast on both Spotify and Apple. That's a terrific zero-cost way to support us. And on both Spotify and Apple, you can leave us up to a five-star review. Please also check out the sponsors that I mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have questions for me or comments about the podcast or topics or guests you'd like me to consider for the Huberman Lab Podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled "Protocols: An Operating Manual for the Human Body." This is a book that I've been working on for more than five years, and that's based on more than 30 years of research and experience. And it covers protocols for everything from sleep to exercise to stress control, protocols related to focus and motivation, and of course, I provide the scientific substantiation for the protocols that are included. The book is now available by presale at protocolsbook.com. There you can find links to various vendors. You can pick the one that you like best. Again, the book is called "Protocols: An Operating Manual for the Human Body." If you're not already following me on social media, I am hubermanlab on all social media channels. So that's Instagram, X, formerly known as Twitter, Threads, LinkedIn, and Facebook. And on all those platforms, I discuss science and science-related tools, some of which overlap with the contents of the Huberman Lab Podcast, but much of which is distinct from the contents of the Huberman Lab Podcast. Again, that's hubermanlab on all social media channels. If you haven't already subscribed to our Neural Network Newsletter, our Neural Network Newsletter is a zero-cost monthly newsletter that includes podcast summaries as well as protocols in the form of brief PDFs of one to three pages where I spell out the specific dos and in some cases do nots, but mostly dos related to things like how to optimize your sleep, how to regulate your dopamine levels. There's a protocol for neuroplasticity and learning, as well as protocols for fitness, which we call the foundational fitness protocol, includes everything, sets, reps, cardiovascular training. Again, all available completely zero cost. You simply go to hubermanlab.com, go to the Menu tab, scroll down to Newsletter, and provide us your email. But I should point out, we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Matthew Hill. And last but certainly not least, thank you for your interest in science.