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

1. 0:00 – 7:16

   Sponsors: Eight Sleep, LMNT & BetterHelp

   1. AHAndrew Huberman0:00

      (uptempo music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Matthew Hill. Dr. Matthew Hill is a professor of cell biology and anatomy at the University of Calgary. His laboratory studies cannabis and its effects on stress, its effects on feeding, and its effects on the behavioral impacts of cannabis exposure at different stages of development. The origin of today's podcast episode is a bit unique, so I'd like to share a little bit of that background with you. Previously, I did a solo episode of the Huberman Lab Podcast about cannabis, the biology of cannabis, some of its medical applications and uses, as well as some of its potential harms. That episode came out several years ago now and remains a very popular episode. It's had millions of views and millions of listens. Several months ago, we posted a clip of that episode to X, formerly known as Twitter, and Dr. Matthew Hill responded to that clip on X with criticism about the specific points made within that clip, most notably my discussion of the data that cannabis use can, in some individuals, cause psychosis. He also took issue with some of the specific points I made in that clip related to potential differences in the biology of the effects of different strains of cannabis, most notably indica versus sativa strains, and a few other points as well. Now, as somebody who's been in the field of science for several decades now, I'm very familiar with the fact that every field, every single field within science, has debates within it, controversies, and sometimes outright battles. And to me, that's part of what makes science interesting. It's an evolving process. It's something for which we should all be very curious to try and understand what we know, what we don't know, and try and get to the real answers. So right off the bat, on X, I invited Dr. Hill onto the podcast, and he accepted the invitation. So today's episode is really a unique one in that, first of all, we cover an enormous amount of biology and clinical data as it relates to cannabis, meaning today's discussion is not a debate. It is really an up-to-date discussion about how cannabis works. So we talk about THC versus CBD. We address the question of whether or not indicas versus sativas have different biological and subjective effects or not. We, of course, talk about the potential correlation, maybe even causation, between cannabis use and psychosis. I think you'll find that discussion very interesting. And we talk about how cannabis relates to hunger, to memory, to anxiety, and to the treatment of anxiety. I'm certain that given the widespread use of cannabis nowadays, that you'll find the discussion to be both an informative and potentially useful one that could help guide decisions as to whether or not you or others should or should not use or avoid cannabis, as well as one that can simply inform about this very interesting compound. And of course, you'll learn a lot of neuroscience and biology along the way. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep-tracking capacity. Now, I've spoken many times before on this podcast about the critical need to get sleep, both enough sleep and enough quality sleep. Now, one of the key things to getting a great night's sleep is that your body temperature actually has to drop by about one to three degrees in order for you to fall and stay deeply asleep. And to wake up feeling refreshed, your body temperature actually has to increase by about one to three degrees. One of the best ways to ensure all of that happens is to control the temperature of your sleeping environment. And with Eight Sleep, it's very easy to do that. You program the temperature that you want at the beginning, middle, and the end of the night, and that's the temperature that you're going to sleep at, and it will track your sleep. It tells you how much slow-wave sleep you're getting, how much rapid eye movement sleep you're getting, which is critical, and all of that also helps you dial in the exact parameters you need in order to get the best possible night's sleep for you. I've been sleeping on an Eight Sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better. Eight Sleep recently launched their newest generation pod cover, the Pod 4 Ultra. The Pod 4 Ultra cover has improved cooling and heating capacity, higher fidelity sleep-tracking technology, and the Pod 4 cover has snoring detection that will automatically lift your head a few degrees to improve airflow and stop your snoring. If you'd like to try an Eight Sleep mattress cover, you can go to EightSleep.com/Huberman to save $350 off their Pod 4 Ultra. Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU, and Australia. Again, that's EightSleep.com/Huberman. Today's episode is also brought to us by LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes sodium, magnesium, and potassium in the correct ratios, but no sugar. Now, I and others on the podcast have talked a lot about the critical importance of hydration for proper brain and bodily function. Research shows that even a slight degree of dehydration can really diminish cognitive and physical performance. It's also important that you get adequate electrolytes in order for your body and brain to function at their best. The electrolytes sodium, magnesium, and potassium are critical for the functioning of all the cells in your body, especially your neurons, or nerve cells. To make sure that I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of LMNT in about 16 to 32 ounces of water when I wake up in the morning, and I drink that basically first thing in the morning. I also drink LMNT dissolved in water during any kind of physical exercise I'm doing, especially on hot days if I'm sweating a lot and losing water and electrolytes. If you'd like to try LMNT, you can go to DrinkLMNT.com/Huberman, spelled Drink L-M-N-T dot com slash Huberman, to claim a free LMNT sample pack with the purchase of any LMNT drink mix. Again, that's DrinkLMNT.com/Huberman to claim a free sample pack.Today's episode is also brought to us by BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. There are essentially three things that make up great therapy. First of all, great therapy consists of having good rapport with somebody that you can really trust and talk to about the issues that you're dealing with. Second of all, that therapist should provide support in the form of emotional support or directed guidance. And third, expert therapy should provide useful insights, insights that allow you to better understand not just your emotional life and your relationship life but, of course, also your relationship to yourself and to career goals and school goals, meaning excellent therapy should also inspire positive action. BetterHelp makes it very easy for you to find an expert therapist with whom you really resonate with and that can provide the benefits that I just described. Also, because BetterHelp therapy is done entirely online, it's very time-efficient and it's easy to fit into a busy schedule because it involves no commuting to a therapist's office, finding a parking spot, or sitting in a waiting room. If you'd like to try BetterHelp, you can go to betterhelp.com/huberman to get 10% off your first month. Again, that's betterhelp.com/huberman. And now for my discussion with Dr.

2. 7:16 – 12:08

   Cannabis, THC, Cannabidiol (CBD), Terpenes

   1. AHAndrew Huberman7:16

      Matthew Hill. Dr. Matt Hill, welcome.

   2. MHDr. Matthew Hill7:19

      Thanks for having me.

   3. AHAndrew Huberman7:20

      Delighted to have you here because you're an expert in the biology of cannabis, a topic that many, many people are curious about for a variety of reasons. So just to kick things off, maybe we can get people up to speed on what cannabis is, a little bit about how it works in the brain and body to produce the various effects that it produces, and how some of that comes to be, and then we can dig into some of the nuance. I have a lot of questions about different types, if you will, of cannabis-

   4. MHDr. Matthew Hill7:51

      Mm-hmm.

   5. AHAndrew Huberman7:51

      ... um, the relationship to mental health, potentially to mental illness. We're going to drill into all of that. So just to kick things off, what is cannabis?

   6. MHDr. Matthew Hill8:00

      I mean, cannabis is a plant that has been around for some time. It's kind of got, like, a very rich history of use around the world for different cultures, (sighs) um, for both kind of medicinal and spiritual and recreational purposes over several centuries. Um, the plant has kind of become... I mean, in the West, it really wasn't a thing mainstream-wise until about the '60s, uh, and then it became kind of introduced as, like, a drug of choice that a lot of people started using during the rise of the hippie era, and I think that was a lot of the time that cannabis got popularized. Um, and then I'd say more recently, cannabis has, you know, into the '90s and on, has become kind of a very heavily used drug by a large swath of people ranging from teenagers on up. Uh, in terms of what it is inside it, I mean, it's a plant with a lot of very complex chemistry and biology behind it, so there's a lot of molecules that it carries in it. Uh, we call these cannabinoids, and they come in a lot of different flavors, but the main one that's the most important one when we talk about cannabis and what drives the kind of intoxicating and what I would refer to as psychoactive effects of cannabis is, uh, delta-9 tetrahydrocannabinol, or what we call THC, um, and that really is what dictates, you know, the psychoactive and intoxicating properties of the plant. And so the amount of THC that is within the cannabis plant will influence the, you know, how high a person's going to get when they consume it. Uh, there are probably 70 to 100 and some odd other cannabinoids that are within cannabis. Most of them are at pretty trace levels, like, and they vary from different types to cannabis from one another, uh, but the other one that's had a lot of attention is cannabidiol, or what we call CBD. Uh, CBD is... structurally looks pretty similar to THC, but doesn't behave anything like THC. It's not intoxicating at all, um. I'm not sure, I would probably say it's not psychoactive in the sense that people can't tell if they're on it or not, but I would... Some people still say it's psychoactive because people claim, you know, it can affect anxiety state or mood state or other things, so in that context, maybe psychoactive is still somewhat appropriate of a word to use. Um, and then there's a whole bunch of other things like cannabinol, cannabigerol, and these other minor cannabinoids, most of which we really don't understand any of the biology of. We don't know what they're doing, um, they may influence some of the effects of THC, they may not, um, but they're there and they vary in their composition from, you know, different flavor of different cannabis to different flavor. Uh, and then there's those other things called terpenes-

   7. AHAndrew Huberman10:30

      Mm-hmm.

   8. MHDr. Matthew Hill10:30

      ... which are kind of highly volatile compounds, but they're not specific to cannabis. They're found in tons of other plants. So this is... a lot of which seems to contribute at least to some of the smell and the flavors of cannabis, so these are things like limonene which, uh, you know, gives some cannabis kind of a citrusy odor or flavor to it, um, pinene, which gives things more of, like, a earthy tree kind of smell, uh, beta-caryophyllene, myrcene, and these terpenes are also... some of which do have known biological activity, some don't, and they vary quite heavily across different kinds of cannabis as well. And again, there's some thought that they may be influencing some of the psychoactive or intoxicating properties of cannabis, but the reality is we really don't know a lot about them at this point. There's kind of some emerging work that's starting to come out now that kind of plays with, you know, giving someone THC and adding in one other terpene or one other minor cannabinoid and seeing how it influences things, and so you can imagine with the plethora of molecules that exist in cannabis, doing this in a piecewise manner could take decades to kind of really get to a point where we understand all the interactive, um, components of cannabis. But people tend to refer to this as like an entourage effect. That's kind of a phrase that gets used quite widely in the cannabis world, and the idea behind that is that if you took pure THC, um, and so there are some, like, distillate pens and things that exist out there now in the product market which are basically isolated THC with trace levels of anything of other stuff, would be very different than if you had THC in combination with some of these other molecules and how they might influence how THC itself is working or not, so.

3. 12:08 – 16:55

   Psychoactive Effects, Cannabis “High”; Time Perception

   1. AHAndrew Huberman12:08

      Mm-hmm.Fascinating plant. You mentioned the psychoactive effects. Um, some people listening to this and watching this presumably have experienced those psychoactive effects, others perhaps have not. How could we describe for both groups, um, what the quote unquote psychoactive effects are? You mentioned, um, the higher the concentration of THC, the quote unquote higher someone will get, right?

   2. MHDr. Matthew Hill12:35

      Yeah.

   3. AHAndrew Huberman12:35

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

   4. MHDr. Matthew Hill12:49

      So, I mean, the way that people would usually describe the- the intoxicating effects of cannabis is, uh, they would, they... I mean, people often refer to it as there being some euphoria or some positive mood, not on the same order as what people would describe with, say, cocaine or some other stimulants, but there certainly is some kind of positive aspect. I mean, if there wasn't, people wouldn't be using it if they didn't feel positive about it afterwards. Uh, there can be, you know, other aspects, uh, in terms of changes in feeding behavior, people might find things funnier than they found things, it might change the way they perceive va- various environmental stimuli. Um, but it can also, for some people, create a bit of a dissociative state to some degree, where people might feel a little bit out of body. So it's kind of a, a complicated intoxicating state to describe, I would say-

   5. AHAndrew Huberman13:37

      Mm-hmm.

   6. MHDr. Matthew Hill13:37

      ... because usually if someone's referring to something like a stimulant, they're just like, "Oh, people feel like they're God." They're like, you know, jacked up.

   7. AHAndrew Huberman13:43

      Possibility everywhere. (laughs)

   8. MHDr. Matthew Hill13:45

      Yeah, exactly. Like, they're very happy and they're kind of jacked up. And I think with cannabis, the way people would describe it would be very different. It's like kind of an introspective state. You might be more aware of your bodily feelings and, um, states that are going on inside of you, your kind of internal state, but you also have like a different perspective on external stimuli, you might process information a bit differently, focus on things a bit differently. So it's kind of a, a complicated state to describe, I would say. Usually when people are assessing if someone's intoxicated, like, um, the kind of lab work where people get someone high, they just kind of use a, what we call a visual analog scale, which is like a one to a hundred or something, or zero to a hundred and say, "Do you feel high? Do you enjoy this? Would you say you feel euphoric? Is your mood elevated?" So they're kind of scaling, things like that. So I think that's more typically in a lab setting how you would define if someone's high or not from it.

   9. AHAndrew Huberman14:35

      Mm-hmm.

   10. MHDr. Matthew Hill14:35

       And this is why when people do studies with something like a placebo cannabis or a very low THC cannabis, you'll see kind of a scaling. So, um, even if you give someone a placebo cannabis, if they think that they're getting cannabis, a lot of people still respond by saying they feel a bit high.

   11. AHAndrew Huberman14:49

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

   12. MHDr. Matthew Hill14:54

       I'm not actually certain if you are allowed to have someone in a drug study if they've never done something before. I think-

   13. AHAndrew Huberman15:01

       Hm.

   14. MHDr. Matthew Hill15:01

       ... they have to have had some previous experience with a drug, uh, to be enrolled.

   15. AHAndrew Huberman15:06

       Mm-hmm. And they pay you, so now-

   16. MHDr. Matthew Hill15:06

       Yeah. (laughs)

   17. AHAndrew Huberman15:06

       ... pot smokers everywhere are running to look at some-

   18. MHDr. Matthew Hill15:08

       Yeah, but I think, yeah, I don't think you can use drug naive people. I mean, I don't run human clinical lab studies, so I can't explicitly say it, but that's my understanding is that-

   19. AHAndrew Huberman15:16

       Mm-hmm.

   20. MHDr. Matthew Hill15:16

       ... someone has to have had even limited like, you know, not much, but at least once or twice they have to have experienced the drug before. So I don't know if you would take someone who was completely blind, 'cause I don't know how they would replicate that state-

   21. AHAndrew Huberman15:28

       Mm-hmm. Interesting.

   22. MHDr. Matthew Hill15:29

       ... um, if they're not expecting it.

   23. AHAndrew Huberman15:31

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

   24. MHDr. Matthew Hill15:45

       Yeah.

   25. AHAndrew Huberman15:45

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

   26. MHDr. Matthew Hill15:55

       I wouldn't say it's well worked out. There definitely seems to be some like temporal dilation, like you're saying, where people think things have... You know, someone will be high and someone will ask them, "How long do you think time has passed?" They would report usually longer periods of time have passed than actually have. I feel like there is some older work I could dig up to see if I could find that is either in like, it might even be in pigeons, uh, but it might be in rodents that's looking at like temporal ordering and they give animals cannabinoids and that's kind of a cleaner way of seeing, 'cause they are very good at learning, like, "If I wait 10 minutes and then I engage in a behavior, I get a reward." And so you can really train animals to have this ordinal timing where they kind of know distinct periods of time, and if they give them cannabinoids, they respond differently. So it, in that context, it does still seem to produce some state where there's a, an altered perception of time passing.

   27. AHAndrew Huberman16:43

       Mm-hmm.

   28. MHDr. Matthew Hill16:43

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

   29. AHAndrew Huberman16:53

       Mm-hmm.

   30. MHDr. Matthew Hill16:53

       I can't think of anything modern

4. 16:55 – 26:19

   Cannabis & Brain, CB1 Receptor, Endocannabinoids

   1. MHDr. Matthew Hill16:55

      where people have actually looked at this.

   2. AHAndrew Huberman16:56

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

   3. MHDr. Matthew Hill17:06

      Mm-hmm.

   4. AHAndrew Huberman17:07

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

   5. MHDr. Matthew Hill17:31

      Yeah.

   6. AHAndrew Huberman17:31

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

   7. MHDr. Matthew Hill17:39

      Yeah, I think we almost need to take a step back actually to talk about how cannabis works in the brain-

   8. AHAndrew Huberman17:43

      Mm-hmm.

   9. MHDr. Matthew Hill17:43

      ... before we kind of go into that.

   10. AHAndrew Huberman17:44

       Great.

   11. MHDr. Matthew Hill17:45

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

   12. AHAndrew Huberman17:55

       CB1.

   13. MHDr. Matthew Hill17:56

       Yeah, CB1 is the shorthand for it.

   14. AHAndrew Huberman17:58

       Mm-hmm.

   15. MHDr. Matthew Hill17:58

       And I think, um, you know, as people tend to create analogies to describe what receptors are, for those of you who don't know, it's most people use like a lock and key analogy that like a receptor would be a protein that sits on a cell and a molecule that binds to it like THC is the key that fits in that lock. When it activates it, it triggers some biological process in the cell, in this case a neuron, that changes its activity in some capacity. Um, and so THC acts on these CB1 receptors, which, um, are very widely expressed. In fact, outside of like...... kind of ion channels that are expressed in the brain. The CB1 is, I think, one of the most, if not the most widely expressed receptor in the brain. It's everywhere.

   16. AHAndrew Huberman18:35

       Wow.

   17. MHDr. Matthew Hill18:35

       So it's really important. Um, and I think as, as kind of you had alluded to previously, uh, it didn't, it doesn't exist in the, you know, this didn't evolve in humans in the hopes that one day humans would find cannabis. This is just-

   18. AHAndrew Huberman18:47

       Although cannabis users everywhere will use that argument. (laughs)

   19. MHDr. Matthew Hill18:50

       Yeah. Um, I know, people love to leverage, uh, things if it's a plant, it's, you know, it's natural and safe. And there's obviously issues we'll talk about with that. Um, but I mean, really this is just biological redundancy. I mean, you know, nature only has so many ways to create something and so there's gonna be things that end up overlapping in the way that they function. And so the receptor that's in the brain and throughout the body, the CB1, and there is also a CB2 receptor, it's not really expressed in the brain. It's in some of the immune cells in the brain and maybe, maybe some limited distribution in, um, actual brain cell neurons.

   20. AHAndrew Huberman19:22

       Hm. Where, where in the body is it expressed?

   21. MHDr. Matthew Hill19:24

       It's mostly immune cells. So you'll see CB2s mostly on like macrophages or other kind of immune cells.

   22. AHAndrew Huberman19:29

       Cells that gobble up debris.

   23. MHDr. Matthew Hill19:31

       Yeah. And that basically, you know, regulate inflammatory processes. And so the main role of CB2 seems to be much more about like regulating inflammation, um, so that's kind of a separate role. That can certainly impact the brain in different ways. But, uh, when we talk about the effects on the central nervous system and the brain and behavior, we're talking almost entirely about CB1. And so both the CB1 and CB2 receptors, like I said, don't exist because nature was like, "Humans are gonna find cannabis. They'll, this will all work together now." So there are molecules our body produces, which we call endocannabinoids, um, and they are kind of funny little molecules 'cause they don't really behave, like certainly in the brain, they don't behave like a normal neurotransmitter. So I mean, I assume most people who listen to your podcast are relatively adept with the basic idea of how neurons work. So you have neuron A, let's call it the presynaptic neuron because you have that gap between the two cells where they communicate called the synapse. So neuron A releases a transmitter, and it can be something that excites the neighboring cell, neuron B, or it can inhibit it. Um, and so the way that we always kind of talk about neurotransmission in the brain is neuron A releases a chemical that crosses the synapse, acts on neuron B, and it can either, you know, jack that neuron's activity up or it can scale it down, and that affects, you know, brain-wide patterns of activity. Uh, and we call that anterograde because it moves from neuron A to neuron B, which is kind of the general flow of things, um, and how we usually think about it. So endocannabinoids are kind of this, you know, little bit of an oddity in the sense that they could do the reverse. And so endocannabinoids are actually made in neuron B on the postsynaptic side, and then they go backwards and act on neuron A to regulate how much transmitter is released. And so in many ways this is like, I kinda liken it to a thermostat model for the most part. Certainly if we're talking about something like excitability. So if neuron A is dumping out something that excites neuron B, like glutamate, which is an excitatory neurotransmitter, as neuron B gets too excited, it's gonna start releasing endocannabinoids to go back and tell neuron A to stop driving it, so-

   24. AHAndrew Huberman21:32

       So sort of a homeostatic scale-

   25. MHDr. Matthew Hill21:34

       Yeah.

   26. AHAndrew Huberman21:34

       ... and trying to maintain a middle range.

   27. MHDr. Matthew Hill21:35

       Yeah, I mean, at the end of the day, no matter how you discuss it and what system you discuss it, I think the majority of people in the cannabinoid field would agree that the primary physiological role of endocannabinoids is to maintain homeostasis. That's what they do. They keep everything in its happy place, let's say. So like, uh-

   28. AHAndrew Huberman21:52

       And that's probably why the CB1 receptor is so widely distributed-

   29. MHDr. Matthew Hill21:55

       Exactly.

   30. AHAndrew Huberman21:55

       ... is that neurons can excite or inhibit each other, um, that is raise or reduce the amount of electrical activity in the, let's say, nearby neuron 'cause-
5. 26:19 – 33:46

   Endocannabinoids Types: Anandamide, 2-AG

   1. MHDr. Matthew Hill26:19

      But even within the endocannabinoids, um, I mean there's, there's two primary endocannabinoids. And again, this is one of the weird things about how endocannabinoids work because if you talk about things like serotonin or dopamine, you have a single molecule that gets released in the typical anterograde way and it diversifies at the level of a receptor. So serotonin has like, I don't know, like 15 receptors or 20 or something now. Uh, dopamine has at least five. Uh, and so the different actions that serotonin or dopamine will have is all driven by the diversification of the receptors. It's one molecule. Whereas cannabinoids are the reverse. Not only do they work backwards across the synapse and work in this retrograde fashion, but really you have one receptor that is regulated by two molecules. So the diversification happens more at the level of the molecule than at the receptor, which is again, very unique. And the two molecules that we know are kind of the bonafide endocannabinoids, there could be more, um, they're called anandamide, which, um, is actually a kind of a funny name because it comes from the Sanskrit word anand for bliss. And so, um, Rafi Mechoulam, who was in Israel when he discovered the molecule, you know, 30 odd years ago, uh, wanted it to reflect inner bliss (laughs) . And so he named it anandamide. So it's like inner bliss with an amide bond is kind of the joke he had for it. And so-

   2. AHAndrew Huberman27:36

      He discovered, um, anandamide and decided to call it bliss because he had familiarity with cannabis or because he-

   3. MHDr. Matthew Hill27:42

      Yeah.

   4. AHAndrew Huberman27:42

      ...he took anandamide as a, as a direct experience?

   5. MHDr. Matthew Hill27:45

      No, no, I mean-

   6. AHAndrew Huberman27:45

      Because it takes a lot for a scientist to discover a molecule, but then for a scientist to discover a molecule and then name it bliss-

   7. MHDr. Matthew Hill27:51

      Yeah.

   8. AHAndrew Huberman27:51

      ...for a particular reason, you have to speculate-

   9. MHDr. Matthew Hill27:54

      (laughs) Well-

   10. AHAndrew Huberman27:54

       ...that they, they had some familiarity with-

   11. MHDr. Matthew Hill27:56

       I mean-

   12. AHAndrew Huberman27:56

       ...with the compound.

   13. MHDr. Matthew Hill27:56

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

   14. AHAndrew Huberman28:22

       Well, now that, that-

   15. MHDr. Matthew Hill28:23

       (laughs)

   16. AHAndrew Huberman28:23

       ...now that, um, potential myth is definitely gonna propagate.

   17. MHDr. Matthew Hill28:27

       Yeah.

   18. AHAndrew Huberman28:27

       Um, interesting.

   19. MHDr. Matthew Hill28:28

       But yeah, so he, he had, he'd been in the field for a while, and so he had studied cannabis on that side. And then in 1990 his lab isolated anandamide as being the first molecule that activated the receptor endogenously. And so, um, it was kind of, uh, yeah, I think it was a little tongue in cheek that he named it the way he did. A few years later, the second molecule, which is just called 2-arachidonylglycerol or what we call 2-AG that was discovered kind of in tandem both again by Mechoulam but also by a Japanese group. Um, and so we understand these two molecules don't do the same thing. Like they are a bit different.

   20. AHAndrew Huberman29:00

       Mm-hmm.

   21. MHDr. Matthew Hill29:00

       So the way anandamide binds to the receptor is it's what we would call a high affinity but low efficacy, um, agonist or molecule at least. And what I mean by that is very low levels of anandamide are required to actually bind to the receptor, but once it binds its ability to stimulate a biological response in that neuron is, kind of caps out pretty fast. So it doesn't have like a sledgehammer effect, whereas 2-AG seems to require a bit more concentration in the synapse to be able to bind to the receptor. So it has a lower affinity for the receptor, but once it binds to the receptor, it's like pretty heavy duty. So it evokes a very robust, um, intracellular signaling response. And so why we have two endocannabinoids, we're not totally sure. Some of us have theories. I'm of the camp that I think they may play somewhat differential roles either based on the synapse or the circuit that they're working in, or this idea that maybe anandamide might be more of a tonic molecule. And what I mean by that is, we'll say it's like a stage setter. So like anandamide might just be kind of made by neurons on an ongoing basis and just released, and its job may be to kind of keep the steady state of a brain circuit in a desired range so that under resting conditions it's not too active or too quiet. Um-

   22. AHAndrew Huberman30:16

       Mm-hmm. Your thermostat analogy is perfect here.

   23. MHDr. Matthew Hill30:18

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

   24. AHAndrew Huberman30:22

       Mm-hmm.

   25. MHDr. Matthew Hill30:22

       Whereas 2-AG is like let's say the pinch hitter (laughs) who gets brought in to do the heavy lifting. And so 2-AG during a situation like let's say something like even like a seizure as an extreme example where you have a huge amount of neural activity, those neurons that are getting heavily activated during, you know, massive amounts of neural activity start dumping out huge amounts of 2-AG and that acts as the, "Okay, we really need to turn off this circuit very quickly in this situation." And in most of these forms of like synaptic plasticity, like I was saying earlier, where you need to either strengthen or weaken a synapse in response to a change in the environment or in response to an experience or something that's going on, most of that is driven by 2-AG signaling. And so, um, you know, all these forms of like turning things up or down in an, in a kind of rapid and on-demand manner, that's mostly 2-AG. So most people who study like neurophysiology and like recorded activity in neurons and look at endocannabinoids, they're almost entirely talking about 2-AG when they play with stuff. Um, so-Yeah, that's kind of one of the ways we do it. We say that anandamide might be more tonic and 2-AG might be more phasic.

   26. AHAndrew Huberman31:30

       Mm-hmm.

   27. MHDr. Matthew Hill31:30

       And like brought online when needed, but doesn't do a lot. There is some evidence that 2-AG may also have a role to regulate some circuits under kind of resting conditions as well and there certainly are some situations where anandamide might get brought into play, um, to affect plasticity but as kind of like an umbrella idea of how we look at it-

   28. AHAndrew Huberman31:48

       Mm-hmm.

   29. MHDr. Matthew Hill31:48

       ... that's often how we divide those two up. So we kinda have these two molecules, they end of the day do the same thing, they're regulating neurotransmitter release, um, through retrograde signaling, but what stimulation brings them online or what drives their activity may differentiate and we don't really understand all the details behind that outside of the fact that we very clearly know 2-AG is activity dependent, so as that neuron becomes more active it's gonna make 2-AG to regulate its inputs.

   30. AHAndrew Huberman32:14

       Mm-hmm.
6. 33:46 – 42:17

   “Munchies”, Cannabis & Appetite

   1. MHDr. Matthew Hill33:46

      the brain, so.

   2. AHAndrew Huberman33:46

      Mm-hmm. Very interesting.

   3. MHDr. Matthew Hill33:48

      Yeah.

   4. AHAndrew Huberman33:48

      Um, a lot of, uh, kind of, uh, aficionado questions about the receptor biology I'll just, um, spare everyone the details by just, um, highlighting something that you already said far more eloquently than I will, which is, I think it is fascinating that this whole system has both a tonic, like a steady release capability, and, uh, a phasic, you know, so the ability to spike, forgive the pone-

   5. MHDr. Matthew Hill34:13

      Yeah.

   6. AHAndrew Huberman34:13

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

   7. MHDr. Matthew Hill34:21

      Yeah.

   8. AHAndrew Huberman34:21

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

   9. MHDr. Matthew Hill34:31

      Yeah.

   10. AHAndrew Huberman34:31

       So very interesting, um, uh, unique system-

   11. MHDr. Matthew Hill34:35

       Yeah.

   12. AHAndrew Huberman34:35

       ... in a, in a number of ways that raise a number of, uh, key questions.

   13. MHDr. Matthew Hill34:38

       So yeah, if you go back to the munchies question you had, um, so if we tie into that one of the... So there's a few ways, I mean, cannabinoids and feeding are a really interesting (laughs) thing because proto... Like if you ask people like kind of the prototypical responses to consuming cannabis most people would usually say munchies is one of the things that pops up pretty regularly. And so, you know, the cannabinoid receptors are very, um, they are expressed in these feeding circuits in the hypothalamus, um, and you know, there's a lot of complex circuitry there that can regulate food seeking behavior and...

   14. AHAndrew Huberman35:12

       Yeah, we just had an episode with Zach Knight-

   15. MHDr. Matthew Hill35:14

       Yeah.

   16. AHAndrew Huberman35:14

       ... from HHMI and UCSF where he talked about like the AgRP neurons-

   17. MHDr. Matthew Hill35:19

       Yeah, exactly.

   18. AHAndrew Huberman35:19

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

   19. MHDr. Matthew Hill35:28

       Yeah.

   20. AHAndrew Huberman35:29

       ... craving and, and, and then needing.

   21. MHDr. Matthew Hill35:30

       And so we know that like cannabinoids, they regulate again those inhibitory inputs around AgRP neurons for example, and so one thing they can do is disinhibit those AgRP neurons-

   22. AHAndrew Huberman35:39

       Mm-hmm.

   23. MHDr. Matthew Hill35:39

       ... so they become more active and that can drive food seeking behavior. So that's certainly one mechanism of it but there's also a huge reward component to this, um, in terms of the munchies. And so we know that like you can also just dump anandamide for example. This is, you know, Steve Muller and Kent Berich did this work years ago where they just put anandamide into the nucleus accumbens and that can also stimulate palatable food intake. So you also have this ability to inte- integrate with the reward circuitry. Um, and then there was also this fascinating paper from a Japanese group in PNAS I think about 12 years ago and what they found was they would, um, give a rodent a cannabinoid and then they would stimulate different taste bud populations and then they would look at the gustatory cortical response to stimulating the populations and what they found is under the influence of a cannabinoid, if you stimulated sweet taste buds you got an enhanced response in the gustatory cortex but not if you did salty, bitter, or sour, I don't know if they did umami in that one, but it was very explicit to sweet tasting and so you have this kind of ability to like jack up the way the brain is processing sweet tasting foods, you have this engagement of the reward circuitry and then you also have this ability to regulate AgRP neurons as well as the POMC neurons, there's kind of both sides to that in the, in the arcuate nucleus, um, to regulate multiple components of feeding. But a big question is like my lab has become kind of interested in this as well because we have a, a component of my lab that studies feeding behavior and one of my post-docs has been doing these projects for years now trying to understand almost like at a behavioral mechanism level what the munchies are, and what she's been looking at is we kind of started thinking about the idea that, you know, what is it that... 'Cause it's not just food seeking and it's not just, you know, like they just want to consume something, there's, there's a maintenance of eating and so we know from humans and animals you can satiate them, you can make someone full and then get them high on cannabis and they'll re-initiate eating. So-... that's an interesting thing in and of itself because that means you're disrupting either the ability of the brain to detect satiety or you're messing with a process we call reward devaluation. And so reward devaluation is like, you know, if you haven't eaten for a day and you see, like, a picture of a pizza or someone brings a pizza in front of you, it just looks delicious. That first slice tastes amazing. It's salty, it's fatty, it's delicious. You eat five of those slices, it feels greasy and nasty. And so that process of how you perceive the food and its reward salience degrades as you eat and as your brain basically shifts into a thing of, "We don't need to consume calories and food anymore. We're okay. We're full now." Um, and so we've done a series of experiments in the lab where you'd get the animals and either satiated in advance where they have already devalued the food and under a normal state, they won't eat it anymore, they won't work to get access to it. Um, and you get them high on like a cannabis extract. We have these vape chambers that are like, um, I don't know how else to describe it outside of like a little hot box. (laughs) It's probably the best way to des-

   24. AHAndrew Huberman38:31

       Mm-hmm.

   25. MHDr. Matthew Hill38:31

       'Cause it's essentially a kind of a, a locked airtight box that the rat goes in and it gets like vapor puffs and it fills up and then they inhale this and then it clears out and they get another puff and then it fills up and we do this for like 15 minutes. And we've titrated all this to get exactly blood levels of THC that you would achieve in someone who's, you know, consuming cannabis through smoking. Um, and so we get them to that point and then give them access to food and they will, you know, go gangbusters. They eat food, doesn't matter what you give them. You give them plain chow, they go to town. You give them fatty, you give them sweet, they love it all. But you pre-satiate them and they, get them stoned, they will re-initiate eating again. And you make them work for it where they have to like lever press um, and you get them stoned and they will go to town on that and they will work. And, you know-

   26. AHAndrew Huberman39:17

       Proof that even under the influence-

   27. MHDr. Matthew Hill39:18

       (laughs)

   28. AHAndrew Huberman39:18

       ... of cannabis, um, animals will work hard.

   29. MHDr. Matthew Hill39:21

       Yeah. They ... Uh, for food. (laughs)

   30. AHAndrew Huberman39:23

       Mm-hmm.
7. 42:17 – 44:06

   Sponsor: AG1

   1. MHDr. Matthew Hill42:17

      goosing up endocannabinoid activity.

   2. AHAndrew Huberman42:20

      As many of you know, I've been taking AG1 for more than 10 years now, so I'm delighted that they're sponsoring this podcast. To be clear, I don't take AG1 because they're a sponsor, rather they are a sponsor because I take AG1. In fact, I take AG1 once and often twice every single day and I've done that since starting way back in 2012. There is so much conflicting information out there nowadays about what proper nutrition is, but here's where there seems to be a general consensus on. Whether you're an omnivore, a carnivore, a vegetarian, or a vegan, I think it's generally agreed that you should get most of your food from unprocessed or minimally processed sources which allows you to eat enough but not overeat, get plenty of vitamins and minerals, probiotics and micronutrients that we all need for physical and mental health. Now, I personally am an omnivore and I strive to get most of my food from unprocessed or minimally processed sources, but the reason I still take AG1 once and often twice every day is that it ensures I get all of those vitamins, minerals, probiotics, et cetera, but it also has adaptogens to help me cope with stress. It's basically a nutritional insurance policy meant to augment, not replace quality food. So by drinking a serving of AG1 in the morning and again in the afternoon or evening, I cover all of my foundational nutritional needs. And I, like so many other people that take AG1, report feeling much better in a number of important ways such as energy levels, digestion, sleep, and more.So while many supplements out there are really directed towards obtaining one specific outcome, AG1 is foundational nutrition designed to support all aspects of well-being related to mental health and physical health. If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs with your order, plus a year's supply of vitamin D3 K2. Again, that's

8. 44:06 – 52:37

   THC & Anandamide, Pharmacology

   1. AHAndrew Huberman44:06

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

   2. MHDr. Matthew Hill44:15

      Mm-hmm.

   3. AHAndrew Huberman44:16

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

   4. MHDr. Matthew Hill44:27

      Yeah.

   5. AHAndrew Huberman44:27

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

   6. MHDr. Matthew Hill44:41

      Yes. I mean, they dynamically change all the time, so-

   7. AHAndrew Huberman44:43

      W- w- but you're ta- I'm talking about, um, you're talking about experimentally or recreationally-

   8. MHDr. Matthew Hill44:47

      Yeah.

   9. AHAndrew Huberman44:47

      ... adjusting their levels, but how does one do that, um, without using THC?

   10. MHDr. Matthew Hill44:52

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

   11. AHAndrew Huberman45:03

       So it sort of mimics the-

   12. MHDr. Matthew Hill45:05

       Yeah.

   13. AHAndrew Huberman45:05

       ... uh, anandamide and, and 2-AG.

   14. MHDr. Matthew Hill45:07

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

   15. AHAndrew Huberman45:25

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

   16. MHDr. Matthew Hill45:35

       Yeah.

   17. AHAndrew Huberman45:35

       Um, so essentially what I was saying is that at very high THC concentrations, the amount, maybe not the binding affinity but the amount of THC that is available to the CB1 receptors is going-

   18. MHDr. Matthew Hill45:48

       Is high.

   19. AHAndrew Huberman45:49

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

   20. MHDr. Matthew Hill45:57

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

   21. AHAndrew Huberman46:03

       Mm-hmm.

   22. MHDr. Matthew Hill46:03

       ... to be honest exactly how it works. I mean, I think the main way that most people in the cannabinoid theory, uh, field would look at this is that THC is not, like, a very strong agonist. I mean, even if you look at its ability to trigger an intracellular response, it's much lower than 2-AG. So-

   23. AHAndrew Huberman46:21

       So-

   24. MHDr. Matthew Hill46:21

       ... it's actually more like anandamide.

   25. AHAndrew Huberman46:22

       So you said anandamide is high affinity, low efficacy.

   26. MHDr. Matthew Hill46:25

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

   27. AHAndrew Huberman46:30

       But it is high affinity.

   28. MHDr. Matthew Hill46:32

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

   29. AHAndrew Huberman46:43

       Mm-hmm.

   30. MHDr. Matthew Hill46:43

       ... in that sense, it's almost blocking the effects, not, um, amplifying them.
9. 52:37 – 58:57

   THC & CB1 Receptors, Intoxication & Appetite

   1. AHAndrew Huberman52:38

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

   2. MHDr. Matthew Hill52:44

      Yeah.

   3. AHAndrew Huberman52:44

      And since we're here, we might as well, um, talk about, uh, CBD and-

   4. MHDr. Matthew Hill52:48

      Yeah.

   5. AHAndrew Huberman52:48

      ... and the, I think you're gonna tell us, the lack of interaction with CB1-

   6. MHDr. Matthew Hill52:52

      Yeah.

   7. AHAndrew Huberman52:52

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

   8. MHDr. Matthew Hill52:57

      Yeah, so-

   9. AHAndrew Huberman52:57

      Because, um, it makes me wonder whether or not these receptors are the whole story or whether or not cannabis is, you know, as you mentioned, you know, 70 plus, uh, active molecules in there, terpenes and a bunch of other things that may modify their action, that this thing we call cannabis has many more actions than just mimicking the endogenous cannabinoid system.

   10. MHDr. Matthew Hill53:18

       Yeah, I mean, I think, I would say the main way that we think about this is the difference between endocannabinoids and THC is endocannabinoids are gonna be released in a very specific spatial and temporal manner. So-

   11. AHAndrew Huberman53:30

       They evolved to do that.

   12. MHDr. Matthew Hill53:31

       Yeah.

   13. AHAndrew Huberman53:31

       Yeah.

   14. MHDr. Matthew Hill53:31

       So there's gonna be, and I think like it's very clear that like anandamide, for example, is not active at every synapse it has CB1. And so when we boost anandamide signaling by inhibiting its metabolism, all we're doing is amplifying anandamide signaling at the synapses it already exists.

   15. AHAndrew Huberman53:47

       Mm-hmm.

   16. MHDr. Matthew Hill53:48

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

   17. AHAndrew Huberman54:00

       You're introducing the ligand, the thing that binds the receptor.

   18. MHDr. Matthew Hill54:03

       Yeah.

   19. AHAndrew Huberman54:03

       This is far and away different than say like the actions of amphetamines-

   20. MHDr. Matthew Hill54:08

       Yes.

   21. AHAndrew Huberman54:08

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

   22. MHDr. Matthew Hill54:13

       Yes.

   23. AHAndrew Huberman54:13

       ... right? Um, if that was all just, uh, nerd speak for those listening, it's one, i- in the context of amphetamines, what you're doing is you're taking an endogenous system, a naturally occurring system, and you're greatly amplifying the amount of dopamine, the amount of norepinephrine that's available.

   24. MHDr. Matthew Hill54:29

       Yeah.

   25. AHAndrew Huberman54:29

       With what we're discussing today, the endocannabinoid system seems to be producing a set of effects that might overlap with the THC effects, but THC is doing a bunch of other things, and s- and that's because THC, and we'll talk about CBD, but at least THC is acting as the ligand. It's in some sense, we don't wanna say replacing, but it's masking the effects of anandamide.

   26. MHDr. Matthew Hill54:52

       I think the problem is when you just blanket activate all the CB1 receptors in the brain indiscriminately like you do when you consume cannabis with THC, the resulting effect is the intoxicating state. And it's probably because there's a lot of CB1 receptors in the cortex and those are gonna be differentially regulated at different times by endocannabinoids, whereas when THC hits them, all of them are gonna get affected at once. And if you think of the way that-

   27. AHAndrew Huberman55:16

       Mm-hmm.

   28. MHDr. Matthew Hill55:16

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

   29. AHAndrew Huberman55:27

       So you're changing all the networks simultaneously?

   30. MHDr. Matthew Hill55:28

       Yeah, so if you hit a whole bunch of networks simultaneously, you're just gonna change the way that information processing and perception occurs, and I think as a consequence of that, that's what produces the intoxicating state, not that THC is like a, you know, a super duper version of an endocannabinoid or that it's boosting endocannabinoids, it's kind of like...... just indiscriminately activating all the receptors as opposed to a system that's very finely tuned-
10. 58:57 – 1:04:09

    Cannabis & Focus, Memory

    1. MHDr. Matthew Hill58:57

    2. AHAndrew Huberman58:57

       Very interesting.

    3. MHDr. Matthew Hill58:57

       And so then you, then yeah, you go into food-seeking behavior mode.

    4. AHAndrew Huberman59:00

       Hmm. Super interesting. Well, I have to imagine that there are many people who use cannabis not to stimulate appetite but for other reasons. They either like the euphoria or to adjust their anxiety. Um, what are some other, uh, known mechanisms by which, um, cannabis can change people's psychology? Um, let, let me focus in on one particular, uh, aspect of subjective experience, which is focus. Do you think that some people use cannabis because it allows them to focus better? Um, and I raise this specifically because I think that in the past, uh, cannabis has had a bit of a reputation for making people spacey.

    5. MHDr. Matthew Hill59:40

       Mm-hmm.

    6. AHAndrew Huberman59:40

       Um, you used the word stoned.

    7. MHDr. Matthew Hill59:41

       Yeah.

    8. AHAndrew Huberman59:41

       Um, kind of out of it. And yet I've heard of some potential uses for enhancing focus.

    9. MHDr. Matthew Hill59:47

       I mean, honestly, this is a bit of a tricky one to speak to because I just don't think there's good evidence for it. Um...

    10. AHAndrew Huberman59:52

        Either way or...

    11. MHDr. Matthew Hill59:54

        I just don't... I mean, as far as I'm aware, it hasn't been studied in a lot of depth. I mean, there's some things, you know, a lot of the stuff that's been done is usually more like kind of acute memory tasks, like a working memory, or recall, or something like this as opposed to explicitly studying focus. S- anecdotally, there is certainly a lot of people that report that, so...

    12. AHAndrew Huberman1:00:12

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

    13. MHDr. Matthew Hill1:00:21

        I don't think I would say that. I don't think you could lump anything in that context. I mean, I would say the only thing you can say confidently that I would be comfortable saying is that acutely while someone's intoxicated on cannabis, there is definitely short term effects on memory processing. So people tend to...

    14. AHAndrew Huberman1:00:36

        Negative effects or en- enhancements or decrements?

    15. MHDr. Matthew Hill1:00:40

        I would say most of it has to do with recall or consolidation so there does seem to be some... I mean, certainly the animal evidence is very compelling there, but again, we can talk to what some of the limitations of that are. Um, but in humans, I would say most of the work that's been done would suggest there is some short term memory deficits that are present during the intoxicated state.

    16. AHAndrew Huberman1:01:00

        Mm-hmm.

    17. MHDr. Matthew Hill1:01:01

        I have not seen very much compelling evidence of long term effects that emerge like when someone's not intoxicated but they use cannabis somewhat regularly.

    18. AHAndrew Huberman1:01:09

        Mm-hmm.

    19. MHDr. Matthew Hill1:01:09

        I don't think there's anything compelling for that.

    20. AHAndrew Huberman1:01:11

        Mm-hmm.

    21. MHDr. Matthew Hill1:01:12

        Um, and even in that case like Kerry Cutler who's at Washington State, she's done a lot of this stuff looking at cognitive processing and different kinds of memory tasks in users while they're stoned often and within a person, either they have adapted to using it as much as, as they do or they've developed some form of tolerance to it, but even in regular users, the impact on memory processing is usually not super robust.

    22. AHAndrew Huberman1:01:39

        Mm-hmm.

    23. MHDr. Matthew Hill1:01:39

        Um, it's still there, I mean, I think the effects that are more often seen in kind of, um, let's say, smaller laboratory studies where they're using people who've used cannabis but aren't regular users might be a little bit more profound because they may not be...... you know, used to that state, let's say. I mean, there's certainly something we call state dependent learning, which I'm sure you're familiar with. Um, and this is something people... I mean, I remember learning about this in undergrad through alcohol.

    24. AHAndrew Huberman1:02:03

        Mm-hmm.

    25. MHDr. Matthew Hill1:02:04

        So like, you know, someone, first time they get drunk, tries doing something, they're very bad at the task. But if every time they're drunk they do that task, they become better at doing it under the influence. And so then all of a sudden, you know, they regularly do this task while they're drunk and someone tests them and they don't look like they're impaired at all because they've done it so much. And so-

    26. AHAndrew Huberman1:02:22

        I should just say this point has often been confused by undergraduates and others, to assume that just because one can gain proficiency at a task while under the influence of, of a substance does not mean that you have higher proficiency-

    27. MHDr. Matthew Hill1:02:35

        Yeah. (laughs)

    28. AHAndrew Huberman1:02:36

        ... at that particular task-

    29. MHDr. Matthew Hill1:02:37

        Yeah.

    30. AHAndrew Huberman1:02:37

        ... while under the influence. In fact, the way it was presented to me when I was an undergraduate, um, uh, was incorrect. The, I remember, the lecturer said and later corrected himself, um, I won't call him out here 'cause that's unfair.
11. 1:04:09 – 1:15:12

    Routes of Administration, Concentration, Cannabis Research

    1. MHDr. Matthew Hill1:04:09

       replicable or reliable or, or-

    2. AHAndrew Huberman1:04:10

       Mm-hmm.

    3. MHDr. Matthew Hill1:04:11

       ... stable in any way. So yeah.

    4. AHAndrew Huberman1:04:13

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

    5. MHDr. Matthew Hill1:04:23

       Yeah.

    6. AHAndrew Huberman1:04:23

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

    7. MHDr. Matthew Hill1:04:44

       Yeah.

    8. AHAndrew Huberman1:04:44

       Okay.

    9. MHDr. Matthew Hill1:04:44

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

    10. AHAndrew Huberman1:04:51

        Is that right?

    11. MHDr. Matthew Hill1:04:52

        I mean, you look at edibles, for example. I mean, this may be an interesting segue into route of administration stuff 'cause I think it's an important point that a lot of people don't recognize, is the difference between someone inhaling cannabis versus someone orally consuming cannabis is, like, a different game. Like-

    12. AHAndrew Huberman1:05:08

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

    13. MHDr. Matthew Hill1:05:17

        Yeah.

    14. AHAndrew Huberman1:05:17

        ... um, routes of entry, um, for, uh, THC into the system, um, into, to get, to arrive at the brain.

    15. MHDr. Matthew Hill1:05:25

        Yeah.

    16. AHAndrew Huberman1:05:25

        Right? Um, the numbers I gave you in the previous discussion about this were related to how quickly inhaled smoke moves from the lungs to the bloodstream and crosses the blood-brain barrier.

    17. MHDr. Matthew Hill1:05:34

        Yeah. Which is very fast, yes.

    18. AHAndrew Huberman1:05:35

        Um... Right, which is very fast.

    19. MHDr. Matthew Hill1:05:37

        Yeah.

    20. AHAndrew Huberman1:05:37

        Um-

    21. MHDr. Matthew Hill1:05:37

        I don't know if it's different than nicotine. I'm not sure. Again, I don't know if I would say that, but yeah, I, I... It's very fast.

    22. AHAndrew Huberman1:05:43

        Mm-hmm. Okay.

    23. MHDr. Matthew Hill1:05:43

        It's like-

    24. AHAndrew Huberman1:05:43

        So, so there may be, um... It may be that it is the same as nicotine, it may be that it's faster, but, um, importantly, it can, it can be fast.

    25. MHDr. Matthew Hill1:05:53

        Yeah.

    26. AHAndrew Huberman1:05:53

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

    27. MHDr. Matthew Hill1:06:10

        Two to five minutes, I would say.

    28. AHAndrew Huberman1:06:11

        Two to five minutes.

    29. MHDr. Matthew Hill1:06:11

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

    30. AHAndrew Huberman1:06:29

        I don't know, I've seen some people not titrate it very well. (laughs)

Episode duration: 3:52:37