Dr. Matthew Hill

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614 appearances 1 recordings 1 series first heard Jul 2024 last heard Jul 2024

Dr. Matthew Hill’s voice in public audio — every appearance, attributed to the second.

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Huberman Lab · How Cannabis Impacts Health & the Potential Risks | Dr. Matthew Hill · 8 Jul 2024 podcast

I mean, certainly people can do stupid things while they're intoxicated that result in their death. But in the same manner that someone can die from consuming too much opiates, that doesn't seem to be physically possible with cannabinoids as far as we've seen so far. 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. Cool.

So, yeah, if you go back to the munchies question you had. So if we tie into that, one of the – so there's a few ways. I mean cannabinoids in feeding are a really interesting thing because proto – like if you ask people like kind of the prototypical responses to consuming cannabis, most people would usually say munchies is one of the things that pops up pretty regularly. And so –

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 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 like you can also just dump anandamide, for example. This is, you know, Steve Mahler and Kent Barrage 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 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. 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 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 arcuate nucleus 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 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, you know, what is it that – because it's not just food seeking and it's not just – you know, like just want to consume something, there's a maintenance of eating.

And so we know from humans and animals, you can satiate them. You can make someone full and then get them high on cannabis and they'll 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 like 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 satiate it in advance where they have already devalued the food and under a normal state, they won't eat it anymore. They won't work to get access to it. And you get them high on like a cannabis extract.

We have these vape chambers that are like, I don't know how else to describe it outside of like a little hot box. It's probably the best way to, because it's essentially a kind of a, a locked airtight box that the rack 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 presatiate them and they get them stoned. They will reinitiate eating again. And you make them work for it where they have to, like, lever press. And you get them stoned and they will go to town on that and they will work.

Yeah, they, for food, I don't know about other stuff, but for food, they certainly will. I mean, and at least Wiertz and Cassie Moore have done this at Hopkins as well. They've shown similarly using what we call progressive ratio, which is essentially a thing where it's like the first time you press a lever, you immediately get a sugar. Next time you got to hit it twice to get a pellet.

Then you have to hit it four times to get one. That's like life. Yeah, then you got to hit it 16 and then it kind of scales exponentially up. I mean, we've had this one female we kind of joke about in the lab, this one female rat, and you get her high and she'll do like 300 lever presses to get one sugar pelt. Like she really wants it. So you can really kind of goose up their motivation to eat.

And so there's clearly a rewarding aspect of this. because they're motivated to engage enough in working to get access to the food. But you can also do another way of testing this question, which is you can pair a food with something that will make the animal feel nauseous, like lithium chloride. This is kind of the way that you would test 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 kind of devalue a food is by pairing it with a nauseant so the animal no longer likes it.

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