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

So again, same situation, you can get the animal stoned and it will re-engage in eating that food that it had devalued through being paired with a nauseant. So through either satiety or making it kind of a negative associated flavor because the animal got nauseous before. you can kind of override these effects by giving THC.

And so that could be a complex process that either involves changes in the reward circuitry. This could be something that's like from the orbit of frontal cortex, which is a very important part of the brain that scales reward and kind of assesses how much someone wants to work or an organism wants to work to achieve a reward at the end.

So we haven't figured out the circuitry of this and where exactly it's acting. But I would say a lot of the stuff that, you know, we and others have done kind of supports this idea that a lot of what the munchies is, is this ability to kind of almost lock in the reward value of food so that it doesn't decay.

Despite satiety, despite eating over time, it just keeps it highly salient so that they want to work for it still. And then similarly, we and others have also done work to show it can block satiety signals. So we know endocannabinoids, at least, are capable of overriding leptin.

So leptin is an anorectic molecule, comes out from the fat, and usually we release it when we've eaten a lot, and it's one of these things that tells our brain, stop eating. It works through, again, populations in the arcuate nucleus and changes the way those neurons function to drive food-seeking behavior.

And we and others have shown previously that, you know, if you elevate endocannabinoids, you can override that. And actually one of the mechanisms by which leptin seems to suppress feeding is actually by turning on the metabolism of endocannabinoids so that their levels decline. And so as you lose that endocannabinoid function, the animal is less interested in eating.

And so you can prevent these anorectic effects of leptin by like goosing up endocannabinoid activity. Yeah.

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

So, okay. A few things there. We'll take a step back. So THC itself isn't going to – it does its thing by –

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

Yeah. I mean, you don't really actually need much THC in the brain to produce psychoactivity. It's a little bit of a mystery, to be honest, exactly how it works. I mean, I think the main... way that most people in the cannabinoid theory field would look at this is that THC is not like a very strong agonist.

I mean, even if you look at its ability to trigger an intracellular response, it's much lower than 2-AG. It's actually more like anandamide.

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

It's high affinity. So it has the ability... But the tricky thing with that is... It can out-compete 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.

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.

No psychoactive.

Yeah, no one can guess.

Well, I mean, it was developed... The first molecule really was developed by Pfizer to look at if it could work on pain. The first trial that was done did not work. It was like a...

kind of strange osteoarthritic knee pain trial that was like, even in that trial, the positive control of naproxen barely worked, but because the pha inhibitor, which is, take a step back, pha is the enzyme that chews up anandamide. So the drug that is developed inhibits that enzyme. So you prevent the enzymatic breakdown of anandamide. So we just call them pha inhibitors.

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