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

Um, so this drug will boost anandamide levels quite high and in 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. Aleve. Yeah, essentially. Yeah. So, um, and that drug didn't work that great to begin with.

So it was maybe some issues with the trial, but it essentially killed the development of the drug from that point on because everyone's like, oh, it's not going to work. So it kind of shelved for a while. Um, A colleague of mine, Marcus Heilig and Leah Mayo, Leah is now a colleague of mine in Calgary, but at the time she was a postdoc with Marcus in Sweden.

And they were able to get access to this molecule right before COVID essentially. And they did a trial in 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 like looking at heart rate or skin conductance. I think skin conductance was the measure we did in there, but it's a proxy for like adrenaline release.

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 reduce remove this like conditioned fear memory that they had trained people to do. And so I worked with them on kind of doing the biochemistry of this to make sure the drug was working properly.

But it was very interesting because we did see in that situation where elevating anandamide produced kind of like a reduction in stress perception, a reduction in stress physiology responses and kind of help kind of reduce fear. And so that is kind of 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. But so that's kind of one of the things. The drug has not really been used that widely yet. It's still... 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 kind of wide.

They're not like out in the market. So you can just go and get them. You really have to. Try and get access from the drug companies to be able to do trials with them. And so we are in the midst of trying to do that. We did just complete a trial that Lee and Marcus ran that I worked with them on as well that was on PTSD. And so there are various potential indications for this.

I mean, Johnson & Johnson developed one as well, and they looked at it in social anxiety disorder. They had some moderate efficacy in their trial. So I'd say the jury's still out on exactly what we're 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, I mean, when Pfizer first made the drug, they were actually initially concerned that it wasn't getting in the brain because no one could tell they were on the drug. I mean, this was the Wild West at this point. No one had any idea what endocannabinoids were actually gonna do. People were basing it on what we knew about THC.

So the assumption was people would have psychoactivity. But they didn't. Pfizer then actually had to do – they did a sleep study to show that it did have some effects on sleep cycle the same way THC does. And then they also did like an in vivo PET binding study to show that they could displace a radioactive molecule that would bind to the enzyme in the brain.

So what's it doing?

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 going to be released in a very specific spatial and temporal manner. They evolve to do that. Yeah, so there's going to be, 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. 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.

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 – I mean, in its simplest form, what cannabinoid receptors do is they change the way that two neurons talk to each other. And so – So you're changing all the networks simultaneously. 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 – like 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 to do very specific things at very specific times.

Yeah, this is a lot more to do with just, yeah, the nature of how it hits everything because... Like, 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 like 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 kind of going up and up following kind of fasting periods. And part of this is because they're trying to engage that feeding circuitry now, and they're shifting the activity of those neurons to promote food-seeking behavior. Because an organism is basically like

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