Dr. Matthew Hill

speaker

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.

Trend

recordings per month · last 12 months

No recordings in the last 12 months.Older appearances are listed below; set an alert to hear about the next one.

Appearances

newest first · ▶ plays the moment

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

And so Rafi Mishulam, who was in Israel when he discovered the molecule, you know, 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.

Ravi Mishulam was also the guy 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 – 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. Yeah. And so the joke is, is this where 420 came from?

Because the original birth date of the first THC paper was 420, 1964.

But yeah, so 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 it was kind of... 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 Mishulin, 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.

So the way anandamide binds to 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 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 intracellular signaling response. 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 and a desired range. So that under resting conditions, it's not too active or too quiet.

So in that context, it kind of is like just the thermostat of the house. Whereas 2AG is like, let's say the pinch hitter. who gets brought in to do the heavy lifting. 2AG during a situation like, let's say, something even like a seizure as an extreme example, we 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 2AG 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 2AG signaling.

And so, you know, all these forms of like turning things up or down in a kind of rapid and on-demand manner, that's mostly 2AG. So most... people who study like neurophysiology and like 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 kind of one of the ways we do it.

We say that anandamide may be more tonic and 2-AG might be more phasic 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. to affect plasticity, but

as kind of like 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. So, yeah, you have this very complex system, and it's really widely distributed in, you know, it's everywhere.

The cannabinoid receptors in the endocannabinoid molecules are in the cortex, they're in the hypothalamus, they're in the striatum, the hippocampus, the cerebellum. All over the brain. Except the one area where it's really interesting, actually, where you don't really see much receptor is in brainstem populations that regulate, you know, kind of unconscious cardiac and respiratory function.

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 kind of cardiorespiratory parts of the brainstem, 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. And so that's, I mean... There's always the saying, there's never been an account of someone actually dying from a cannabis overdose or a THC overdose.

Showing 61–80 of 614 · page 4 of 31