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

And we call that anterograde because it moves from neuron A to neuron B, which is kind of the general flow of things 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 kind of 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 going to start releasing endocannabinoids to go back and tell neuron A to stop driving it.

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.

Exactly.

So you want to keep things in where they should be. And so you want neurons to get excited, but you don't want them to get overexcited. So endocannabinoids, in kind of a very prototypical sense, act as this circuit breaker, essentially, where they go back and gate how much is coming in. And they do this by...

through various mechanisms essentially turning off the electrical activity of that presynaptic neuron so that it stops releasing neurotransmitter. They can also regulate, though, inhibitory neurotransmitter release as well. And this is usually done through a little bit more of a complex process where it's driven by excitation, but then it regulates the inhibitory pathway.

So inhibiting the inhibitor leads to more excitation. Exactly. I usually liken it to basically taking the brakes off of a car while you're going downhill kind of thing. You'd use your braking system to keep things in check, but if you want to go faster, you take the foot off the brakes and you let things accelerate. And so this can be really important for things like...

forms of synaptic plasticity or neuroplasticity, let's say, where you want synaptic strengthening to happen. So like under a learning event or something, you want that synapse to really hardwire better. And so having endocannabinoids kind of turn off the inhibitory component is one of the mechanisms to facilitate that.

But at the same time, if you want to have a bit more adaptive flexibility, endocannabinoids can weaken that synapse at the same time by acting right at the excitatory terminal itself. And so their ability to kind of play with the relative activity of a circuit is really dependent on which neuron they're acting on. And so they can regulate excitation or inhibition differentially.

And I mean, CB1 receptors are found on virtually every single kind of neuron in the brain, except one. I think you'll find this interesting because it's dopamine. And dopamine neurons are basically the only neurons in the brain that don't really, at least as far as we've been able to characterize to date, express cannabinoid receptors.

I wouldn't say that cannabinoids don't affect dopamine because what we understand in the ventral tegmental area, which is kind of a hotspot of dopamine neurons, or at least the ones that are involved in motivation and stuff, those neurons are regulated by a lot of inhibitory neurons that dump out inhibitory transmitter and keep those neurons kind of quiet.

So there's an opportunity for indirect response. Exactly. So what you have is those neurons that regulate the dopamine neurons are very rich in cannabinoid receptors. This is actually kind of similar to how mu opioid receptors work for things like morphine or heroin. And essentially what the cannabinoid receptors will do is when they're activated, they'll turn off that inhibitory control.

And that allows dopamine neurons to kind of move into a state where they're more prone to go into burst firing and have big dumps of dopamine. Whether or not that relates to, you know, the positive affect or the euphoria, I don't think anyone has... cleanly demonstrated that. I mean, obviously dopamine's very complicated in terms of its relation to endpoints and whether it's reward or motivation.

But cannabinoids definitely do have an influence on dopamine transmission. They just don't tend to do it directly. And I think that's this very bizarre and interesting component of cannabinoid signaling is why the brain would have evolved in a way to allow every other neurotransmitter system to be actively and directly regulated by endocannabinoids, but dopamine is kind of spared from this. So...

I don't know. I mean, obviously, you can always just theoretically guess as to why somebody would do that. I don't know what the reason for it would be, but it is something that has kind of intrigued a lot of people because every other system in the brain is so tightly controlled to some degree by endocannabinoids, and this one circuit is kind of free of it. So...

But yeah, so the main role of endocannabinoids is really to regulate plasticity or homeostasis, allow flexibility of circuits to either goose up their activity or ramp it down if they need to, depending on the environment, depending on the experience of the organism. So there's a lot of kind of roles that endocannabinoids play in that domain. But even within the endocannabinoids...

I mean, 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 the receptor. So serotonin has like... I don't know, like 15 receptors or 20 or something. No.

Dopamine has at least five. 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 bona fide endocannabinoids. There could be more. They're called anandamide, which is actually kind of a funny name because it comes from the Sanskrit word anand for bliss.

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