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, then you have no idea what you're consuming anywhere, I would say. Just because outside, I mean, again, Netherlands is a little bit of a different situation. They're not legal. They're decriminalized. I don't know how well the regulation over there of the product is.

I am baffled that you heard that. I have no idea. Let's just say I did more than hear it. See, I've observed it. I cannot even understand that. That is the strangest thing I've ever heard, but okay. Yeah.

Um, you know, that's, that's so, um, I mean, I agree with you on that point for sure that you should not be consuming more if you're having a bad reaction to it, because that will just like grease the wheels going downhill for sure.

So, yeah, there's not a simple answer to that. And I think that also is a question over whether you're talking about acute drug-induced psychotic episode versus the development of a chronic psychotic disease like schizophrenia. So the first arm of that is just can people acutely have a psychotic episode to THC or cannabis? And the answer to that is yes. It's not common.

I would say in terms of adverse events that happen with people consuming cannabis, it's on the rarer side. But it definitely can happen. So less than 5% of people that – Much less than that. I mean, and certainly, I mean, if something like this was happening at a regular frequency, it would be very well known.

Yeah, anxiety attack is, I'd say, more of a standard indication that someone's kind of gone overboard. Like, that's not- Dosage overboard?

Both. So I think there's some contextual component to it. There was like, I mean, back in the 70s when they did more, let's say, interesting studies, there's one where basically they dosed people on THC and then had them undergo oral surgery, which seems like, in hindsight, a very bad idea. And I think virtually everyone in that study had a panic attack.

So it really potentiated the stress of what they were undergoing. And Had they been given that same dose in a different setting, I'm not sure it would have evoked that kind of response. But there is definitely a dose effect to this in terms of like, you know, the kind of classic low dose aspects of THC or cannabis that are usually considered more the positive, pleasurable aspects.

responses that are why people use, like it reduces anxiety, it relaxes, blah, blah, blah. That is more of like a low to normal-ish dose, let's say, of what someone consumes to produce those responses. If they start going upwards, though, it's not like it's graded. It's like a full flip. Like it's not linear at all. It's almost like it goes in the opposite direction.

So, you know, someone can use cannabis to reduce anxiety, but then cannabis can also trigger anxiety in other people and even in the same person if they consume too much. And a lot of this, at least, we think has to do with the ability of it to regulate both excitatory neurotransmission and inhibitory.

For reasons that we don't totally understand, there's way more cannabinoid receptors on inhibitory neurons than there is on excitatory neurons. But in the early days of creating the genetic lines, Giovanni Marsicano and Beat Lutz were over in Europe created deletion of CB1 only from excitatory neurons or only from inhibitory neurons.

full body deletion of CB1 and you give a mouse THC, it doesn't respond to it at all. Not surprisingly. That's a comforting experiment.

Yeah, exactly. So that's how we know CB1 drives all the kind of psychoactive effects of THC. So if you delete CB1 off of inhibitory GABA neurons, even though that removes like 70% of the CB1 receptors in the brain, those animals look just like wild type.

They still exhibit all the classic signs of intoxication in terms of how that would respond to pain sensitivity or locomotion or these other assays we use in mice to tell if they're high. If you delete the CB1 only off of excitatory neurons, the glutamate neurons, then you see what looks like the full knockout. So now the animals don't seem to get high.

So even though the majority of CB1 receptors seem to be on these inhibitory GABA neurons, It's the CB1 on the glutamatergic excitatory neurons that mediate most of the classic signs of what we would consider intoxication from THC or cannabis. But what's interesting is Biat worked with the Spanish group 10, 12 years ago.

Then they showed they're looking at anxiety that if you delete CB1 only off of excitatory neurons, you lose the anti-anxiety anxiolytic effects of THC. but you still have the panicky, anxiogenic effects of high dose. If you delete CB1 off of only the inhibitory GABA neurons, you still have the low dose anti-anxiety effect, but now you don't have the high dose, anxiogenic, panicky effect.

So what that was suggesting was that For some reason, THC will initially hit CB1 on kind of glutamatergic neurons. And essentially, the thought is this will reduce excitatory transmission and probably quiet down circuits. And if we're talking about something like the amygdala, this is probably how it's reducing anxiety.

Whereas as dosing starts to increase and you start to saturate the CB1 on the GABA neurons and turn off inhibition, then the network effect is more of an amplification. And that seems to result in the development of kind of an anxiogenic pro-anxiety response that's obviously undesirable. Why there's this differential shift, it's not exactly clear.

I mean, it's probably either due to some of the biology of exactly where the CB1 receptors sit, on excitatory or inhibitory neurons relative to all the machinery that regulates transmitter release. I mean, Beat Lutz has definitely done some stuff looking at the ability of cannabinoid receptors to evoke signaling responses in a cell.

And on glutamate neurons, they're much more sensitive than they are in GABA neurons. So there's probably a dose threshold. So it does look like this kind of low dosing, what most people are trying to achieve, I would assume, when they consume cannabis is probably these effects mediated by quieting down excitatory transmission.

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