Dr. Matthew Hill
Appearances
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so I think if we were going to really understand the mechanism of it, that would probably be the way to go. But I'm not super familiar with the work because no one's... I mean, anything I can think of is pretty old. I can't think of anything modern where people have actually looked at this. Interesting.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Okay. So, yes. So going back to just the idea with the indica sativa thing. So the indica and sativa –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
names at least from everything i've understood from everyone that i talked to and being in this field is it's those are botanical terms that largely refer to shape of the plant the you know the way the bud grows blah blah blah they do not track with chemical composition in any way um in fact nick jacomas has done like a lot of analysis of like thousands and thousands of
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
different kinds of cannabis that have been submitted for kind of biochemical analysis to understand THC, CBD, terpenes, minor cannabinoid content. And essentially, his work, as well as from all the people who have done the genetics on this, is The variability that exists within what someone calls an indica or a sativa is greater than the variability that there is between them.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And there is no such thing as a chemical profile that exists in something that's a sativa versus something that's an indica.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I think in Nick's analysis, there was like a couple of terpenes that may have loaded on a little bit onto things that were sativas, but there was tons of sativas that didn't fall into that bracket. Okay.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I would, my honest opinion is this is expectancy bias. This is all expectancy bias.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
20 people tell you that taking this makes you calm. You cannot remove your expectation bias from the fact that when you consume it, you feel calm. Like, and this has been, I think one of the most common things with, with cannabis is like this whole area is so ripe with these expectancy biases that people have about what they assume.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
If you go, someone goes into, you know, and a bud tender tells them this is a sativa, it's going to energize you. There's no way to remove that expectancy bias from what you get.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I mean, like from talking to a lot of people that kind of study this more explicitly, they always say the biggest predictor of what someone feels when they consume cannabis is what they're told on the label it's going to do to them. I mean, and a lot of- It's pretty wild.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's across the board. I mean, again, this is not unique to cannabis in any way. It's just cannabis is so ripe for this because of the lore that it just exists. People say this. I mean, the issue has been, And I just asked Ryan Vandrie this.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
As far as I know, I don't believe there's actually ever been a clinical trial that has blinded people and given them sativas or indicas and actually had them predict what they are or been able to characterize any kind of phenotypic description of what that intoxicated state feels like. And
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Because all the – like the paper that you were referring to where it was users who had got the product, they can't remove their own inherent biases from their own experience. It's going to influence it. There's no way around it. And so people kind of lean into this and I –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Probably not consciously, but they – I mean the amount of people I've talked to that really genuinely believe this to their core that sativa does this and indica does this is fascinating to me. Because again, like you have these two – like THC is what drives the high. That's very clear.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And you can take a sativa and an indica that have virtually identical levels of THC and yet people will report very different intoxicating states that come out of that.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I have to believe the majority of that's an expectancy bias. I have a hard time believing that these things are really driven by fundamental biological differences within... Because anything else that's... I mean, that's the thing, like... Sure.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Some of the labs now, there is a movement to start looking at, can certain compositions of other things in cannabis start to maybe modulate or influence? This is called, like I think I've said this before, the entourage effect, this idea that THC alone might do one thing, but then layering in other things. Terpenes or minor cannabinoids may influence that effect. That is a theory.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
That's not a thing that we know definitively in any way. And in fact, there's virtually no research that's ever been done to test this.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There's some stuff that's starting to come out now, like Ryan Vandery at Hopkins recently published a paper where they kind of, in a dose-dependent manner, added limonene, which is one of these terpenes, like I said, I think gives it like a citrusy odor, into the THC and did find at a really high dose, Probably a dose that I don't think you could actually find in cannabis.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's a little bit higher than what you would have gotten there. But limonene did seem to be able to curb the ability of high dose THC to make someone feel anxious. And this was done in a blinded manner. So there's, I think, some validity to the interaction, whether that's occurring in cannabis, naturally, because of the levels of THC to limonene, I don't know.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But it really was one of the first demonstrations that adding in a terpene could actually influence a component of the intoxicated state in a blinded manner, I think is interesting. And Ziva Cooper, who's here at UCLA, is doing some work with beta-caryophyllene, which is probably... probably the second most abundant terpene, I think, from Nick Chikomas' work.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think myrcene may have been the highest prevalent terpene across all types of cannabis. Beta-caryophyllene is probably the second, and limonene, I think, is probably the third. And So I think they, I mean, and so they're looking at, I think Ziva's work is in the context of pain.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So they're trying to look at if a fixed dose of THC, if you add in varying levels of beta-caryophyllene, does this influence this? So, because again, you do see this in patient communities where they say, well, this strain helps my pain better than that strain. And so it's like, okay, is there actual legitimacy to this?
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Or again, is this just an expectancy bias because someone who sold this to you told you that this strain is better for pain? And the problem is these are all subjective endpoints. I mean, this is, Like pain, sleep, anxiety, these are all how someone personally experiences it.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And we know from all the clinical trials that study pain, sleep, and anxiety, there's massive placebo effects that happen in all these conditions. And so it's very difficult to actually make any kind of sound statements about this in the absence of there being kind of clinical trials that have clearly started to do this. But it's like, as you can imagine, when you start doing the math,
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
given the amount of terpenes and the amount of combinations at different levels, how overwhelming this could become. Because maybe, you know, there's a few that you need in there that interact with THC, not just one. There is like a lot of work that's happened in the last few years that has really started to try and look at if these terpenes or minor cannabinoids act at the cannabinoid receptor.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
which none of them seem to. So this isn't like you've got things that modulate how THC is binding to CB1. If they're doing something else, it's probably through an interaction with another neurochemical system that's influencing what THC is doing. So I'm not against the idea that different chemovars or what people call strains of cannabis could do different things subjectively.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I just am remiss to believe this until I see some blinded data because I think outside of that, we know how powerful an expectancy bias is. So it makes it very, very challenging to make any kind of firm statements. And so kind of in the context of like how you introduced this, that was – again, I think like one of the issues that I took with the other podcast was because –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
As you've said, I understand the thought process you went through. Like, you know, you had this paper where people were reporting subjective effects. There's some neuroimaging data that's been done with cannabis. You kind of said, okay, this is what that was, and that was what sativa did versus this is what indica did.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think we almost need to take a step back actually to talk about how cannabis works in the brain before we kind of go into that. So THC as a molecule exerts almost all its effects. They're acting at this one receptor for the most part that's widely expressed through the brain called the cannabinoid type 1 receptor. CB1. Yeah, CB1 is the shorthand for it.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I mean, I would say that's definitely not true nowadays. That pre-legalization anywhere outside of Colorado, that was true. People were gravitating there towards it.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, I mean, the first thing that's interesting that I think a lot of people don't understand about CBD is CBD doesn't really exist in any form of street cannabis, and it hasn't for a very long time.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There's some. There's very, very low levels of CBD. And the reason that is, is because THC and CBD are both made from the same precursor molecule. And which direction it goes in is based purely on which synthetic enzyme converts it to either THC or CBD.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so as people have clearly chased THC and wanted cannabis that's rich in THC, and so cannabis has been bred to become higher content in THC, by default, CBD has been bred out of the plant. And it has largely been bred out of the plant for quite some time.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so this – I always find it interesting that there's this community that's like, oh, well, THC is the recreational cannabis and CBD is the medical cannabis. And I'm always like, that's bizarre because historically there's always been like THC has been what people have bred cannabis for.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so kind of any medical benefits that people have reported from cannabis per se usually are THC and CB1 driven. CBD is this other molecule that – we can go into the pharmacology in a second, but
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think, you know, as people tend to create analogies to describe what receptors are, for those of you who don't know, most people use like a lock and key analogy that like a receptor would be a protein that sits on a cell and a molecule that binds to it like THC is the key that fits in that lock. When it activates it, it triggers some biological process in the cell, in this case a neuron.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Again, it's just – I mean, I think in the analysis that Nick Chacoma did of all these strains and types of cannabis that exist in the United States when they went through their thing of thousands and thousands of kinds of cannabis, it was like 3% of them maybe had like more than 1% CBD. Like it's very low. Like there's almost none.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And in Canada, to get a CBD-rich strain, you have to basically explicitly buy it because it has to be bred properly. to make CBD. And so this is the kind of chemo of our distinction. I think you did allude to this last time, which is the type one, type two, type three. So type one is high THC. Type two is like somewhat balanced and type three is high CBD.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And now I think like 90 to 90 something low percent of all canabuses that are out there are type one. Like they're all high THC because that's what's been bred. There's a few that have been mixed. So are kind of equal proportions, but you're high equal proportions. So like a high THC cannabis is like 20 to 30%.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
If you go for type two, which is mixed, they're both going to fall around 12%, uh, maybe a little more, but in that range. And then same, if you've got a type three, it's high CBD, it's going to be 20% CBD and very low THC.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so no one has ever kind of grown CBD rich cannabis outside of this recent boom in the last decade that's happened about people wanting CBD because of the Charlotte's web, which was popularized by, uh, I think Sanjay Gupta on CNN in like 2012 or something. It was a while ago. But that was what got a huge movement going around this idea of CBD.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And yeah, so the Charlotte's Web was like, I believe that was what they had named that kind of cannabis that they'd extracted it from. And so it was this, it was a tincture that they were using that was very high CBD content that they were finding was controlling pediatric seizures in kids. Now, this has actually been studied pretty effectively. Most of it's come out of Boston.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Elizabeth Thiel said, has been one of the main leads on this, and she's a neurologist there that has done a lot of the work on this. And so they have, I think, very clearly, and the data is incredibly compelling, their research is one of the reasons why CBD has been descheduled or changed in its scheduling down to a, what is it, a five? What is it, class? CBD? Yeah, like CBD.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So it's been kind of a lot of it's been like shifted in its classification status because it actually has been shown very clearly to have medical benefit. And so it was very specific. It was a very specific form of pediatric epilepsy called Dravet syndrome. Now, there's other forms of pediatric epilepsy I know Elizabeth has studied in addition that has found comparable levels of efficacy.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But essentially what they have shown is that like very high doses of CBD are are relatively effective at calming down the seizures. In some kids, it's profound. Like in some kids, you're talking about kids that were having dozens of seizures a day to essentially none.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so, and I can understand, I mean, from a grassroots perspective, I can understand if you were a parent who had a child with a disease like this that was largely intractable and not that well controlled from the medications they were on, and then something came around that showed this level of efficacy, you would gravitate towards it. Like, that makes sense to me.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
that changes its activity in some capacity. And so THC acts on these CB1 receptors, which are very widely expressed. In fact, outside of like kind of ion channels that are expressed in the brain, the CB1 is, I think, one of the most, if not the most widely expressed receptor in the brain. It's everywhere. So it's really important.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think the work that Elizabeth and her colleagues have done has been really important to establish the efficacy of this, of CBD in these communities. disease states. And so I don't think at this point there's a lot of controversy around that. The question that comes out though is, so how is it working? And we don't have a mechanism.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So as you had said, like CBD receptor, there is no CBD, like there's no receptor that CBD binds to.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like you can certainly, I mean, you can have products that are made that are like oil-based products, at least, that have a certain amount of CBD and a certain amount of THC. And people do go for those. And there's this – I mean one of the arguments people make is they say, oh, introducing CBD reduces the adverse effects of THC.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I'm like, well, if you're using it in a strain, that's simply because the strain of cannabis has less THC now. So it's impossible to separate. So you've bred it out. But I mean like a lot of this was based on some work that came out a long time ago from Brazil where they showed that like giving CBD with a relatively high dose of THC could curb some anxiety that came out from high-dose THC.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There is some evidence to support that, that we would call these allosteric modulators. There's some evidence to suggest that CBD may interact with an allosteric site on the cannabinoid receptor that makes THC bind less.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's definitely more complex than that.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So the most convincing thing that I've seen that CBD binds to is the work that C.C. Hillard has done looking at its ability to essentially block adenosine uptake. And so it can inhibit the adenosine transporter.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
No, because you're getting more adenosine. So you get an accumulation. It blocks the adenosine transport mechanism.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So you get an accumulation of adenosine, which is more sedative. And that, I mean, in the PNAS paper that CC's lab had from 2006, they showed that that also mediated. It was the adenosine, I think, 2A receptor that drove the anti-inflammatory effects of CBD. So it was a secondary effect by- Sort of the opposite of-
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
That's kind of how I describe to people if they ever ask me for what the pharmacology of CBD is. I'm like, that's not the only mechanism. But the thing that was important in CC studies that I think is relevant is that it was not super high concentrations of CBD that caused that. So you could get this adenosine accumulation at...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
you're not talking like micromolar levels of CBD, which is what a lot of studies have done. And so even when we're talking about the allosteric modulatory site, like yes, there's evidence for it. And it is convincing evidence. It's just the dose range in there. You're kind of like, who's getting hit with CBD at that level where you're getting these effects and more so,
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think as kind of you had alluded to previously, it doesn't exist in the, you know, this didn't evolve in humans in the hopes that one day humans would find cannabis.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
when they've done the blinded work, like when Ryan Vandery at Hopkins again, who is one of the main people who's done a lot of this work, has actually blindly given people CBD dosing with THC, finds the opposite, that it actually amplifies some of the effects of THC.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And this was something we learned from the pediatric epilepsy world was that when you start giving CBD at relatively high doses, one of the things it does is saturate a lot of liver enzymes. And so some of the efficacy in the pediatric epilepsy space may be a secondary effect due to an accumulation of some of the anti-epileptics as well because they're not being metabolized the same way.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And this has now been very well replicated. We know that once you start taking CBD, when they hit doses that are at the clinical level, you're going to start having hepatic effects. So it's going to affect the liver, and it's going to affect the ability of the liver to chew up other drugs. And there's very specific –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
CYP enzymes, like the cluster of enzymes that metabolize things, is very specific ones that CBD hits. And so as a consequence, one of them is what choose THC up. So you can get a potentiation of THC by inhibiting its metabolism if you have high enough CBD on board.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I know people love to leverage things. If it's a plant, it's natural and safe. And there's obviously issues we'll talk about with that. But I mean, really, this is just biological redundancy. I mean, nature only has so many ways to create something. And so there's going to be things that end up overlapping in the way that they function.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. I mean, so what you're saying is like what we said is the entourage effect. And I think that is a theory that is held by a lot of people that this exists. I mean, the reality is these terpenes and minor cannabinoids exist at such low levels that like, there's a couple of kinds of cannabis that might have like a high enough level where you're seeing something, but
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I mean, I agree to the extent that it would be a little wild if everyone's subjective experience across different kinds of cannabis was entirely driven by some kind of expectancy, which I can't imagine is accounting for all of it. But I think when we talk about
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
sativa versus indica i think there's a huge bias that's going into there um but one of the things with cbd that's interesting unlike thc is you can actually do pretty clean blinded studies because it's really hard to give someone thc and them not know they're on thc right this was the big problem with the mdma trial that happened recently is that people who got the placebo
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's very challenging to give someone a psychoactive drug and a placebo and them not know which one they have. Whereas because CBD doesn't produce an intoxicating state and it's not really perceptible from the person who's taken it that it's doing anything, that actually does make it far more amenable to do blinded trials with. And so...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, the interesting thing with CBD, and this is where I get a lot of people that get angry at me as well, is that I would argue that the overwhelming majority of the effects of CBD that people report are all placebo effects. And I say that because people leverage the epilepsy stuff and some of the clinical work and say, but we know it does things.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And my response to them is, do you know what dose those people are getting? Because this is something that for some reason has not made the transition from science into pop culture. Right.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so the receptor that's in the brain and throughout the body, the CB1, and there is also a CB2 receptor. It's not really expressed in the brain. It's in some of the immune cells in the brain and maybe some limited distribution in actual brain cell neurons. Where in the body is it expressing? It's mostly immune cells. So you'll see CB2s mostly on like macrophages or other kind of immune cells.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think that's a placebo effect. And I say that because the majority of gummies are about like two megs, five megs, 20 megs maybe.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, yeah. I mean, THC and sleep is definitely a whole other thing. But sure, a lot of people report this with CBD. But again, so most CBD edibles or things that people take that are sold through commercial markets are in the range of 2 to 25 megs of CBD. So then I say to them, so you're aware that in the pediatric epilepsy studies, the dose ranges are like 1,500 to 2,000 makes.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then you're talking about a child who weighs on the order of what, 20 kilos, maybe, you know, like 40, 60 pounds, somewhere in that range versus... So if you start dosing by weight, which is how most of these things are done, well, they'll say 20 megs per kg or whatnot.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So someone my size, so I weigh a bit over 200 pounds, for me to take that dose of CBD at let's say 20 megs per kg at like 90-odd kilos, I mean, you're talking about me taking – A liver-damaging dose of CBD. Insane. Maybe I wouldn't say damaging. It's definitely influencing how the liver metabolizes other things because it's going to saturate those enzymes. But you're taking a very high dose.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I can't speak to that because I actually do not know the metabolism of alcohol well enough. I don't believe so because that's alcohol dehydrogenase. So that would probably be a separate enzyme pathway than the SIPS.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, but I don't know if it would have an effect in that capacity. I mean, they've definitely seen this, like they know the list of medications that this is a problem for. So it's things like warfarin and like blood thinners. Blood thinners. And the anti-epileptics funnel into the same metabolic pathway as this THC. So there's certain things that this would influence.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't know if I would say this would be in the context of alcohol, but I think more so, I mean, what I try and point out to people repeatedly is I have yet to see a blinded clinical study that has found any effect of CBD that's efficacious that's under 300 to 500 milligrams. And-
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And yet in the wild and people who are using it on their own, we're using doses of 10 to 20 milligrams and reporting these effects. And the thing is that I think a lot of people don't also realize is CBD has absolutely horrific bioavailability.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like, so if you take it orally in an oil or in a gummy or whatever you consume it in, now this might be different with some of these beverages that are out there. I don't know if anyone's actually ever done the pharmacokinetics on them. At least I've never seen it. But standard roots, we're talking 4%. like very, very little, actually leaves your gut into your bloodstream.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Cells that gobble up debris. Yeah. And that basically, you know, regulate inflammatory processes. And so the main role of CB2 seems to be much more about like regulating inflammation. So that's kind of a separate role that can certainly impact the brain in different ways.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now we do know from the studies from GW who created the pharmaceutical version of CBD that was used for a lot of the pediatric epilepsy studies that they did, I don't know if it was random or intentional, find that opposite to something like alcohol, If you had just eaten a fatty meal, that actually enhanced the bioavailability of CBD dramatically.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So then it went up to like maybe 20% got into the blood. But that's probably because, again, CBD is a fatty molecule. It likes fatty environments. And for some reason, having fat in the stomach and in the gut seems to promote its ability to get into the bloodstream. You can see it now.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But yeah, I mean, and so because of this, it's like you're taking very low doses of CBD that have very poor bioavailability. And then people really stand by the effects of these. And so I'm like, you know, what I would always say is if it works for you, there's no reason to stop it. because you're having benefit from it. But would I ever recommend someone do this?
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
No, I wouldn't, because I can't say that I think that this has any biological activity. Because even when we start looking at these potential targets of what CBD could interact with, there's a couple of receptors. People have said, you know, it might interact with serotonin receptor.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There's some of these like random orphan receptors that we don't know a lot of what they do that CBD might interact with. But like the concentrations you need to hit those are reasonable. And you're not getting that in the blood and certainly not in the brain of people from consuming incredibly low doses of CBD. So the whole market that exists for CBD to me is a little bizarre.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think for a lot of us in the cannabis field, this has been one of the most bizarre social experiments we've ever watched. Because if you asked me in 2010 to walk into a room and ask How many people knew what CBD is? Like maybe one out of a hundred. Like no one knew what CBD was.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And now it's like 80 to 90% would know what it is because everyone – you can't walk down a street in any city in North America and not see CBD products, whether it's some kind of cream or like – a shake or some random concoction that people have added CBD because now it's going to – you're saying the energy drinks.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But when we talk about the effects on the central nervous system and the brain and behavior, we're talking almost entirely about CB1. And so both the CB1 and CB2 receptors, like I said, don't exist because nature was like, humans are going to find cannabis. This will all work together now. So there are molecules our body produces, which we call endocannabinoids.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's bizarre to me how much this has taken off because it seems to have somehow migrated into being a health product in some capacity.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. I mean, again, I think from my point of view, it's an ethical thing as well, because this isn't covered by insurance. People are spending their own money on this. And so I find it really challenging to recommend someone to be spending what can... I mean, especially if you're talking about an actual clinical dose.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, for someone to take CBD at the level where it could actually be shown to have some benefit in some condition, of which currently it really is just pediatric epilepsy. Like, This idea with sleep, pain, anxiety, there's not a lot of super conclusive data. I'd say most of the trials that have been done have not found really good evidence of benefit in any capacity.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So it makes it very challenging to recommend this in any capacity, especially, I mean, if someone, if finances aren't an issue, sure, go for it. But, you know, I understand people are, like you say, looking for solutions. It doesn't sound like CBD is the solution. I am not convinced by the data that exists that it's really doing what a lot of people claim it's doing.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's a great study of the placebo effect.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And they are kind of funny little molecules because they don't really behave. Like certainly in the brain, they don't behave like a normal neurotransmitter. So, I mean, I assume most people who listen to your podcast are relatively adept with the basic idea of how neurons work.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. So health harms, I mean... Someone smoking, obviously there's risks for lung damage. I would say the evidence for things like lung cancer certainly don't hold the way they do with cigarette smoke.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't think you could make the argument about fewer carcinogens per se. I think... Probably it relates more to the frequency. I mean, Donald Tashkin, who's in California here, I think he was at UCLA. I'm not 100% sure, but I know he was in California.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
He did like very long-term studies tracking cannabis smokers and basically did not find associations with lung cancer the way that you do with cigarette smoking. Why that's the case, I don't think anyone has. Like people have theories. Some suggest because a lot of this in vitro animal work with really high dosing suggests it could have anti-proliferative effects for tumors.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Whether that's real or not, I don't know. But like... I think more likely it's because most people who smoke cigarettes, at least that were, you know, the relationship with lung cancer were people who were smoking regularly throughout the day. And it's very rare someone smokes cannabis at that frequency. Maybe if they isolated that population, they would see relationships with lung cancer.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I just don't think it's been borne out by the data the same way. Certainly lung damage, emphysema, things like that are on par. If you have any combustion product, you're going to have damage there. There's no question about that. So, again, harm reduction perspective would be, you know, oral routes of administration bypass lung damage. They come with their own issues with dosing and whatnot.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But if you're talking about physical harms, that's one thing to avoid that you could bypass that aspect of it with. There is some, I don't think we are at a point where we can say the state of it. There is something with cardiovascular function and cannabis that relates to higher frequency of strokes perhaps, or cardiac events in some capacity. The data is not entirely clear in this sense yet.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So you have neuron A, let's call it the presynaptic neuron because you have that gap between the two cells where they communicate called the synapse. So neuron A works. releases a transmitter, and it can be something that excites the neighboring cell, neuron B, or it can inhibit it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, we don't see, again, it's not like super clean relationships like we're seeing that were there when they established, you know, cigarette smoking and lung cancer kind of thing. I think that effect was so profound and the population of smokers used to be so high.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would probably guess, and this is a guess, that anything, again, combustion smoke-wise, I mean, maybe not vaping plant matter, but at least the combustion from smoking probably exacerbates this just because any kind of combustion product is going to have some vascular effects to some degree on the system. So I imagine we'll make it worse.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But THC itself has a very complex effect on cardiovascular function because it tends to cause – typically vasodilation. So you get widening of the blood vessels, which is why it relates to a lot of people will experience postural hypotension. So sometimes when, what that is is if you stand up and your blood pressure doesn't catch up with you, so you get really lightheaded and people will collapse.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so this is not uncommon to happen to people when, and with edibles as well. So it's not just from smoking. Um, But when they've consumed cannabis in some capacity, there are some people that seem to be very sensitive to the vasodilating effects. And so when they stand up, their blood pressure can't match the shifting gravity that happens.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's a bit of a tricky thing because obviously if there is some underlying heart or a cardiac sensitivity or issue, the tachycardia itself can be a problem.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, so like, you know, if someone has like an underlying heart condition where at rest it may not present itself, but the shifts into that kind of beating faster to compensate for the fact that you've got a drop in blood pressure can put strain on the heart in a way that could unmask a vulnerability or an event.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And again, this is me theorizing what I think it could be based on what we understand to some degree about how it affects cardiovascular function. There are occasionally people who have reported having like elevated blood pressure. I mean, some of that also could be from like an anxiety state or whatnot coming around.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But the typical response, and this is usually driven by cannabinoid receptors that are in the vascular beds themselves, that it causes a vasodilatory response. And so that is usually the first step. The second is the uptick in the heart rate. So you get these kind of effects over time. There's some work looking at like vascular stiffness that can evolve over time.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so the way that we always kind of talk about neurotransmission in the brain is neuron A releases a chemical that crosses the synapse, acts on neuron B, and it can either jack that neuron's activity up or it can scale it down. And that affects brain-wide patterns of activity.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And cannabis users, there's some evidence to suggest that you might get more of that emerging. And so again, that could relate to a vulnerability to have strokes or other kind of cardiovascular events in that sense. So I think the issue in terms of like why it is more difficult for us to say anything definitively at this point is just obviously the timeline of this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, you know, cigarette smoking was an easier thing to establish in that context because, you know, once antibiotics and medicine advanced in like the 40s and the 30s and stuff and people started living longer, you started seeing a lot of these effects of cigarette smoking emerge.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Oh, I know. It's wild.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean my grandparents grew up in Belfast. They had smoked for years and they had even said like when they were younger, doctors would say, oh, have a cigarette after a meal. It promotes digestion. So it's kind of wild to hear that stuff when you think of how cigarettes are viewed nowadays. But –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It is, I don't think we've kind of been able to track this long enough to be able to say with certainty what we're seeing. But I think there's, like if people ask me about risks and harms of cannabis, the first thing I always say is, you know, schizophrenia and bipolar. Those are the main concern areas, I think, where you want to avoid cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I would also say if anyone has cardiovascular issues, they should avoid cannabis just because that's more of like I would say a being safe because I don't know how to actually explicitly say what I would say the harms associated with it are. But I think there is something there. I've seen enough evidence that's like starting to coalesce into a story that's like there's something here. Mm-hmm.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So that's where I would say that I think there's risk. There's also things like this bizarre cyclic vomiting syndrome, which is this really strange thing that has become really apparent.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We've seen this in Canada a bit more now with legalization, again, because people are going into ERs more, where it's this somewhat strange phenomenon where it's usually people who are pretty excess cannabis users. They just start like puking and they can't stop it. And it's like this intractable vomiting that they get into.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then bizarrely, like one of the things that seems to cure it is a hot shower, which is, I can't even begin to understand this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I really struggled to understand because certainly I don't think it was doctors that figured this out. This was people, I think, who were experiencing this. And then they started telling doctors this. And then I think... And I can only imagine, I'm like, maybe they're going in the shower because they're like vomiting on themselves. Probably.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then inadvertently realize that being in a hot shower somehow seemed to calm this down. I have seen a study where they actually applied capsaicin cream and that also seemed to provide benefit.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's something with thermoregulation because the other thing that seems to have shown some benefit is propanolol. which again would suggest some kind of sympathetic. Which is a beta blocker. It's a beta blocker. So yeah, it's your effect. So there's something with autonomic. It must be messing up some kind of autonomic balance or something with thermoregulation.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Why that results in this kind of bizarre vomiting syndrome, I have no idea. But I remember when I first started hearing the stories of this years ago, and I was just like, how? Because I mean, it is, again, surprisingly counterintuitive because one of the medical uses that people have used cannabis for is as an anti-nauseant, especially in the context of chemotherapy.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so something that typically has anti-nauseant qualities suddenly triggering a vomiting syndrome is kind of a paradoxical.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think that's how most people have tried to conceptualize what's going on. It seems to involve the insular cortex. At least the anti-nauseant effects of cannabinoids are involved through the insular cortex. Maybe you have burned out those receptors from chronic use. That endogenous mechanism isn't working or it's somehow flipped in the other direction now and that circuit becomes sensitized.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But it is a very bizarre but very real thing that seems to happen. Again, this isn't common. Like I've heard a couple of people I've met describe it, but it's not like – It's happening to every 10th or 20th person or something.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's a little more infrequent, but it's certainly happening enough that we've now captured it at a federal data level that this is a thing that people are showing up in the ER for. Interesting.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. So apparently if it happens, a hot shower is what people claim. So for me, I would say the main – harms that people need to be aware of, the schizophrenia, bipolar, possible cardiovascular effects. And then this is one of these syndromes that can come out of it, as well as possible lung damage from smoking.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Those are the main, I think, genuine bona fide health issues associated with cannabis that people should be aware of. I mean, I know we're not going to probably go into depth with it. On the other side, with the medical stuff, it's a little bit more challenging. I mean, a lot of this is just because we really don't have
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
good studies that have been done in any capacity that have really definitively told us if cannabis has really bona fide medical benefit?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, you look at, I mean, the other one that wasn't on there, but you've mentioned this before, and I have as well, is pain. So chronic pain. Pain, thank you. Pain is, I would say, the number one. So pain is certainly the one that there's the most amount of evidence for. Thank you.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would say when you talked about this in the previous podcast, you were mostly correct about this component of it in the sense that it's not that cannabis is a profound analgesic. It's that cannabis, it has some analgesic properties, but it's not like super sledgehammer in that sense. But what it does seem to do is it seems to strip away the affective component of pain to some degree.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so what I have consistently heard from chronic pain patients when they use cannabis is they say, yeah, my pain's still there, but now the pain's background noise. So I can sleep at night. And just being able to sleep, I think, is actually providing a huge amount of the benefit to that community. But it's the day-to-day.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like, they're able to function with the pain because it doesn't – they don't become focused on it the same way because they're able to kind of push it to the background. That seems to be the main – Ability of cannabis, I mean, yes, there's some mild analgesic properties to it to some degree, but it really seems to be much more of that component of it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think you'd alluded to something like that in the previous podcast. You'd said something about how it's changing the emotional state of pain.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, so the pain thing, I think, is a central one. And that's one of the only ones that there's a little bit of actual research on. Most of it's either with isolated THC. I think there's one or two studies that have actually looked at smoke cannabis and found small signals of benefit. But so anxiety is an interesting one.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so, I mean, obviously, this is more near and dear to my heart because I study stress and anxiety as my primary area and cannabinoids and endocannabinoids in that space. And, yeah, you look at questionnaire-based – studies about why people smoke cannabis and like 85% of them will say because it reduces stress and it makes me feel less anxious.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, that was like a big impetus as to why we started studying endocannabinoid regulation of it because similar to feeding and pain where we know endocannabinoids are involved in regulated feeding circuits and endocannabinoids are also integrated into pain circuitry and can provide some endogenous analgesic signals.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We figured the same was going to be true for stress and anxiety, which to some degree it is. But it's very complicated because it can be, like I said before, biphasic where some lower doses are anxiolytic, higher doses can promote anxiety. But for the majority of people who use cannabis regularly, it's because it helps reduce anxiety.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, whether that would hold weight in a clinical trial is a different story. There is some old evidence from like
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I'd say the 70s, early 80s, where they were using synthetic forms of THC like nabilone, which is something you can get in Canada, or marinol or dronabinol, which I think is what's accessible in the States, where they did find some evidence to suggest it was on par with like a benzodiazepine, like diazepam or something.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I can't remember exactly what the comparator they'd used in there, but there was some evidence for... there being some anti-anxiety properties of THC. And that tracks generally well with the self-reported literature that's out there. Now, whether that's the same as an ability to have benefit in something like PTSD is a different question.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It gets a little bit more complicated because obviously PTSD has an anxiety component to it, but there's a lot more to it as well. And again, there's very little research in this space. There was one really, really small study study done by the Canadian military. First, they did one version of it that was an open label.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Open label trials for people who don't know, it's just basically everyone knows what they're getting. It's not blinded in any way. But because of the self-reported data from the veteran population about cannabis helping, especially with sleep. And the big thing that they reported was that it suppressed their nightmares. And so...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Post-traumatic stress disorder is a very complex disease for many reasons, and one component of it is the re-experiencing events that happen during sleep where there's a lot of nightmares and individuals will kind of re-experience the trauma that led to the development of the PTSD.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And there does seem to be some suggestion that because they're remembering it and maybe changing the details because they're in a dreamscape space that they reconsolidate it a little bit more. And there's often a high degree of sympathetic activation and arousal that goes on with these nightmares.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And some of the belief is that this is part of the sensitization process that can happen in PTSD where the disease can worsen over time because the re-experiencing and the reconsolidation and the sensitization of the disease that happens over time in this kind of sleep state can make it worse.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
The majority of veterans who have used cannabis and report benefit if you actually talk to them about it, as I've done in a few different situations and also just look at the anecdotal data, almost all of it talks explicitly about sleep. And they say, oh, we use cannabis or THC before bed. We find we don't have the nightmares and just the simple trickle-down effect of that.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
is hugely beneficial for them. And so the Canadian military did an open label trial on this, again, not blinded. It was small numbers, but they basically found as soon as they put people on nabilone, this synthetic version of THC, it very, in like a large proportion, I think like 85% of them almost stopped having these nightmares.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And this was like a treatment resistant population that was pretty severe. So this was a big benefit. So they then took open label and did what you should and moved forward to do a double-blind placebo-controlled. Now, it was a very small sampled studies. And that is obviously always a problem with human work is if this was like 15 or 17 people.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So not powered enough to really make any kind of firm conclusions, but interesting in the sense that at least it was done in a proper crossover design where they got placebo at one point, they got Nablon at one point, it was switched, they didn't know which one they were on. Um, because they're taking it right before bed, maybe that will remove some of the subjective bias.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Again, you can't totally remove it, but like if someone's taking it within, you know, an hour or so of going to sleep, they may not feel behind the same way. But, uh, even under the double-blinded conditions, they found a very effective suppression of the, of the nightmares and the re-experiencing.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then they also, at the same time, found this increase in kind of quality of life measures, which tracked with the fact that they were probably sleeping better. Um, I don't think they actually reported any change or even looked at maybe the overall PTSD score. They only reported or really focused on the nightmare component of it because that was the primary outcome of the study.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I thought that was interesting because that's – if you look at the anecdotal data in PTSD, that's where a lot of it is focused on is using it as kind of – I wouldn't – maybe call it a sleep aid because it's really more of a modulator of the dream state.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, depression and PTSD are both two disorders that are characterized by changes in REM. Like they have earlier onset to REM, so they go into REM faster. They tend to have some altered architecture of the REM component of their sleep. So in those states, maybe suppressing REM isn't actually a bad thing.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
At least certainly for PTSD, I would imagine in terms of the context of the nightmares, that's providing some benefit. Whether or not it globally is changing the disease severity or improving the disease, I don't think we really have any evidence to say. But again, I can understand the...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
the desire for people to kind of self-medicate, let's say, by using this as an approach to try and reduce that component of their sleep so that they sleep better, they feel better. Maybe down the road, it would help the prognosis of the disease long-term if it's not sensitized in the same way. But I don't think we have any strong data that we can leverage in that capacity to be able to say it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But to me, it's one of the more interesting areas. I think anxiety disorders in general, there's definitely some potential. So as I had mentioned earlier,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
the the pha inhibitor that elevates anandamide levels so johnson and johnson did do a trial in social anxiety disorder it's published i think from a few years ago at 21 or something i can pull up the reference for that where they did find some benefit it wasn't huge and some of this had to do with the design of the study because they kind of underdosed the patients a bit and so
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Not everyone actually showed the elevation in anandamide when they went back and looked, but when they actually isolated the group of people that had higher anandamide, in that proportion of the patients, they did see some symptom improvement. So it did support it. And this is, I mean, very similar.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like for us, this is a big thing because all of the work that we focused on is looking at how stress and stress hormones regulate anandamide. largely anandamide signaling. And one of the main things that we've demonstrated that's been replicated relatively well over the years is that stress exposure can actually cause a rapid loss of anandamide signaling.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And it's that loss of anandamide signaling that seems to facilitate some synaptic strengthening in the amygdala and promote activity in areas that are involved in these anxiety circuits. And so... The thought has always been, well, if anandamide, you know, it's that job as its kind of tonic housekeeper at keeping things in that homeostatic range.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Let's say we're talking about explicitly an anxiety circuit. You know, there's individual variation that exists in humans across everything. So one of our predictions has been maybe people who are on the high end of the anxiety spectrum might be on the low end of their tonic anandamide signaling spectrum.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And we've gotten a little bit of support from that from animal work where we've screened animals based on anxiety and looked at endocannabinoid levels in the amygdala and found lower anandamide
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There is some evidence to actually support it. So my buddy Sachin Patel, who's at Northwestern now, but he was at Vanderbilt when he did this study, they basically played with these drugs that you can use to prevent endocannabinoid synthesis. So you can create a state of like impaired endocannabinoid function. In humans? And they did this in rodents.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So this was done in mice. And they basically, but one of the questions was is, so A, does reductions in endocannabinoid function produce states of anxiety? And they did demonstrate that. So you could deplete endocannabinoid levels and you got the emergence of an anxiety state. So then you could give drugs that would boost the endocannabinoids to normalize this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, again, it kind of fit with the idea. But then they did one key study where then they gave THC and saw could THC fill in the gap. And they found that like boosting endocannabinoids, giving THC on a background of low endocannabinoids was able to reverse that anxiety phenotype and bring it back into more of the normal range. So, again –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Maybe for some people, this is, again, this is theoretical, so I don't know how much of a spectrum there is if there are people that are at this low end, but certainly I think from the animal literature, there's some foundation for making a theory that's similar to what you're saying, which is maybe some people are trying to fill in a gap of something that's deficient in them, and therefore that can help them feel less anxious.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And that, again, may be very different than someone who is very anxious for different reasons or has normal endocannabinoid function or something else might be at play there. So- Very interesting. Yeah, I think it could explain some of the heterogeneity that exists out there for sure, yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I mean, we have definitely found in human populations through work I've done with a lot of clinical collaborators and others, like... We look at endocannabinoids in the blood, and it's not in the brain, but they are lipids that can move pretty easily back and forth.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And we have found relationships between peripheral endocannabinoid levels and mood states, both anxiety and kind of depressive measures, which does somewhat relate to... The possibility that this could be real, we don't know. It's been hard, obviously, for various reasons to really track this. But we've never looked at an anxiety disorder population.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We've done some work with post-traumatic stress disorder populations. There's been work in depression populations that have found some relationships that are pretty similar. So it's certainly a possibility. But again, this is all like our theory at this point. So we'll see as things kind of move forward if they pan out. But yeah.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Thanks. And I think it's also important. I think it's good, as you had said, that like for people to see that scientists can have disagreements. Absolutely. I think it's important. I think it's good that you kind of provided me an opportunity to correct the record and did so in a very appropriate manner. I think this was a great discussion for people to understand different perspectives.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Also good to highlight. where it was that I had had issue with your previous podcast. And I think the discussions that came out of that were for the better. So that's all the best. And hopefully if there's other contentious issues that happen down the road, similar things, move forward and you chat with people. Oh, I always, yeah.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think it's really good for people in the public to know this is how science progresses. This is, you know, someone says something, someone disagrees with it. You get an opportunity to clarify things. And I think that that's really good just to move things forward. So I think that was a good process that we've gone through.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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?
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Because the original birth date of the first THC paper was 420, 1964.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, certainly people can do stupid things while they're intoxicated that result in their death. But in the same manner that someone can die from consuming too much opiates, that doesn't seem to be physically possible with cannabinoids as far as we've seen so far. And a lot of that is just because of the localization. For some reason, it's just not the receptors in that part of the brain. Cool.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, yeah, if you go back to the munchies question you had. So if we tie into that, one of the – so there's a few ways. I mean cannabinoids in feeding are a really interesting thing because proto – like if you ask people like kind of the prototypical responses to consuming cannabis, most people would usually say munchies is one of the things that pops up pretty regularly. And so –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
you know, the cannabinoid receptors are very, um, they are expressed in these feeding circuits in the hypothalamus. Um, and you know, there's a lot of complex circuitry there that can regulate food seeking behavior.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so we know that cannabinoids, they regulate, again, those inhibitory inputs around AGRP neurons, for example. And so one thing they can do is disinhibit those AGRP neurons so they become more active and that can drive food-seeking behavior. So that's certainly one mechanism of it. But there's also a huge reward component to this in terms of the munchies. And so...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We know that like you can also just dump anandamide, for example. This is, you know, Steve Mahler and Kent Barrage did this work years ago where they just put anandamide into the nucleus accumbens, and that can also stimulate palatable food intake. So you also have this ability to integrate with the reward circuitry.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then there was also this fascinating paper from a Japanese group in PNAS, I think about 12 years ago. And what they found was they would give a rodent And then they would stimulate different taste bud populations. And then they would look at the gustatory cortical response to stimulating the populations.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And what they found is under the influence of a cannabinoid, if you stimulated sweet taste buds, you got an enhanced response in the gustatory cortex. not if you did salty, bitter, or sour, or I don't know if they did umami in that one, but it was very explicit to sweet tasting. And so you have this kind of ability to like jack up the way the brain is processing sweet tasting foods.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You have this engagement of the reward circuitry, and then you also have this ability to regulate AGRP neurons as well as the POMC neurons. There's kind of both sides to that in the arcuate nucleus to regulate multiple components of feeding. But A big question is like my lab has become kind of interested in this as well because we have a component of my lab that studies feeding behavior.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And one of my postdocs has been doing these projects for years now trying to understand almost like at a behavioral mechanism level what the munchies are. And what she's been looking at is we kind of started thinking about the idea that, you know, what is it that – because it's not just food seeking and it's not just – you know, like just want to consume something, there's a maintenance of eating.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so we know from humans and animals, you can satiate them. You can make someone full and then get them high on cannabis and they'll reinitiate eating. So that's an interesting thing in and of itself, because that means you're disrupting either the ability of the brain to detect satiety or you're messing with a process we call reward devaluation.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so reward devaluation is like if you haven't eaten for a day and you see like a picture of a pizza or someone brings a pizza in front of you, it just looks delicious. And that first slice tastes amazing. It's salty. It's fatty. It's delicious. You eat five of those slices, it feels greasy and nasty.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so that process of how you perceive the food and its reward salience degrades as you eat and as your brain basically – shifts into a thing of we don't need to consume calories and food anymore. We're okay. We're full now.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so we've done a series of experiments in the lab where you'd get the animals and either satiate it in advance where they have already devalued the food and under a normal state, they won't eat it anymore. They won't work to get access to it. And you get them high on like a cannabis extract.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We have these vape chambers that are like, I don't know how else to describe it outside of like a little hot box. It's probably the best way to, because it's essentially a kind of a, a locked airtight box that the rack goes in and it gets like vapor puffs and it fills up and then they inhale this and then it clears out and they get another puff and then it fills up.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And we do this for like 15 minutes and we've titrated all this to get exactly blood levels of THC that you would achieve in someone who's, you know, consuming cannabis through smoking. Um, and so we get them to that point and then give them access to food and they will You know, go gangbusters. They eat food. Doesn't matter what you give them. You give them plain chow. They go to town.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You give them fatty. You give them sweet. They love it all. But you presatiate them and they get them stoned. They will reinitiate eating again. And you make them work for it where they have to, like, lever press. And you get them stoned and they will go to town on that and they will work.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, they, for food, I don't know about other stuff, but for food, they certainly will. I mean, and at least Wiertz and Cassie Moore have done this at Hopkins as well. They've shown similarly using what we call progressive ratio, which is essentially a thing where it's like the first time you press a lever, you immediately get a sugar. Next time you got to hit it twice to get a pellet.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Then you have to hit it four times to get one. That's like life. Yeah, then you got to hit it 16 and then it kind of scales exponentially up. I mean, we've had this one female we kind of joke about in the lab, this one female rat, and you get her high and she'll do like 300 lever presses to get one sugar pelt. Like she really wants it. So you can really kind of goose up their motivation to eat.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so there's clearly a rewarding aspect of this. because they're motivated to engage enough in working to get access to the food. But you can also do another way of testing this question, which is you can pair a food with something that will make the animal feel nauseous, like lithium chloride. This is kind of the way that you would test conditioned taste aversion.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So you give them access to a food, and then you give them something that makes them feel nauseous, and the animals will avoid that food. And so that's another way to kind of devalue a food is by pairing it with a nauseant so the animal no longer likes it.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so you can prevent these anorectic effects of leptin by like goosing up endocannabinoid activity. Yeah.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yes. I mean, they dynamically change all the time.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, okay. A few things there. We'll take a step back. So THC itself isn't going to – it does its thing by –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, so THC is the same. THC is actually only a partial agonist. It's not even a full agonist at CB1.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, no one can guess.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So what's it doing?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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,
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
energy detecting its periphery and saying, oh, you know, we might be burning through our energy reserves. We should probably eat more. And so there are obviously a few mechanisms that do this. NPY is another one and ghrelin and things like that. So there's a lot of redundancy in these systems, but endocannabinoids are just one of the molecules that seem to fine tune like the feeding circuitry.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so in states of fasting, endocannabinoids go up explicitly in that circuit. And there's some evidence they also go up in like the nucleus accumbens and affect some of the reward circuitry. So they're probably... driving food-seeking behavior and enhancing the rewarding aspects of food at the same time.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so that's like a natural endogenous mechanism to regulate feeding based on nutritional state. THC, on the other hand, you know, it hits the brain. Yes, some of it's going to be the intoxication, but in tandem, you're going to hit the CB1 receptors that are in those feeding circuits as well. And the consequence of that is going to be...
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, the way I kind of analogize it to people is I say it's almost like tricking the brain into thinking that you've been fasting because you're now activating receptors that are normally activated following kind of a fasting state.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And as a consequence of that, it pushes someone or an organism or human or whatever into a state of food-seeking behavior because now food also has high reward value and they're kind of – the way their food circuitry is responding in the brain at least seems to be similar to what would happen if they've been fasted.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And the thought is that's why when people, you know, when someone gets stoned, they're not like going to eat lettuce. They want high calorie food. They tend to like things that are high carb, high fat. That combo seems to be what people like when they're intoxicated with cannabis. And that comes with a lot of calories. And the point of that would be you're trying to replenish lost energy stores.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so This at least is the kind of the theory that I have about what it is that it's doing is, you know, and I think you can make this analogy for multiple different things.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You know, if we talk about pain or stress, we can say similar kinds of things are going on, is that endocannabinoids normally do one thing, but when THC hits the brain, it's still activating these circuits in addition to everything else it hits.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So you still drive that response that the endocannabinoid system normally physiologically controls, but you're almost like tricking the brain into thinking you're in that state now. And so then, yeah, you go into food-seeking behavior mode.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, honestly, this is a bit of a tricky one to speak to because I just don't think there's good evidence for it. Either way or? I just don't. I mean, as far as I'm aware, it hasn't been studied in a lot of depth.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, there's some things, you know, a lot of the stuff that's been done is usually more like kind of acute memory tasks, like a working memory or recall or something like this, as opposed to explicitly studying focus. Anecdotally, there is certainly a lot of people that report that. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't think I would say that. I don't think you could lump anything in that context. I mean, I would say the only thing you can say confidently that I would be comfortable saying is that acutely while someone's intoxicated on cannabis, there is definitely short-term effects on memory processing. So people tend to- Negative effects or enhancements or decrements?
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would say most of it has to do with recall or consolidation. So there does seem to be some, I mean, certainly the animal evidence is very compelling there, but again, we can talk to what some of the limitations of that are. But in humans, I would say most of the work that's been done would suggest there is some short-term memory deficits that are present during the intoxicated state.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I have not seen very much compelling evidence of long-term effects that emerge like when someone's not intoxicated but they use cannabis somewhat regularly. I don't think there's anything compelling for that.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And even in that case, like Carrie Cutler who's at Washington State, she's done a lot of this stuff looking at cognitive processing and different kinds of memory tasks in users while they're stoned often. And – Within a person, either they have adapted to using it as much as they do, or they've developed some form of tolerance to it.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But even in regular users, the impact on memory processing is usually not super robust. It's still there. The effects that are more often seen in kind of, let's say, smaller laboratory studies where they're using people who've used cannabis but aren't regular users might be a little bit more profound because they may not be used to that state, let's say.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, there's certainly something we call state-dependent learning, which I'm sure you're familiar with. And this is something people – I mean, I remember learning about this in undergrad through alcohol. So like, you know, someone, first time they get drunk, tries doing something, they're very bad at the task.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But if every time they're drunk, they do that task, they become better at doing it under the influence. And so then all of a sudden, you know, they regularly do this task while they're drunk and someone tests them and they don't look like they're impaired at all because they've done it so much.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't think better off, no. But they would probably score better than someone who had never studied drunk and came to the test drunk. Correct. Just because they had had some state-dependent learning. And so I think when we're talking about, if you're talking about someone who's a chronic cannabis user, they're going to have done a lot of cognitive tasks while they're under the influence.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so if you acutely test them, the impairment you might see in them is probably less than you would see in someone who's relatively naive or a much less experienced user. That being said, I think it's,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
relatively well established most people would agree that uh acutely intoxication with cannabis doesn't pair memory processes in some capacity what explicit form of memory i don't think i could speak to comfortably just because i'm not a memory researcher and i know there's very specific things of like episodic and declarative and whatnot so um i can't say that but i'd say it's kind of generally and i mean again you can replicate this in animals where if you train them on a task while they're under the influence they don't seem to have consolidated that information as well um
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But again, I don't really think there's super compelling evidence that there's kind of long-term permanent effects on cognitive function in individuals who use cannabis. At least I've never seen anything that's replicable or reliable or stable in any way. So, yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. I mean, I don't actually even think it matters if it's high THC in the cannabis. I think like some people can get very intoxicated off of very, very low doses of cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, you look at edibles, for example. I mean, this may be an interesting segue into root of administration stuff because I think it's an important point that a lot of people don't recognize is the difference between Between someone inhaling cannabis versus someone orally consuming cannabis is like a different game.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Which is very fast.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't know if it's different than nicotine. I'm not sure. Again, I don't know if I would say that, but yeah, it's very fast.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Two to five minutes, I would say. It's pretty fast. I mean, so this is one of the things with cannabis is – And again, this will kind of go into this idea of the change in potency of the plant as well. Yeah. it's pretty quick and people titrate cannabis pretty well. Like at least people who've used it a couple of times and understand this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Depending again on how you, so again, this can vary. So like, you know, cannabis from the 70s was like, I don't know, 5% THC, let's say. It was pretty low. And nowadays cannabis is, a lot of the commercial stuff is between 20 and 30. Although whether those are super accurate numbers, not entirely clear, but so it's gone up a fair amount.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. Basically, you're talking about a beer or a wine to a spirit.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I would say this is what's super interesting. And this was something that came out of the way that cannabis research is done, certainly in the States. And Canada has been quite behind on this, even with legalization, we haven't caught up.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But they have been doing lab-based studies of cannabis, you know, Meg Haney, Harriet DeWitt, this cluster of researchers around the country, Ziva Cooper at UCLA here, have all done this where, you know, you have people come into the lab, you give them cannabis, you measure subjective outcomes or neuroimaging outcomes or whatnot. So to do this,
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
you can't use commercial cannabis and pre even like the state by state legalizations hasn't changed this. So if you are doing cannabis research in humans and you're funded by like NIDA, which is National Institute of Drug Abuse, you get all your cannabis sourced I mean, this may be changing. I think there are some shifts that are happening.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But historically, in all the literature that we would talk about that's kind of pre the last couple of years, all that cannabis came from one source, which was, I believe, a farm in Mississippi that was essentially funded by NIDA to produce cannabis. Lucky farm. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Well, the cannabis that came out of it, though – and this is one of the reasons a lot of the clinical stuff people have kind of been like, oh, I don't know how representative this is because it reflects cannabis that I would say is more from like the 70s or 80s. So it would be like 5% to 9% kind of THC cannabis. Now –
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
when you put someone in a lab setting and you get them to smoke to level of intoxication, people would take, you know, whatever, eight tokes, let's say, something like that. And that's where they would stop. And so, you know, a lot of the labs that use this have always been like, our people who are regular cannabis users are getting high off of it.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's not as potent as the stuff that's on the street, but they're clearly getting intoxicated from it and it's giving us reliable data. So when they started looking at the blood levels of THC that you achieve, it was around 100 nanograms per ml of THC, give or take. That seemed to be where it was. Now, because of the way that you can legally study cannabis in the States,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You couldn't just go down to a dispensary and buy the products that everyone on the street are using, which is kind of like it's been a weird thing for a lot of people because they're like, why wouldn't you study what we're using? But because of the legal aspects of this, you couldn't bring those products into the lab. They'd never been standardized.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
No one knew exactly what was in them, pesticides, all this other stuff that could influence it. So from a safety perspective, it was always like, no, you use the cannabis that's sourced from NIDA.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So there's a group in Colorado, Kent Hutchinson and Angela Bryan and Cinnamon Bidwell have kind of, I would say, became very creative actually to figure out how to study cannabis that's being used, I call it, in the wild, like in kind of an ecological setting, let's say. And so they created what was called the Canavan.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And the Canavan was a way to study people using products on the street, but not have them come into a laboratory setting where it was complicated. And so what they would do is they would drive the Canavan to someone's house, but they'd be parked on the street.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And someone would use the product, whatever it was, in their own property, in their own time, and then come into the Canavan to have blood taken, to look at what their THC levels are, and to undergo testing. And so it was actually like...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think this was a great advance in the field because it was this huge innovative approach that allowed us to start comparing what we've learned from lab-based settings with this kind of old-school weed that was coming from NIDA with what is being used on the street.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I mean, my view is you need both because you need the in-laboratory for the control because we all need control over various things. But you also need the ecological validity to see how it shakes out and make sure it looks the same.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
A novel experience where someone's intoxicated with cannabis can also create a very different altered state. I would want to be stoned in a laboratory. I'll tell you that much. I feel like there's pluses and minuses to both sides, but I think the data together is very compelling, and that's where we get a lot of advance in the field.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So what Kent and Angela and Cinnamon did with the Canavan was kind of create the situation that allowed this – research to occur. And what we found fascinating, I remember talking to Meg Haney about this because all the people in her lab studies tended to always hit around 100 nanograms per male using this relatively lower potency cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
When Kenton and Angela and Cinnamon started studying this in the people and taking blood, despite the fact that these people are now using cannabis that's 20 to 30%, their blood levels are the same. So they're still coming in around a hundred nanograms per mil because people are really good at self titrating. Now where things fall apart is with the concentrates.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So then you go into things like dabs or these like high potency products that are now like, cause cannabis itself, realistically, From what I understand from the botanists that I've talked to, you can't really grow a plant that's gonna exceed more than 25 to 30% THC just by sheer biology. So it taps out there. That's about as high as it's gonna go. Concentrates can go up to like 90, 98%.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Thanks for having me.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So you can get really, really- These are tinctures? Like, yeah, various just in oil-based forms that are very, very high-potency products. Those are incredibly challenging to titrate. Like, they cannot be titrated because the sheer volume of THC that hits the system, even from a single hit, is so overwhelming.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so, when the Colorado group looked at those, their blood levels were closer to 200, 300 nanograms per mil. So, wow. With cannabis plant, there does seem to be this ability for people to relatively self-titrate.
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then my buddy Ryan McLaughlin, who's also at Washington State, he was really one of the ones that pioneered these vape chambers and rats and created this really cool model of self-administration, which was like,
Huberman Lab
Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
A very important thing to actually establish because it was very challenging to get rodents to self-administer cannabis if you're doing like an IV approach or something else because they found it quite aversive. But when you let rodents actually tighter their ability to get vape hits, they will like work for this the same way they will other reinforcing drugs.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So it was a really important finding that you could do this. And what Ryan found was he actually did one study where he gave them access to a low-potency product, we'll call it medium, and then a high. And what you ended up, if you look at the data, is the one the rats liked the best was the medium-potency product. Interesting.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And if you gave them the high-potency product, they would actually take less vape hits off that than they would off the lower ones. And again, all their blood levels tended to cluster in the same range because they – Like even at the rodent level, they're able to titrate because of the lag between inhalation and feeling the effects is only on the order of a couple of minutes.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
People can titrate better. I mean, not just people, it seems like the rodents can as well. So the higher potency cannabis, where it becomes a problem is if someone's highly inexperienced and they consume a whole bunch of it without allowing that time lag to occur. And then they can probably exceed the levels they intended to and consume too much and then have probably an adverse response.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I wouldn't say that. There's definitely some degree of tolerance. The tolerance is definitely more prominent when people start using concentrates. There's no question about that. I mean, we can talk about the concentrates, I guess, separately after.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Because I would say if we're talking about a harm reduction thing, that's more where we need to focus a lot more is this idea of these high potency products.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think you're far more likely to go overboard and have an adverse response. But also I think the problem is if you're using a product of that –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
potency and that much THC floods your system on a regular basis, the biological changes from that are going to be very different than what you get if, again, you're titrating your THC from inhaling plant at roughly the same level, whether that's a 10%, 5%, or 25%, people generally tend to scale.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So the joke I always make to people is I say, go watch a Cheech and Chong movie from the late 70s. Look at the size of the joints that they smoke in movies like that relative to what you would see someone on the street consuming nowadays. It's just, I mean, so the advantage that existed from a titration perspective was with like 70s weed, there's a large window to titrate.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So people could, you know, take small amounts and not overconsume, let's say, because there was a much lower concentration of THC in the plant. So they're able to consume, you know, even if they were doing it relatively fast, because of how little THC was coming into the system, it was a little easier to scale that. So there certainly is the propensity for people to overconsume
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
higher potency cannabis, even independent of concentrates, if they're not allowing that titration to occur. Also, if you have someone who is just exquisitely sensitive to THC for various reasons, even one or two tokes could be too much for them because at the higher potency, they may not have that ability to titrate quite as well.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so a lot of people, anecdotally, you talk to people about cannabis and a lot of people who don't like cannabis have said, oh, you know, I've tried the new stuff's too strong.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And if there's someone who's kind of more in our age range who grew up in an earlier decade where things were a bit different, they may be referencing their own experience from when they were younger and what they were able to consume. And now they try doing the same and it hits them like a sledgehammer. Got it. So it's a little different in that sense.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I don't think it's to say it's like not concerning that cannabis is as high as THC as it is. I just think if I'm going to put my efforts into kind of like public health perspectives of this, I would be digging my feet in much more about the access to concentrates and the issues and the potential harms that are going to come with them than I would about the cannabis flower myself.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
That's just my opinion based on what I see with the concerns and what we've seen from the data in humans. And I think the real world ecological studies that the Colorado group have done have been very informative in this sense because, yeah, if the blood levels of THC you achieve from concentrates are double to triple of what you get even from higher potency flour, that's a concern.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like I think that's where problems start arising because then you're going to start seeing a lot higher degree of tolerance. I mean there used to be more of a debate in the field as to whether people develop tolerance because –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
One of the things with cannabis that I do find very interesting is with a lot of chronic users, they don't escalate the way you would see with cocaine or alcohol where there's very profound tolerance that develops. And so, I mean, people definitely see this in cocaine where people can become tolerant almost immediately. And so dosing starts scaling up very fast.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, cannabis is a plant that has been around for some time. It's kind of got like a very rich history of use around the world for different cultures, for both kind of medicinal and spiritual and recreational purposes over several centuries. The plant has kind of become, I mean, in the West, it really wasn't a thing mainstream wise until about the 60s.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Seriously. Or the cost. I mean, the sheer cost.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, that is required to be able to maintain that. But with cannabis, it seems like there is some degree of tolerance that people exhibit. It varies from person to person. But, you know, as Meg has said to me many times, you know, the guys that come in her studies, these are very heavy users. And then, you know, they will use this relatively low potency product and still get high off of it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so it's not to say that there's no tolerance. It's just it's not as profound as I think we see with a lot of other drugs. And this is probably due to the fact of just like, you know, we definitely see like if we look at some pet imaging studies, chronic cannabis users do have some down.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Not good. Don't get dogs high.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, so a typical PET study in a human looking at this, they'd give a molecule that's radiolabeled that will bind to CB1 receptors. You can scan them and then look at the emission rates of the radiation to get an idea of the density of receptors that are in the brain. Chronic cannabis users tend to have less. What that means in terms of the functional outcome is unclear.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, there could be some... I think there's a lot of evidence that there's some degree of a reservoir of CB1 receptors that, you know, there might be a lot more receptors there than we necessarily always need or are always using, let's say. So we might be down-regulating a component of this, but maybe not all of the ones that are required to produce the psychoactive effects.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There's clearly some maintenance of the system that allows someone to continue to get intoxicated. And so with cannabis users, we do see that. But you do see much more profound tolerance with people using high potency extracts and concentrates and things like this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And again, surely I think as a response to the biology of hitting the system that heavily with that much, you know, THC as it comes in because they can't titrate it the same way.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then it became kind of introduced as like a drug of choice that a lot of people started using during the rise of the hippie era. And I think that was a lot of the time that cannabis got popularized. And then I'd say more recently, cannabis has into the 90s and on has become kind of a very heavily used drug by a large swath of people ranging from teenagers on up.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I'm not going to play with the definition of addiction. I feel like I have enough friends in the addiction space that it's a very contentious field. So, I mean, I will try and not use that word, although I understand talking to the general public, that's kind of, you know, if you say someone has a use disorder versus an addiction, that may not make sense to them.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so, I mean, an addiction is obviously a very complex thing that, again, I don't want to touch it simply because it's not my space. But that being said, there's no question that people can develop cannabis use disorder. I mean, it's definitely a thing. So if we say, is cannabis addictive in kind of a, you know, normal lay speak, I would say, yes, it is addictive. What does that look like?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
How does that relate to other substances of abuse? I mean, certainly... the outcomes associated with it are going to be slightly different than something like opiates or alcohol, because that's a totally different beast. Because you have fatality potential, there's a whole bunch of other health consequences.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But if we look at how we would define a use disorder, the criteria for someone hitting cannabis use disorder is really no different than how someone would hit alcohol use disorder or opiate use disorder in the sense that It can consume their life. It can shift the way that they behave. They can put themselves in risky positions to get access to a drug.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It can consume their time and their energy to have it. Like you said, if they don't have access to it, it can trigger an assembly of behaviors that looks like irritability, anger, frustration, things like that. So, I mean – The numbers in terms of the conversion rate of use to developing use disorder, I would say are not entirely clear.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
The kind of old numbers that used to get tossed around were like nine to 11% of people that would start initiating cannabis use would probably transition to develop use disorder. The more modern numbers, I would say, you know, if we're looking at people who are already using weekly, we're talking probably closer to 30%.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like, so it's a much higher, I mean, when you're using that frequently, then the rates of people who would qualify as having cannabis use disorder probably go higher.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I'd say in that neighborhood, they would probably qualify as meeting criteria for a cannabis use disorder. Because weekly doesn't seem like that often. No, I mean, it depends, again, on how you vary this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I've had a lot of conversations with the public, and I think depending on someone's experience in their own or in their own inner circles, life with cannabis, the way they would view it is very differently. Because I think a lot of people...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
In terms of what it is inside it, I mean, it's a plant with a lot of very complex chemistry and biology behind it. So there's a lot of molecules that it carries in it. We call these cannabinoids. And they come in a lot of different flavors. But the main one that's
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You know, again, regardless of anyone's opinion of alcohol, if someone told you they had a glass of wine with dinner every night, I don't think people would say you have an alcohol use disorder. I think that's not uncommon. I don't think they would.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Similarly, if someone had a brandy at the end of the night or like, you know, a nightcap to go to bed and they did that on a nightly basis, I don't think anyone would say that they have a use disorder. And I think with cannabis, there are a lot of people that kind of fall into that bracket that would use it, you know, even daily, but relatively infrequently and kind of as an end-of-the-day thing.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think some of them certainly would fall under the criteria of cannabis use disorder because if you start looking and say, well, you know, if you travel to like – Egypt. Are you going to go put yourself at risk of going to jail to get access to cannabis because you can't function without it? If you do, then yeah, you've got cannabis use disorder. Are you going to burn relationships?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Are you going to start failing at meeting responsibilities or getting things done on time because you're preoccupied with cannabis? yes, you're going to hit the criteria for cannabis use disorder. If it's someone who's kind of just intermittently using it the same way that a lot of people casually use alcohol, I would say a lot of them probably wouldn't hit criteria.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But I think to someone who has never had cannabis in their inner circle or in their life, they look at it like a drug like cocaine, whereas they're like, wow, if you were using cocaine on a daily basis, we'd be super concerned about you. And so I think that's this like...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's just as you go – I mean cannabis is in this really weird transitionary period I would say of going from illicit to not just because of the changes in the legal regulatory framework. I mean in Canada now we're like five and a half years into legalization.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So in many ways I would say the transition has happened where a lot of people view cannabis very similarly to alcohol whereas you go to some states and the perspective is still very different. Certainly if you're still in one of the states where there's no legal access, people still look at cannabis the same way they look at a lot of other – illicit drugs like cocaine or amphetamines or things.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's ironic, yeah, sadly. It's very, I mean... Obviously, a big push for legalization is not endorsement of the safety of cannabis. It's more the harms associated with prohibition outweigh the harms associated with legalization. I think that's generally the public health perspective. That's certainly what motivated it in Canada. And there was a –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
the most important one when we talk about cannabis and what drives the kind of intoxicating and what I would refer to as psychoactive effects of cannabis is a Delta nine tetrahydrocannabinol or what we call THC. Um, and that really is what dictates, you know, the psychoactive and intoxicating properties of the plant.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
some attempts, let's say, at restorative justice in terms of removing criminal records and things may not have been entirely as successful as people had hoped it would be, but it certainly has changed things. I mean, we can look at our federal data and see that arrest rates related to cannabis are obviously very low compared to what they were.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
That obviously becomes very important because there are clearly minoritized communities. They get hit more with this than other communities. And so the kind of perpetual disenfranchisement that happens with a prohibition model in communities that are already suffering from various other things that affect them just potentiates all that.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I can understand the legal framework behind why there'd be a move to a legalization state over a prohibition state, which again, a lot of people confuse legality with safety, which is a weird, I mean, alcohol is the perfect example of this. I mean, you look at the scale of harms on a public health level, I mean, alcohol stacks at the top.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
across the board in terms of harms to the individual, harms to society, it's a lot. Cannabis has harms. There's no question on that. It just would fall lower than alcohol. But the way that people view it, a lot of people are like, alcohol is legal, therefore it's safe, and it's not something to judge people on. Cannabis, at least historically, was illegal, and in some states still is.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So people view it very differently. And I think it's An interesting thing, because I feel like, you know, despite the fact that some people hate the government and hate the way that it regulates their life, there's this weird passive belief that, like, if the government dictates something is legal, that means it's safe.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. So it depends on how you break this down. So what we've seen in Canada is I would say there's like demographic differences. Proportionately, when we look at the biggest change in use, it's actually elderly communities. It's like 55 plus, especially women over 55 tend to be more cannabis, more cannabis use. Now, granted, their baseline was quite low, pre-legalization.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So if you look at a fold change, it looks like a very dramatic increase. Raw numbers, it's probably not that high. But, I mean, it was like 1% to 2% or something before, and now it's gone up to like 8% or something. So it's a fourfold increase kind of thing. So we do see the magnitude of that seems to be the biggest in terms of where the uses come from.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Definitely the young adult population, like 20, 24, that group has definitely seen increased use as well.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so the amount of THC that is within the cannabis plant will influence the, you know, how high a person's going to get when they consume it. There are probably 70 to 100 and some odd other cannabinoids that are within cannabis. Most of them are pretty trace levels, like, and they vary from different types to cannabis from one another.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Historically, cannabis tended to be more male biased. I would say the gender separation there has kind of narrowed quite a bit where you do see a lot more females used than historically had. There is a little bit of difference. Females tend to prefer edibles over males. So males tend to like inhalation over females. So like roots of administration vary a little bit based on who someone is.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But yeah, interestingly, we don't have a lot of – actual indication that teenagers have used more. So like, you know, you look at 14 to 18 year olds, that has been, now granted, our baseline going in was pretty high, as is down here in the States. I mean, Canada and the States both hover, you look at like grade 12ers and, you know, it's somewhere between 35 and 40% of them have used cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, I mean, you even have some that are like probably around 5% are probably almost daily users. So like you do have a pretty high baseline to begin with in that group, but that has remained relatively unchanged. If anything, some of the states when they legalized saw slight dips in teenage use of cannabis. I think, like, that's obviously an important demographic to have tracked.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
This was one of the concerns with legalization was you'd increase access. Teenagers would get it from their parents and whatnot or had just, you know, other siblings and stuff. And so you get this big boost in consumption. But we don't seem to see that in terms of raw numbers of teenagers who are using cannabis. So that's good. ER visits, yeah. So we did an interesting rollout in Canada.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We legalized flour for a year before edibles came online. So we have kind of a before and after. Once edibles became available, there was a notable increase in –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
unintentional pediatric consumption that resulted in er visits because kids would you know a lot of these look like gummies and candies people are buying them not you know storing them properly kids would find them and eat them and like become very intoxicated i want to make mention of something along those lines um i actually know somebody whose child um
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Well, so this was one of the things that also was influenced by legalization is in Canada, like some of the increase in the ER visits was because of the shift in legalization and the change in policy. And so, you know, if your kid ends up drunk underage, It's not the same ramifications as if your kid used an illegal substance underage.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But the other one that's had a lot of attention is cannabidiol or what we call CBD. CBD is structurally looks pretty similar to THC, but doesn't behave anything like THC. It's not intoxicating at all. I'm not sure. I would probably say it's not psychoactive in the sense that people can't tell if they're on it or not.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so people are – once cannabis was legal, people were more likely to actually go into the ER because the consequences were different.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so, sure, some of this is availability and some of it is just like, OK, I'm not as concerned now about – something happening because I've taken my kid in. I'm not going to have my kid taken away from me or whatnot. So there is, I mean, both those factors I think have contributed to it, but we definitely see the majority at least of kids ending up in the ER is almost all based on edibles.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I can't imagine a situation where that would happen from inhalation. It would be very rare if it would. It's almost always edibles because kids find them.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So edibles... So this throws a wrench in the whole system. And I'll say this in the context of blood levels and then what that means from a regulatory capacity as well because of the impact this has. So edibles are very low doses for the most part. I mean, in Canada, at least, you cannot buy a pack of edibles regularly.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
and I think this law might be changing, at least when they first brought it in, no pack could have more than 10 milligrams of THC in it. So that either meant one 10-meg gummy or two 5-meg gummies or four 2.5-meg gummies, you get it. So you couldn't in one package have more than 10 milligrams of THC. Now, for people who are...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would say relatively naive to cannabis or THC, even people who might use it intermittently, most people will feel five milligrams. Like they'll feel some form of intoxication. You know, some will even feel it at 2.5 mgs. Most people will feel it at five. Virtually everyone will feel it at 10.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, if you look at the blood levels these produce, we're now talking blood levels of two to five nanograms per mil. So folds lower than what you get from inhalation. Before you said 100. Yeah. So this is dramatically lower. And so- Also, the time course of this is fundamentally different. So oral consumption, you know, you're looking at a minimum of 30 to 45 minutes for onset of intoxication.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
For some people, up to 90 minutes after they've eaten. Now, this is also the reason why... The majority of adverse events that happen with cannabis happen with edibles because people don't understand this. And so they eat a cookie or a gummy. They wait half an hour like, I'm not feeling anything. I clearly didn't take enough. And then they'll double their dose.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then like 15 minutes later, it starts hitting them. And then like once it fully kicks in, it's just like a steamroller.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. Yeah. I mean, there was that New York, I think it was Maureen Dowder, someone went down to Colorado and she ate like an insane amount of THC in a chocolate bar, something like 50 or 100 milligrams and spent like the weekend on the floor of a hotel room being like, this was the most aversive experience. Why would anyone do this?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But I would – some people still say it's psychoactive because people claim it can affect anxiety state or mood state or other things. So in that context, maybe psychoactive is still somewhat appropriate of a word to use. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And again, I think people just don't understand the dosing around this. And so This is one of the things we're trying to do in Canada, and I was creating this idea of standardized dosing units so that people have an – like we do with alcohol.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We always say one beer is the equivalent to one glass of wine versus a shot of tequila or something so that there's some comparator that people understand how many drinks are – two drinks you do, you're going to hit legal limit kind of thing. Yeah, it seems very important. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so this is very difficult to do with cannabis because the dosing with oral consumption is just a different ballgame than it is with inhalation. But what happens with oral consumption is like it kind of very slowly leaks out of the GI tract. And it also goes through first pass metabolism in the liver. And what happens there is you get a metabolite called 11-hydroxy-THC, which –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Seems to be a bit more potent than THC is in terms of its ability to activate the receptor. So its efficacy, at least, at driving a response through CB1 receptors seems to be higher than what you would get with just the parent molecule of THC itself. And... So, and it seems to accumulate a lot more as well.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So at any given time, you know, you've got THC kind of leaking out of the gut, going through the liver, making 11-hydroxy, and it progressively accumulates in the brain. And that's one of the reasons why it takes, you know, 45 to 90 minutes to kick in. But then the high itself also lasts like six hours, four to six, sometimes eight, depending on the person, what they've eaten.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Versus inhalation is just this like spike. So you get this very rapid because it goes right through the lungs into the blood, goes into the brain, but it also clears out. And so, yeah, people will start feeling intoxicated two to five minutes. The peak high is like 15 to 30 minutes maybe from consumption. And then they'll start to come back down.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And you will still see some indications of intoxication that can go on for three to four hours. But the bulk of the intoxication from inhalation is done by two hours for the most part.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then there's a whole bunch of other things like cannabinol, cannabigerol, and these other minor cannabinoids, most of which we really don't understand any of the biology of. We don't know what they're doing. They may influence some of the effects of THC. They may not. But they're there, and they vary in their composition from different flavor of different cannabis to different flavor.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, you could still fail a drug test at 80s. I would say – I feel like – I think the way it was worded more, it was like that – you made it sound like that was the standard. I wouldn't say that was the standard at all. I would say – For the majority of people, 30 days probably after that, they would not pass or they would be able to pass a drug test.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, after abstaining for 30 days. And it's going to be highly variable depending on how much you consume. I mean, if you're talking about someone who's used it once, I don't imagine it would be in your system that long. That'd be surprising. The thing is, THC is... a lipophilic molecule. It's fat soluble. Yeah, so it's fat soluble. It likes the store. It doesn't like the blood.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
The blood is aqueous and watery. It likes fat. So it goes into the brain, it goes into the fat, and it kind of resides there. It can essentially kind of slowly leak back. As THC concentrations in the blood would reduce, THC that's in the fat will start kind of leaking back into the blood still. So detectably, you will still have THC for quite some time.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, some of this, again, it's going to be dependent on how much cannabis someone's used, how much THC they've consumed, how long it's been in their system for. I would have thought this was going to be somewhat reflective of people's body fat content, although talking to colleagues who do this, they say not always.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But we do know certain things like exercise, for example, anything that's going to trigger adrenaline because adrenaline is lipolytic. So adrenaline causes fat to – metabolize and release stuff that's inside it. So there are plenty of cases I've heard from people where they were testing themselves and were negative and then went for a run or went to the gym and then tested positive.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Or lost weight. Yeah, or they've lost weight. And anything that's going to cause the lipolysis to occur so that it releases that THC, you can certainly all of a sudden test positive again when someone had tested negative previously just because of the fact that there still is some in the fat.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so this is where something like – and this is what I mean by standardization of regulatory issues become very complicated. I remember – Right when legalization happened in Canada, all these kind of chemists were like talking to me about they're going to create like a breathalyzer for cannabis because this way they'll be able to do roadside detection the same way they could do with alcohol.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I kept trying to say to them, I'm like, the rate limiting step here is not the science of detection thresholds. It's the biology of how the body processes cannabis. And you're never going to get a test that works because you can take someone who has eaten an edible and is profoundly intoxicated, and they will have possibly under five nanograms per ml of THC in their blood.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You get a bit of it from inhalant, but not nearly as much as you get from edibles.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then there's those other things called terpenes, which are kind of highly volatile compounds, but they're not specific to cannabis. They're found in tons of other plants. So this is a lot of which seems to contribute at least to some of the smell and the flavors of cannabis. So these are things like limonene, which, you know, gives some cannabis kind of a citrusy flavor. odor or flavor to it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It is, but it's also the timeline because of the fact that with inhalation, it's like a bolus that hits you at once. You get a high blood level. With edibles, it's like the time course. So, I mean, it's going to be like five nanograms per mil, let's say, but it would be like that for a long time. Whereas the 100 nanogram per mil from smoking is like for 20 minutes and then it starts dropping.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, but the problem is with the way that you detect it is you can take someone who's a chronic cannabis user and is completely sober and hasn't consumed in a day or two. And their basal levels of THC in their blood may be higher than someone who's profoundly intoxicated by an edible.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Just by the sheer nature of the fact that it would reside in their fat tissue or their brain, it would leak back into the blood. And so you have this issue where, let's say your cutoff was five nanograms per mil, which is for some of the stuff detection thresholds would hover around that area. So you could have someone who's dead sober
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
that tests positive and someone who's profoundly intoxicated who tests negative. So it's like, what's the value in this? It's not telling us anything.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Potentially, yeah. So, I mean, it is complicated.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would say it's – There's nothing that's super clean cut. I mean, I know in the previous podcast, you talked about a prolactin thing.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We'll go with cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I understand it, but yeah, a lot of people don't know.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Pinene, which gives things more of like a earthy tree kind of smell. Beta-caryophyllene, myrcene. And these terpenes are also, some of which do have known biological activity, some don't. And they vary quite heavily across different kinds of cannabis as well. And again, there's some thought that they may be influencing some of the psychoactive or intoxicating properties of cannabis. But
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's super mixed. So, I mean, you talk about something like prolactin, for example, that is another one that's obviously involved in this whole cascade stuff. Generally, I would say the bulk of the literature actually says that cannabis would suppress prolactin, not increase it. That's the majority of the literature that's out there.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Probably. I mean, the rodent work would suggest it's through dopamine that's turning off prolactin because you can reverse some of these effects by playing with dopamine signaling. So I don't doubt that's the mechanism. So typically, I would say more often, I mean, there's studies with inhalation and IV that have generally found reduced prolactin.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And in chronic cannabis users, they find somewhat lower resting states of prolactin. That's been found in one study that came out of Yale. Interesting. Testosterone gets a little bit more complicated because... There are a lot of studies that find, A, to begin with, cannabis users may have higher levels of testosterone just at rest.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't know. Yeah. I mean, that being said, a lot of the stuff—now, granted, this was mostly done in the 70s. And, like, this is from my previous life because my undergrad and graduate supervisor, he was a neuroendocrinologist— focused much more on sex hormones and reproductive hormones. So we've written a few reviews. So I've done like reviews on this area. And I know the literature somewhat.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's mixed. But generally from the 70s studies, what they would often see is that if they – would serially look at testosterone after someone consumed, they would have little dips. Like that wasn't uncommon for them to find it. Not every study found it. That being said, the kind of range that testosterone stayed in was always the normative range.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like it was never that it went so low that someone would have classified as being hypogonadal or would lead to something like gynecomastia, at least from a testosterone deficiency side in terms of the balance between testosterone and estradiol. I don't know as much about the aromatization side of it. Again, I'd say it's pretty mixed.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I don't think the gynecomastia stuff is, I mean, certainly people online might be talking about it and there might be some other components to this. I've also heard, and again, this isn't like science. This is just the same kind of stuff you see on random internet communities. People talking about, oh, well, you know, it has plant estrogens.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So maybe they're subbing in and having estrogenic effects. I don't know how valid any of this is.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, and I think that, I mean, when it comes to something like this, I've not seen any compelling evidence for it. So I can't, I certainly wouldn't say that it's a typical side effect that men would experience is like developing breast tissue in response to cannabis. I feel like if that was the case, it would be very known in the scientific community as something that comes out.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
The reality is we really don't know a lot about them at this point. There's kind of some emerging work that's starting to come out now that kind of plays with giving someone THC and adding in one other terpene or one other minor cannabinoid and seeing how it influences things.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like someone who's on steroids or something.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't, I mean, I'd say like, yeah, this enough studies to suggest that you might see transient drops in testosterone from cannabis. And it seems to be relatively short lived. Um, it doesn't seem to, but again, a lot of these studies also find that the basal testosterone is already kind of high to begin with. So you're staying in a normal dynamic range.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Again, it's homeostatic, just like, just like the
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. So, and that's the thing. I mean, testosterone fluctuates across the day anyway. So there's already, I mean, there's other things that fluctuate. It's like cortisol. These hormones have cycles. So as long as you're in this normal range, there really shouldn't be any kind of like behavioral, like in terms of sex drive for testosterone or like physiological...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like gynecomastia or some change in, I mean, now there are potentially effects of THC directly on the testes that could affect sperm. That could happen independent of changes in testosterone.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I mean, a lot of the kind of in vitro stuff definitely would suggest that, some of the animal stuff as well. The human stuff is definitely a bit mixed. I mean, but again, if anything, it would be like, yeah, it could have some effect on sperm.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would say that. I would agree on that. So I would say if someone was asking me this and they were trying to get pregnant and struggling, I would say, well, definitely cut cannabis because – Some people may be more impacted by it than others.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So for some various biological reasons that we don't have a biomarker for, there may be some men that use cannabis and it has a profound effect on their sperm quality, their sperm capacitance, their ability to maintain fertility. And for the bulk majority of men, I'd say that's probably not the case.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You can imagine with the plethora of molecules that exist in cannabis, doing this in a piecewise manner could take decades to kind of really get to a point where we understand all the interactive components of cannabis. But people tend to refer to this as like an entourage effect. That's kind of a phrase that gets used quite widely in the cannabis world. And the idea behind that is that
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But again, if you're someone who is struggling and you use cannabis, male or female, I would say cut that out and see if that has an effect for you.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, it's very, I mean, I've heard higher numbers than that. In the research literature. No, I've heard higher numbers than that as well. Okay, so I'm on the low end of this. Well, I mean, so I've heard as low as two and I've heard as high as 20.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So first thing, going back to the levels, that's challenging because again, this depends on, are you talking about self-report or are you talking about verified blood levels? Because those have varied. So some of the higher numbers actually come from blood levels where they've taken blood samples and found THC, but the women have reported not using cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so the idea that it's like the self-report numbers tend to come in around two or three My guess is the real number is probably somewhere around 10%, but that also is gonna vary depending on what you're talking about because there are a proportion of people who are using cannabis and become pregnant and are unaware they're pregnant and are still using cannabis and that would still qualify
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
under the way that it's defined, that someone used cannabis while pregnant. So the majority, I would say the overwhelming majority of people, once they learn they're pregnant, now that can be all the way up to almost the end of the first trimester, typically stop using cannabis. That seems to be The norm, I would say. Important point there. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think also the number that carry on through the entire gestational period is going to be a lot less, I would guess. Now, the motivations for this quite often are more in the capacity of the kind of anti-nauseant qualities that cannabis can have for some people and for women struggling with morning sickness.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, anecdotally, I have heard women say, you know, with the history of things like thalidomide and other anti-nauseant drugs that had profound teratogenic effects on the fetuses, women have said that they would rather use cannabis than one of these other compounds because they're less concerned about the impacts of cannabis than they are because of the, you know,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
the thalidomide effects that happened.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, I actually have no idea, but I would imagine. I think it would be one of those hard things to sell, given its history especially. So I think there's a reticence of a lot of people to consider using pharmaceuticals to regulate nausea because they're uncertain of the consequences of it. And they feel that cannabis may be safer.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
If you took pure THC, and so there are some like distillate pens and things that exist out there now in the product market, which are basically isolated THC with trace levels of anything of other stuff, would be very different than if you had THC in combination with some of these other molecules and how they might influence how THC itself is working or not.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, that in and of itself could present some problems in terms of that thought process. Now, there was also a study that I thought was like some of these things just – It's where they actually decided to call, this was done in Colorado where they called dispensaries and just acted naive and asked what their recommendations were.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And it was something like 80 to 85% of them were actually recommending that people would use cannabis to manage morning sickness. And I thought that was like, it's just one of these disappointing things where you're like, why are you being so wildly irresponsible? to kind of promote these things.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You said it, not me. Could be. I mean, you can balk at either side of this. I think it's... I mean, I have... a lot of frustration in general with the information that bud tenders put out into the world. Is that what they're called, bud tenders? Yeah, bud tenders. That's kind of the colloquial term that people will use for someone who sells cannabis at a dispensary.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
We see this in Canada, and I've heard this throughout the States as well. I personally have been a huge advocate for the fact that I think – so I worked in restaurants and bars and stuff when I was younger. And for me to serve alcohol, I had to undergo – I don't know if you do this in the States.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
In Canada, you have to do like a – it's like a weekend course essentially called like serving it right or some other terminology where you learn the basics of alcohol, harms, blah, blah, blah, how to tell if someone is intoxicated, when you have to cut them off, all these things that you have to do to be able to serve alcohol. I have no idea if this exists in the States, but –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It was a thing in Canada.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like anything, even if it's just like an online quiz. So my perspective is because pre-legalization, at least in Canada, there was somewhat of, I think, of a misguided thought that people would leverage their physicians for knowledge about cannabis. And what's become very apparent is that the overwhelming majority of people talk to the people selling them the cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And yet those people selling cannabis don't need to have undergone any form of education. And so like this kind of kills me because we've worked very hard to try and create educational platforms that are like agnostic in terms of our position on cannabis that are just based on the science.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I'm an executive director of an organization called the Canadian Consortium for the Investigation of Cannabinoids, the CCIC. And we've done CME courses for physicians to try and train them about cannabis because I think it's important that physicians understand this. But
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I've tried suggesting that I think that anyone selling cannabis should undergo a course like this just so that there's some consensus in the informed level that someone who comes in – because a lot of people going to buy cannabis are quite naive about it. And they just – I mean even when we're talking about dosing, what we've talked about with edibles or smoking or how people consume it, like –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You need to have a reliable source of information at the front line that is able to relay that to people. And it becomes very frustrating to me that they have become the main source of information that people go and I'm uncertain of what their level of training is.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, yeah, exactly. So I think that I just wish, I mean, again, even if this was just like an online course that wasn't that much, but at least had some consensus of information that was the basics about how to, you know, have conversations. And I mean, some of the, our system at least is somewhat provincially regulated.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So like, you know, our organization has worked with like the Ontario group that deals with cannabis distribution, like the OCS, which is Ontario Cannabis Stores, and helped to create some information pamphlets and stuff. Again, it's not the same as a teaching course, but at least it's like these little infographic stuff that kind of like gives people rough breakdowns of things.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
and kind of gives you a little bit of information about dosing and understanding things, like especially with something like edibles, how long you should wait, just stuff like this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, that's the, yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Actually, when I say that- Is she still on the floor in a Colorado hotel? She may have recovered by now.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But like- Yeah, it can become very frustrating. It's just the kind of lack of understanding that exists in this space. And so I think this is one of the reasons why we've really kind of tried to push the public health side of this a lot more. And we have, I mean, there was the Center for Addiction and Mental Health in Canada, which does a lot of the organization of these things.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
They did kind of put together what I found to be really useful, which, again, could be leveraged in the States. These are all accessible online. It's called the Lower Risk Cannabis Use Guidelines. They kind of tried to create a framework that is similar to how people have done stuff with alcohol. Um, that just kind of goes through.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And a lot of it is this low and slow approach, but it's like, obviously you want no risk. You abstain. If you're going to use, these are the different ways to engage in harm reduction. Um, you know, like obviously oral consumption has, you know, you avoid the issue of lung damage that you could get from smoking.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Um, but then, you know, with oral consumption, you have to be aware of dosing and timing and all these other considerations. But what about vaping? Um,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think that will depend on exactly what you're vaping. So in the States, I've noticed when people say vaping, they almost exclusively refer to some kind of oil-based product that's in a pen. Yeah. So in those situations, that's going to really heavily depend on what the concentration of THC in that product is.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, the other form of vaping that I think is a little bit more common in Canada maybe is vaping of the plant matter itself. And so this is where they have like a vaporizer device that heats the cannabis to a point that will essentially hit the lift point to vaporize THC in the cannabinoids.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, yeah, like a volcano. I've seen it. Yeah, but it doesn't create any plant combustion. And so there are studies that have been run on that that have shown that you avoid the combustion byproducts. So people don't like exhale carbon monoxide or these other things that we know can be damaging if they're vaping plant matter. that was actually somewhat approved as like a medical device.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Pre-legalization in Canada, cannabis in Canada was only under medical authorization, um, because of the reduced harm associated with vaporizing the plant matter versus smoking it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Um, that is, I would say as a safe guideline for harm reduction, that if you're going to try and avoid, you know, there's still going to be some issues that happen with vaporization of plant matter, but it's not the same as combustion. So you avoid like some of the other issues that come out when we're talking about, um, oil-based vapor products or whatever they're in.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
They're usually in some kind of oil-based solution. Who knows? I mean, we don't have the research on this. Like, we just don't know. I mean, we certainly know, like, there have been some pretty big errors of, like, the things that happen in the States.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like, there was that problem where all those people developed kind of, I don't know, popcorn lung or that lung inflammation where several people died from vaping products, which seemed to be, like, a byproduct, I believe, of them adding, like, vitamin E acetate or something into the – Because again, everyone just assumes it's inert.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But then when it combusts through the vaporization process, it creates a massive irritant on lung tissue. And so that was just – again, in my mind, this is a problem with a lack of a federal regulatory framework because stuff like this happens. You would not see that on a federal landscape because you would have to go through testing. Like people – it's kind of the Wild West you get down here.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Every state has its own rules. People – there's not really a lot of like regulation of things.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, I mean, the way that people would usually describe the intoxicating effects of cannabis is, they would, I mean, people often refer to it as there being some euphoria or some positive mood, not on the same order as what people would describe with, say, cocaine or some other stimulants, but there certainly is some kind of positive aspect.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, if there wasn't, people wouldn't be using it if they didn't feel positive about it afterwards. There can be, you know, other aspects of In terms of changes in feeding behavior, people might find things funnier than they found things. It might change the way they perceive various environmental stimuli.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But it can also, for some people, create a bit of a dissociative state to some degree where people might feel a little bit out of body. So it's kind of a complicated process. intoxicating state to describe, I would say. Because usually if someone's referring to something like a stimulant, they're just like, oh, people feel like they're God. They're like, you know, jacked up.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
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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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And then the adverse effects when someone consumes too much and they have a negative response, that's probably due to the higher dose starting to saturate on the inhibitory neurons. Now, we obviously can never test something like that in humans because we can't know. But based on what we've seen in animals, that's...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
my theory of kind of how this is working and why we see these kind of classic biphasic effects. So yeah, too much THC, not a good thing, because then you start maybe disinhibiting things like the amygdala and producing these kind of panicky, anxiogenic-like outcomes. On that scale though, I mean, paranoia, obviously that's a hard, I don't know how you study that in a rodent.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, that's just a strange thing. So, but I mean, that's kind of the precedent of when you start going into the psychosis, because obviously paranoia would be a big component of that. Someone wants to ask me a question about, you know, have, you know, what happens in the brain, like imaging wise, when someone's having like a psychotic episode from cannabis?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I was kind of thinking like, how would that study get done?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I can't actually even imagine how that would go down. So I'm like, this is something I don't think we're ever going to have an answer to because I don't think you can actually ever test it. But in terms of people having this kind of psychotic response, it is pretty... rare.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, and I say this because I can think of in Canada, kind of whenever it's happened and someone has actually done something wildly unpredictable because they've had a psychotic response to cannabis, it tends to make headlines. So it's not common. I could not give you an actual number, but it's certainly not a frequent thing because we would hear about this a lot more if we did.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, exactly. Like they're very happy and they're kind of jacked up. And I think with cannabis, the way people would describe it would be very different. It's like kind of an introspective state. You might be more aware of your bodily. feelings and states that are going on inside of you, your kind of internal state. But you also have like a different perspective on external stimuli.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I wouldn't say... I mean, there's certainly... Cannabis is used in tandem with other drugs, alcohol, psychedelics at times for sure. But that being said, I mean, there is clearly a population of people that use cannabis as their only drug that they use. I don't think that's that uncommon. But in the context of the psychosis stuff, I would definitely say – Sure.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, if someone mixed it with amphetamine or something, you could have a very unpredictable response. But I mean, I think the psychotic responses that have been documented are usually purely due to cannabis. Like it's not necessarily due to some kind of drug interaction there.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There is something about the way that cannabis is changing the way the brain functions in a way that for people who seem to be prone to this, they can have a psychotic response. Again, I don't think it's a very typical thing, but... And we're talking about what that means in the context of like an actual disorder, like a chronic disorder like schizophrenia, which is characterized by psychosis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think we're talking about a whole different ballgame here. And this is an area that is, I mean, I think it's an important thing to discuss in the context of science because you can't establish causality. Like in my view, it's virtually impossible because there's just no way to control all the variables that play into this. What we can say definitively is that
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
individuals who have schizophrenia, first of all, they use cannabis at a higher rate than the general population. That's very clear. Yeah. They definitely use cannabis at a higher rate than the general population. There is definitely a relationship between using cannabis and having the initiation of the development of schizophrenia.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And this is where a lot of the statistics that have been used to develop the risk assessment essentially like so that you have a greater risk if you know like you were saying if you've used cannabis as a teenager you use high potency as a lot of the research has shown though they've done these studies and they say it relates to um a greater risk of schizophrenia essentially
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
This is just a statistical association that they found that people who use cannabis, the conversion into schizophrenia happens at a higher rate and there's more people with schizophrenia who are using cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
To be honest, in all the research I've – in all the literature I've read on this, I don't ever remember there being clear sex descriptions of the differences of males and females. I mean, again, historically, cannabis was more used by males than females, so that could lean towards any bias that may be out there in the media or the popular – like just in general, what people talk about.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I can't think of any study that I've ever read that explicitly said this was male bias per se. They usually just report numbers or proportions of people. The issue is, So yes, there's this relationship that exists. And yes, we know that cannabis can trigger psychotic episodes.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You might process information a bit differently, focus on things a bit differently. So it's kind of a complicated state to describe, I would say. Usually when people are assessing if someone's intoxicated, like...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So if there's an individual who has schizophrenia, we know for certain that cannabis can lead to the onset of, you know, increases in positive symptoms like hallucinations and delusions and a full-blown psychotic episode. So I think the first thing to say, which is very clear, is in my view, if someone has schizophrenia, cannabis is contraindicated.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like you shouldn't be using cannabis if you have schizophrenia. I think that's a risk across the board.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I was going to say, the next question is knowing who's going to develop schizophrenia. Obviously, we don't know this. And as you say, the only real predictive variable that we know of is a first-degree family member that has schizophrenia means that you have a higher risk of developing schizophrenia. So again, same with bipolar. I would say if there's bipolar or schizophrenia in a family,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
To me, those are the people who should avoid cannabis. Just in terms of the likelihood, there's a much greater likelihood that they'd have, it would relate to the onset of a disease or could accelerate its presentation in some capacity. I think where things get really complicated in this whole cannabis schizophrenia story is the causality.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And there is a camp of people who have looked at this literature and definitively believe that cannabis causes schizophrenia. Um, and they attribute a proportion of people who have schizophrenia to only having that schizophrenia because of the fact that they used cannabis. Um, and I think you'd had some discussion about this in the last podcast.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I can't remember exactly the way that you described it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
the kind of lab work where people get someone high, they just kind of use a, what we call a visual analog scale, which is like a one to a hundred or something or zero to a hundred and say, do you feel high? Do you enjoy this? Would you say you feel euphoric? Is your mood elevated? So they're kind of scaling things like that.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I think this is what happens when you have I mean, obviously, you're familiar with this. In science, there's different, you know, some things that we can be a little bit more definitive about. And then there's some things that we just can't know for certain. It's just the way it is because of the way that we gather data and because of the way humans are.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And this isn't a question I believe we can ask from an animal model perspective in the same capacity. So I don't think anyone would deny, at least anyone who's read the literature, that there's this relationship between cannabis use, especially in adolescents, and the development of schizophrenia.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Now, my perspective on this is, and I'll explain why I have this perspective and how I justify it, is to me, cannabis is fuel on a fire. So if someone is prone to developing schizophrenia, adding cannabis into the mix I think will make it kick in faster and harder. So if there is a genetic vulnerability for developing schizophrenia or some biological predisposition that's there,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I would say in that situation, cannabis can trigger an initial onset of the first episode, and it can make the prognosis of the disease in the long term a lot worse, let's say.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, I've never heard that, but that would be a stressor, and stressors are other ways. I mean, a lot of... you know, the situations where, uh, I mean, some of it's the age, but like, you know, for example, if someone is prone to develop schizophrenia, they move away to college.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Even that stressor can be something that brings on an episode, but cannabis very specifically, like different than any other drugs like alcohol or cigarettes, as far as I understand it, at least the temporal relationship between cannabis use and the development of a first episode can be pretty linked. Um,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But the arguments that I've always had with people in this area who are very definitive on their end of the spectrum that this is a causal relationship is – First of all, we have a few things that like I would leverage as kind of real world evidence that makes this questionable.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I think that's more typically in a lab setting, how you would define if someone's high or not from it. And this is why when people do studies with something like a placebo cannabis or a very low THC cannabis, you'll see kind of a scaling. So, um,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So the first one is like I was saying earlier in the episode, I mean, we really didn't have cannabis use in the West like as a normal thing, as one of the drugs that was part of the repertoire of what people use recreationally until like the 60s. So unlike alcohol, which has like been there for centuries, we have a little bit of a before and after. What we can look at. The Grateful Dead. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So now, granted, we don't have like really good prevalence data of what schizophrenia was in the era prior. I mean, even nowadays, our prevalence data is not perfect. But if cannabis as a solitary variable was driving the genesis of schizophrenia de novo.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
In the absence of any kind of biological predisposition or genetic predisposition, I find it very hard to believe that we wouldn't have seen a shift in the prevalence of the disease as cannabis became more mainstream and more widely used. And generally, schizophrenia rates have remained largely stable.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
People can make arguments about that, better care, other things to challenge that argument, sure. So another modern perspective would be, okay, well, let's look at Canada and the States, let's say, where we have, as I said earlier, teenagers in Canada and the States, by grade 12, 35 to 40% of teenagers have at least used cannabis, somewhat sporadically.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And somewhere around 5%-ish are probably using almost daily. So we have... concentrated group of what would be the high-risk population here that are using at a pretty high rate. And then we compare that to somewhere like, let's say, Norway or Sweden or any of the Scandinavian countries where cannabis is like not a thing. Certainly not at a recreational level and not in teenagers.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I mean, the use rates there are probably under 5% globally for teenagers, like probably closer to 2% or 3%. So you have two countries that have pretty similar social structures and other capacities of things. We're both Western countries. And yet, Our schizophrenia rates prevalence-wise are relatively comparable.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And yet in Canada and the States, our cannabis use rates in adolescents are wildly amplified compared to those countries. So again, if this was causing schizophrenia to develop as a disease out of nowhere, how would that not track? Like how would that not be seen when you just look at individual variances across countries and prevalence rates?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Even if you give someone a placebo cannabis, if they think that they're getting cannabis, a lot of people still respond by saying they feel a bit high.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
You could probably use Greece or Italy. I mean, they're going to have cannabis use higher than Scandinavian countries, but it's going to be way lower than North America still because it's just.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I have no idea. I mean, I think it's just part of the culture here. It's just evolved totally differently. The Grateful Dead. No, I'm not picking on The Grateful Dead.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But I mean, like you also have like in Europe, though, alcohol is also much more normal, normalized in general. Like kids will drink. It's not abnormal for kids or teenagers to drink. Alcohol is just much more of a cultural thing as well. Yeah. There are just differences. I mean, it's the same thing. You look at like the opioid crisis that we're going through.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Sure, it's there to some degree in Europe, but it's nothing like it is in North America. We are just a different beast for a lot of drug use.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I don't think dramatically. I think we're pretty comparable. I mean, for cannabis rates, I would say they're almost the same. I've not seen – sure, you might get some regional differences. Like we – I think Quebec has much lower rates of cannabis use than some other parts of Canada. And you guys probably in some southern states maybe are a bit different than other states.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I don't know about that. But again, overall at a federal level, I think the – which is where most of the data aggregates, I would say that they're pretty comparable with each other. They're not wildly different at all. And again, even if you talk about climate, a lot of the US is a lot warmer than Canada. And you guys are certainly closer to the equator than we are.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I'm not actually certain if you are allowed to have someone in a drug study if they've never done something before. I think they have to have had some previous experience with a drug to be enrolled.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I mean, we know like you do see higher rates of schizophrenia in urban settings than you do in rural settings.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There's other, I mean, you also have more like, there's just, yeah, there's a lot of transitory populations that come in and out of cities that you don't see as much in rural communities. There's a lot more mental health services. There's other variables that can influence that. No one's really, I think, sussed out a mechanism to explain why you see that.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So there are things that shift across places, but I don't think it has anything to do with the rates of cannabis use. And I mean, the other thing that became very interesting in this whole debate over the last 15 odd years that people have really been talking about this a lot more is the fact that
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
There's also been several studies now that have done genetics either at the GWAS level or just even just looking at polygenic risk scores. And there's at least three papers that I can think of off the top of my head that I could put the citations down for for sure after this that do –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
look at this from a somewhat, let's say, unbiased perspective where they see, you know, there's certainly some genetic architecture that relates to people either initiating cannabis use or people developing cannabis use disorder. And there's clearly some genetic architecture that relates to risk for schizophrenia.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And what these studies have found kind of across the three of them was quite similar, which was from their analysis, the directionality suggested much more that having genetic risk for schizophrenia predicted cannabis use, more so than cannabis use predicted the development of schizophrenia. Interesting.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So what that would mean is that there is some underlying biology that might be shared between a biological vulnerability to develop schizophrenia and some factor that relates to people using and or liking and or excessively using cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah, but I think, yeah, I don't think you can use drug-naive people. I mean, I don't run human clinical lab studies, so I can't explicitly say it, but that's my understanding is that someone has to have had even limited, like, not much, but at least once or twice. They have to have experienced the drug before.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, I mean, and this is, you know, I've debated with other researchers in the area in print and in person about the different interpretations of this. And one of the possibilities is, again, this idea of self-medication. I mean, independent of there being some underlying biological… thing that just is a third variable that explains the relationship between cannabis and schizophrenia.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
The other possibility is self-medication. And there are some studies that suggest this and others that don't support it. Anecdotally, from having done work in the community and talked to individuals who have schizophrenia, who use cannabis, what their perspective on it is, what I've heard from a few of them is the medications that they're provided to manage the disease are
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
relatively effective at managing, let's say, the positive symptoms like hallucinations, delusions. That aspect of the disease is somewhat well managed. But then there's another component, which is the negative symptoms, which is kind of like things that, you know, abolition. So I don't like engaging in stuff. There's some anxiety, some depression, some social withdrawal. And
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
A lot of the medications don't manage that component of the disease, and they have said that they find cannabis helps that side of it, or it helps them de-arouse a little bit. Even though a lot of them recognize it may trigger the development of some of the positive symptoms, they feel that they don't have any tool in their kit to manage the negative symptoms.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so it could be, in my mind, when I look at that, it could be a bit of a vicious cycle, where someone's using it to kind of band-aid one aspect, but making other aspects of the disease worse at the same time. So it can get very complicated, but...
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So, I mean, there are various ways of looking at this in terms of, you know, so it's either you could say there's a causal argument, which is made by many saying cannabis causes schizophrenia. And therefore, if we eradicated it, I think you had alluded to something like that in the last podcast, that if you removed it would have this big effect. in terms of reducing schizophrenia rates.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I don't know if you would take someone who was completely blind because I don't know how they would replicate that state if they're not expecting it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And that's similar to the argument that a lot of the researchers in Britain have made. And I'm not personally convinced of that. And I say that simply because I look at the data from Scandinavia and I'm like, well, there you have a population that barely uses any cannabis and yet their schizophrenia rates are the same. So the only way in my mind
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
If I look at this kind of scientifically from a data perspective that cannabis could be causing schizophrenia de novo in a subset of people is that there must be an equal proportion of people for whom for some reason and somehow cannabis is preventing them from developing schizophrenia so that it's a zero-sum game at the end of the day and there's no change in rates.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Like I can't actually understand any other model that could explain this. Yeah.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
for in like heredity family trees, for example, where you look at something like bipolar schizophrenia, the two do kind of track together. So it's not, I mean, I think it's hard to separate these in some capacity because, you know, I remember years ago at Society for Neuroscience, Glenn Close was one of the, I don't know if you were at that meeting,
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Glenn Close was one of the public speakers and she had talked about schizophrenia and her family tree and she kind of put up this family tree of her family and the previous relatives in her family and showed the individuals who had schizophrenia and bipolar as well.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And this is something I think that's been seen a fair amount is there is some co-relationship in the way that these track at a heredity level. And so I don't know that area really well enough to be able to comment on it. And from the cannabis perspective, bipolar is definitely much less studied and focused on than schizophrenia is.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But I think also to the comment about the high THC thing, I think this is the other part of the argument that's emerged out of this. And this is the other part where I see a lot of the causality arguments kind of crumble onto themselves to some degree. And there's been others who've made these very similar arguments to what I'm making here, which is
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So the push that came out of this, out of the UK at least, was much more that it's this high potency kind of skunk cannabis they referred to, which first of all was based on a smell, which they didn't really hadn't done a lot of analytics on. So it was people make the assumption if it smells stronger, it's more potent cannabis. That's not really true because THC doesn't dictate the odor.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So I was saying more of a terpene thing, but certainly I'm sure some of the skunk cannabis they're referring to is high potency cannabis. And so the analysis on this, if you actually go back to those papers and read, is they often use like hash or low potency cannabis as their control where they show no association with cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so that's what's used this argument that it's the high potency cannabis that has driven this. So now the problem with this argument, in my view, again, I look for what is the – Answer that fits in with the data, like what's the most parsimonious explanation here that everything can be explained by?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so the problem with that argument is if you look at the cannabis schizophrenia literature, everything goes back to this one 1987 Lancet paper out of Sweden, where in that paper, they essentially looked at, they have really detailed life records and health records, and this was Swedish conscripts.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And they essentially found that if someone had used cannabis, the rate, the risk of developing schizophrenia had gone up and up. And so this was based on a cohort of people when it was published in 87 that the data would have been collected through like the 60s, 70s, early 80s. So we're talking about Sweden and cannabis together.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It's not a country that has high cannabis use rates and in an era when cannabis was hovering in a 2% to 5% THC range. That was the initial finding that provided this association between it. And yet the cannabis in that study that they would have been referring to would have been incredibly low potency compared to what has happened or like what it is today.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
So if the argument is that it's only related to high potency, how would that initial finding have ever been found? because it doesn't make any sense.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Whereas the alternate explanation that others have put forward, which I agree with and is far more sound, is that there is some biological reason why individuals who are either prone to develop or who have schizophrenia like cannabis, and they will tend to seek out the highest potency product they can get access to. So in the 70s in Sweden, that would have been two to 5% THC cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Nowadays, it's higher potency cannabis.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I wouldn't say it's well worked out. There definitely seems to be some like temporal dilation, like you're saying, where people think things of, you know, someone will be high and someone will ask them, how long do you think time has passed? They would report usually longer periods of time have passed than actually have.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
It could be, but... I mean, they also... There's no question there's a lot of nicotine consumption. I mean, individuals with schizophrenia use... They smoke a lot of cigarettes. I mean, that's also much higher than the general population rates.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And there could be other reasons. You know, again, there may be some reason why they like it. And I think this is... something that I think we just don't understand. It's a very challenging thing to figure out why it is that individuals that have certain diseases may like certain substances. Is it helping them?
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I mean, some people have argued that perhaps nicotine, for example, might enhance cognition in individuals with schizophrenia, and that may be why they like it.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Well, yeah. Nicotine is a whole other thing, which I – yeah. We'll have you back to talk about nicotine. No, I would definitely do not know enough about that to have any kind of informed conversation. But so I don't know. I would say to me at the end of the day, if I put all the data together, what I would kind of – the perspective that I have on this is –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
For some reason, be it genetic architecture or biological predisposition, individuals who are prone to develop schizophrenia also seem to be prone to use cannabis and use it, possibly at excessive levels or possibly at higher potency products they seek out. Using cannabis, if someone is prone to develop it, may initiate or trigger the onset of the disease.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I think in the long term, it will likely make the prognosis of the disease worse. So
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
If you were a psychiatrist in a clinic and you consistently see patients presenting saying, I didn't have psychosis, I used cannabis and now I have psychosis and it converts into schizophrenia, I can understand why the association would be made regularly that there's kind of a domino effect here and causality becomes attributed.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But I think when we take a step back and look at the larger data in its kind of entirety, to me, it's a very tricky argument to make because there's a lot of things that you just can't explain from that perspective. And this is also one of the things that I find absolutely bizarre about cannabis in general is it's a wildly polarizing thing. topic of conversation.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I feel like there is some older work I could dig up to see if I could find that is either in like, it might even be in pigeons, but it might be in rodents that's looking at like temporal ordering and they give animals cannabinoids. And that's kind of a cleaner way of seeing because they are very good at learning. Like if I wait 10 minutes and then I engage in a behavior, I get a reward.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And people have incredibly deep-rooted opinions on both sides of the spectrum. And for some reason, if I don't say cannabis is the devil and causes disease, that means I'm an advocate. And then on the other side of the coin, if I don't say cannabis cures everything, I'm a prohibitionist. So I'm in this fun position where I get hate mail from both sides.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And everyone just generally, depending on their perspective, thinks that I have a bias kind of going in one way or the other. And I'm very... you know, want it this way or want it this way. And at the end of the day, I'm just like, no, I just like data. So I'm like, I'm going to try and answer things as best I can with that. And to me, that's the perspective I've maintained.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I do think that, like, these aren't trivial questions because when we went through the legalization process in Canada, this was something that came up again and again and again was this association with schizophrenia.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And in the UK, this is something that comes up again and again and again because whenever there's any discussion about the UK moving forward to legalization, these ideas come back. And so the public health kind of consequence of this is not intangible. And so for people to be making these very strong causality arguments and having this kind of opinion that a lot of people just take up –
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
I think can have a lot of influence. And so that's why, like, there's literally no reason I should have a dog in this fight. I don't study schizophrenia in any capacity. And it's not my area of research, but because I'm in the cannabis field, I always feel very strongly that we need to maintain clarity over what the data says and not get caught in these opinion-based arguments.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And I feel like this is one of these areas that has just kind of, the amount of people I talk to that regularly tell me that they know that cannabis causes schizophrenia and they're terrified if someone uses it because it's going to caused them to become schizophrenic, I am just kind of shocked by. So this has clearly permeated the general population that there's a widespread belief of this.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
And so you can really train animals to have this ordinal timing where they kind of know distinct periods of time. And if they give them cannabinoids, they respond differently. So in that context, it does still seem to produce some state where there's an altered perception of time passing.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
Yeah. And I mean, I think, again, this is, again, no endorsement that that doesn't mean that it's safe and that it's without harm. I'm just strong of the opinion that I don't think individuals with schizophrenia or who have, you know, first degree relatives should use cannabis because I think there's a high degree of risk there.
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Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks
But that's a very different argument than making saying cannabis causes schizophrenia. And if we remove it from society, we'll see drops in rates of schizophrenia. I don't believe there's any evidence that actually could support that. So... It's just a nuanced argument, and this is a good thing about more of a long-form podcast is it allows for nuance.