- Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Matthew Hill. Dr. Matthew Hill is a professor of cell biology and anatomy at the University of Calgary.

His laboratory studies cannabis and its effects on stress, its effects on feeding, and its effects on the behavioral impacts of cannabis exposure at different stages of development. The origin of today's podcast episode is a bit unique, so I'd like to share a little bit of that background with you.

Previously, I did a solo episode of the Huberman Lab Podcast about cannabis, the biology of cannabis, some of its medical applications and uses, as well as some of its potential harms. That episode came out several years ago now, and remains a very popular episode. It's had millions of views and millions of listens.

Several months ago, we posted a clip of that episode to X, formerly known as Twitter. And Dr. Matthew Hill responded to that clip on X with criticism about the specific points made within that clip. Most notably, my discussion of the data that cannabis use can, in some individuals, cause psychosis.

He also took issue with some of the specific points I made in that clip related to potential differences in the biology of the effects of different strains of cannabis, most notably indica versus sativa strains, and a few other points as well. Now, as somebody who's been in the field of science for several decades now, I'm very familiar with the fact that every field, every single field within science, has debates within it, controversies, and sometimes outright battles.

And to me, that's part of what makes science interesting. It's an evolving process. It's something for which we should all be very curious to try and understand what we know, what we don't know, and try and get to the real answers. So right off the bat on X, I invited Dr.

Hill onto the podcast, and he accepted the invitation. So today's episode is really a unique one in that, first of all, we cover an enormous amount of biology and clinical data as it relates to cannabis, meaning today's discussion is not a debate. It is really an up-to-date discussion about how cannabis works.

So we talk about THC versus CBD. We address the question of whether or not indicas versus sativas have different biological and subjective effects or not. We, of course, talk about the potential correlation, maybe even causation, between cannabis use and psychosis. I think you'll find that discussion very interesting. And we talk about how cannabis relates to hunger, to memory, to anxiety, and to the treatment of anxiety.

I'm certain that given the widespread use of cannabis nowadays, that you'll find the discussion to be both an informative and potentially useful one that could help guide decisions as to whether or not you or others should or should not use or avoid cannabis, as well as one that can simply inform about this very interesting compound.

And of course, you'll learn a lot of neuroscience and biology along the way. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost to consumer information about science and science-related tools to the general public.

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Again, that's betterhelp.com/huberman. And now for my discussion with Dr. Matthew Hill. Dr. Matt Hill, welcome. - Thanks for having me. - Delighted to have you here because you're an expert in the biology of cannabis, a topic that many, many people are curious about for a variety of reasons. So just to kick things off, maybe we can get people up to speed on what cannabis is, a little bit about how it works in the brain and body to produce the various effects that it produces and how some of that comes to be.

And then we can dig into some of the nuance. I have a lot of questions about different types, if you will, of cannabis, the relationship to mental health, potentially to mental illness. We're gonna drill into all of that. So just to kick things off, what is cannabis? - 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.

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.

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 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 delta-9 tetrahydrocannabinol, or what we call THC.

And that really is what dictates the psychoactive and intoxicating properties of the plant. And so the amount of THC that is within the cannabis plant will influence how high a person's gonna 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, and they vary from different types to cannabis from one another. 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.

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. 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.

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.

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 gives some cannabis kind of a citrusy odor or flavor to it.

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 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, you know, giving someone THC and adding in one other terpene or one other minor cannabinoid and seeing how it influences things. And so 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 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, so.

- Fascinating plant. You mentioned the psychoactive effects. Some people listening to this and watching this presumably have experienced those psychoactive effects. Others perhaps have not. How could we describe for both groups what the quote-unquote psychoactive effects are? You mentioned the higher the concentration of THC, the quote-unquote higher someone will get, right?

The greater the intensity of the high. What is the high? And I know people are probably chuckling saying, does Huberman not know because he's never done it? I mean, that's my own business. I just want people to understand what you mean by psychoactive effects. - 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. I mean, if there wasn't, people wouldn't be using it if they didn't feel positive about it afterwards. There can be other aspects 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. 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, 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. - Possibility everywhere. - 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. 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 the kind of lab work where people get someone high, they just kind of use what we call a visual analog scale, which is like a one to 100 or something, or a zero to 100 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. 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, 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. - That's interesting, is that true even if they've never used cannabis before? - 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. - And they pay you, so now pot smokers everywhere are running to look at subjects. - 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, you know, not much, but at least once or twice.

They have to have experienced the drug before. So, I don't know if you would take someone who was completely blind, 'cause I don't know how they would replicate that state if they're not expecting it. - What about the effects of cannabis on time perception? You know, there's this reputation that cannabis has for disrupting time perception, that people will think a long period of time has passed when in fact very little time has passed.

Maybe it's sometimes even the reverse. Is the mechanism by which cannabis can adjust time perception known? - 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.

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. It's looking at, like, temporal ordering, and they give animals cannabinoids, and that's kind of a cleaner way of seeing, 'cause they are very good at learning, like, if I wait 10 minutes and then I engage in a behavior, I get a reward.

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. And so I think if we were gonna really understand the mechanism of it, that would probably be the way to go, but I'm not super familiar with the work, 'cause 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. You mentioned effects of cannabis on appetite, and I know one of the medical uses of cannabis is in people that are undergoing treatment for cancer in order to stimulate appetite, because oftentimes they have very low or even no appetite due to the cancer treatment.

Is the mechanism by which cannabis can stimulate appetite known? And if so, what is the general trend of effect? Makes people hungrier, obviously, but we hear again in kind of recreational terms of people getting the munchies, becoming exceedingly hungry. Is that related to some cannabis induced effect on say blood sugar, like insulin or glucose regulation, or is it happening at a different level?

- 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 through acting at this one receptor for the most part that's widely expressed through the brain called the cannabinoid type one receptor.

- CB1. - Yeah, CB1 is the shorthand for it. And I think 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 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 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. 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. This is just- - Although cannabis users everywhere use that argument. - I know people love to leverage things.

If it's a plant, it's, you know, 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, you know, nature only has so many ways to create something. And so there's gonna be things that end up overlapping in the way that they function.

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 expressed?

- It's mostly immune cells. So you'll see CB2 is mostly on like macrophages or other kinds of immune cells. - 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. 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 gonna find cannabis.

This will all work together now." So there are molecules our body produces, which we call endocannabinoids. And they are kind of funny little molecules 'cause 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.

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 releases a transmitter and it can be something that excites the neighboring cell, neuron B, or it can inhibit it. 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. 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 little bit of an oddity in the sense that they could do the reverse.

And so endocannabinoids are actually made in neuron B on the postsynaptic side, and then they go backwards and act on neuron A to regulate how much transmitter is released. And so in many ways, this is like, I kind of liken it to a thermostat model for the most part.

Certainly if we're talking about something like excitability. So if neuron A is dumping out something that excites neuron B, like glutamate, which is an excitatory neurotransmitter, as neuron B gets too excited, it's gonna start releasing endocannabinoids to go back and tell neuron A to stop driving it. - So sort of a homeostatic scale trying to maintain a middle range.

- 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.

So like- - And that's probably why the CB1 receptor is so widely distributed is that neurons can excite or inhibit each other. That is, raise or reduce the amount of electrical activity in the, let's say, nearby neuron. 'Cause we're talking about retrograde signaling. But ultimately you don't want runaway excitation 'cause that looks like epilepsy.

- Exactly. - And you don't want runaway inhibition because that looks like suppression of ability to think, move, et cetera. - Exactly. So you wanna keep things in where they should be. And so you want neurons to get excited, but you don't want them to get overexcited. So endocannabinoids in kind of a very prototypical sense act as this circuit breaker, essentially, where they go back and gate how much is coming in.

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

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

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

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

And so they can regulate excitation or inhibition differentially. And I mean, CB1 receptors are found on virtually every single kind of neuron in the brain, except one. I think you'll find this interesting 'cause 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.

- Interesting. If I may, earlier you mentioned one of the potential psychoactive effects of cannabis is euphoria. Does that mean that the euphoria associated with cannabis use is independent of dopamine and is more reliant on something like perhaps the opioid receptor system or the serotonergic receptor system? - I wouldn't say that cannabinoids don't affect dopamine because what we understand in the ventral tegmental area, which is kind of the hotspot of dopamine neurons, or at least the ones that are involved in motivation and stuff, those neurons are regulated by a lot of inhibitory neurons that dump out inhibitory transmitter and keep those neurons kind of quiet.

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

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

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

So I don't know. No one, I mean, obviously you can always just theoretically guess as to why someone 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 then this one circuit is kind of free of it.

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

And again, this is one of the weird things about how endocannabinoids work, because if you talk about things like serotonin or dopamine, you have a single molecule that gets released in the typical anterograde way and it diversifies at the level of a receptor. So serotonin has like, I don't know, like 15 receptors or 20 or something, no.

Dopamine has at least five. And so the different actions that serotonin or dopamine will have is all driven by the diversification of the receptors. It's one molecule. Whereas cannabinoids are the reverse. Not only do they work backwards across the synapse and work in this retrograde fashion, but really you have one receptor that is regulated by two molecules.

So the diversification happens more at the level of the molecule than at the receptor, which is, again, very unique. And the two molecules that we know are kind of the bona fide endocannabinoids. There could be more. They're called anandamide, which is actually kind of a funny name because it comes from the Sanskrit word anand for bliss.

And so Rafi Mashulam, 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. And so- - He discovered anandamide and decided to call it bliss because he had familiarity with cannabis or because he took anandamide as a direct experience.

- No, no, I mean- - It takes a lot for a scientist to discover a molecule, but then for a scientist to discover a molecule and then name it bliss for a particular reason, you have to speculate that they had some familiarity with the compound. - Rafi Mashulam 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.

And so the joke is, is this where 420 came from? Because the original like birth date of the first THC paper was 420, 1964. - Well, now that potential myth is definitely gonna propagate. - Yeah, but yeah, so he'd been in the field for a while. And so he had studied cannabis on that side.

And then in 1990, his lab isolated anandamide as being the first molecule that activated the receptor endogenously. And so it was kind of, yeah, I think it was a little tongue in cheek that he named it the way he did. A few years later, the second molecule, which is just called 2-arachidonylglycerol, or what we call 2-AG, that was discovered kind of in tandem, both again by Mashulam, but also by a Japanese group.

And so we understand these two molecules don't do the same thing. Like they are a bit different. So the way anandamide binds the receptor is it's what we would call a high affinity, but low efficacy agonist, or molecule at least. And what I mean by that is very low levels of anandamide are required to actually bind to the receptor.

But once it binds, its ability to stimulate a biological response in that neuron kind of caps out pretty fast. So it doesn't have like a sledgehammer effect. Whereas 2-AG seems to require a bit more concentration in the synapse to be able to bind to the receptor. So it has a lower affinity for the receptor.

But once it binds to the receptor, it's like pretty heavy duty. So it evokes a very robust intracellular signaling response. And so why we have two endocannabinoids, we're not totally sure. Some of us have theories. I'm of the camp that I think they may play somewhat differential roles, either based on the synapse or the circuit that they're working in, or this idea that maybe anandamide might be more of a tonic molecule.

And what I mean by that is, we'll say it's like a stage setter. So like anandamide might just be kind of made by neurons on an ongoing basis and just released. And its job may be to kind of keep the steady state of a brain circuit in a desired range.

So that under resting conditions, it's not too active or too quiet. - Your thermostat analogy is perfect here. - So in that context, it kind of is like just the thermostat of the house. Whereas 2-AG is like, let's say the pinch hitter, who gets brought in to do the heavy lifting.

And so 2-AG during a situation, like let's say something like even like a seizure is an extreme example, where you have a huge amount of neural activity. Those neurons that are getting heavily activated during massive amounts of neural activity, start dumping out huge amounts of 2-AG. And that acts as the, okay, we really need to turn off this circuit very quickly in this situation.

And in most of these forms of like synaptic plasticity, like I was saying earlier, where you need to either strengthen or weaken a synapse in response to a change in the environment or in response to an experience or something that's going on. Most of that is driven by 2-AG signaling.

And so, you know, all these forms of like turning things up or down in a kind of rapid and on-demand manner, that's mostly 2-AG. So most people who study like neurophysiology and like record activity in neurons and look at endocannabinoids, they're almost entirely talking about 2-AG when they play with stuff.

So yeah, that's kind of one of the ways we do it. We say that anandamide may be more tonic and 2-AG might be more phasic. And like brought online when needed, but doesn't do a lot. There is some evidence that 2-AG may also have a role to regulate some circuits under kind of resting conditions as well.

And there certainly are some situations where anandamide might get brought into play to affect plasticity, but as kind of like an umbrella idea of how we look at it, that's often how we divide those two up. So we kind of have these two molecules, they end of the day do the same thing.

They're regulating neurotransmitter release through retrograde signaling, but what stimulation brings them online or what drives their activity may differentiate. And we don't really understand all the details behind that outside of the fact that we very clearly know 2-AG is activity dependent. So as that neuron becomes more active, it's gonna 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. There's cannabinoid receptors and the endocannabinoid molecules are in the cortex, they're in the hypothalamus, they're in the striatum, the hippocampus, the cerebellum. - All over the place. - Except the one area where it's really interesting, actually, where you don't really see much receptor is in brainstem populations that regulate, you know, kind of unconscious cardiac and respiratory function.

So this is one of the things that really differentiates cannabis from opiates, because a lot of the signaling mechanisms between opioid receptors and cannabinoid receptors are quite similar. But as it's been well-established, people can overdose and fatally and die from opiates relatively easily. And the way that that tends to happen is when you activate the opiate receptors in the kind of cardiorespiratory parts of the brainstem, it depresses neural activity.

So as the person loses consciousness, they also unconsciously will stop regulating their own heart and breathing and it can be a fatal response. Because cannabinoid receptors don't really exist in those regions, you don't get the same kind of impact in terms of suppressing heart rate and breathing function. And so that's, I mean, you know, there's always the saying, like, there's never been an account of someone actually dying from a cannabis overdose or a THC overdose.

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.

Like for some reason, it's just not the receptors in that part of the brain, so. - Very interesting. A lot of kind of a aficionado questions about the receptor biology. I'll just spare everyone the details by just highlighting something that you already said far more eloquently than I will, which is, I think it is fascinating that this whole system has both a tonic, like a steady release capability and a phasic, you know, so the ability to spike, forgive the pun, the neuroscientists will know what I'm talking about, to spike more activity of the system superimposed on that tonic activity, because this is something that you see in the dopamine system.

This is something that you see in essentially every neuromodulator, neurotransmitter system, but it seems that the endocannabinoid system has accomplished this quite a bit differently. So very interesting, unique system in a number of ways that raise a number of key questions. - 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 and 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, you know, the cannabinoid receptors are very, they are expressed in these feeding circuits in the hypothalamus, and, you know, there's a lot of complex circuitry there that can regulate food-seeking behavior. - Yeah, we just had an episode with Zach Knight from HHMI and UCSF, where he talked about like the AGRP neurons and different neurons of the hypothalamus, we can link to that in the show note captions.

Nowadays, a rich understanding of the neurons that stimulate food-seeking, craving, and then eating. - And so we know that like 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 we know that like you can also just dump anandamide, for example. This is, you know, Steve Mahler and Kent Berridge 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. 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 a cannabinoid, and then they would stimulate different taste bud populations.

And then they would look at the gustatory cortical response to stimulating the populations. 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, but not if you did salty, bitter, or sour. 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. 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. 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, what is it that, because it's not just food seeking, and it's not just, like just want to consume something. There's a maintenance of eating. 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 re-initiate 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. And so reward devaluation is like, if you haven't eaten for a day, and you see like a picture of a pizza, someone brings a pizza in front of you, it just looks delicious.

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. 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.

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.

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, 'cause it's essentially a kind of a locked airtight box that the rat 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, 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 consuming cannabis through smoking. And so we get them to that point, and then give them access to food, and they will go gangbusters. They eat food, doesn't matter what you give them.

You give them plain chow, they go to town, you give them fatty, you give them sweet, they love it all. But you pre-satiate them, and they get 'em stoned, they will re-initiate eating again. And you make 'em work for it where they have to like lever press, and you get 'em stoned, and they will go to town on that, and they will work, and-- - Proof that even under the influence of cannabis, animals will work hard.

- Yeah, they, for food, I don't know about other stuff, but for food, they certainly will. I mean, and at least Weiritz 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 gotta hit it twice to get a pellet, then you have to hit it four times to get one. Yeah, then you gotta hit it 16, and then, and 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 pellet, like she really wants it.

So you can really kind of goose up their motivation to eat, and so there's clearly a rewarding aspect to 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. 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.

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.

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 orbitofrontal 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.

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 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.

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've also, we and others have also done work to show we can block satiety signals. So we know endocannabinoids at least are capable of overriding leptin.

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." You know, it works through, again, populations in the arcuate nucleus and changes the way those neurons function to drive food-seeking behavior.

And we and others have shown previously that 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.

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Again, that's drinkag1.com/huberman. You're talking about increasing endocannabinoid activity, and we've said all this in the context of cannabis. So maybe we could talk a little bit about how the components in cannabis, THC mainly, but also CBD, impact these receptors, the CB1, and let's just leave CB2 out for the moment because it sounds like it's more of an immune system thing.

But just to make it very clear, is there a way to increase the activity of endocannabinoids without ingesting THC? - Yes, I mean, they dynamically change all the time, so- - But you're talking about, you're talking about experimentally or recreationally adjusting their levels, but how does one do that without using THC?

- So, okay, few things there, we'll take a step back. So THC itself isn't going to, it does its thing by acting directly on the cannabinoid receptor, not- - So it sort of mimics the anandamide and 2AG. - 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 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. - By the way, Matt's referring to the fact that I said that in a previous solo episode about this, and there I was nesting it in the concentrations of THC that can be found in high THC cannabis.

- Yeah. - So essentially what I was saying is that at very high THC concentrations, the amount, maybe not the binding affinity, but the amount of THC that is available to the CB1 receptors is going to exceed what's normally found in terms of the amount of anandamide that can bind to CB1 receptors, because what you're talking about is a super physiological condition.

- Yeah, I mean, you don't really actually need much THC in the brain to produce psychoactivity. Like 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.

I mean, even if you look at its ability to trigger an intracellular response, it's much lower than 2-AG. So it's actually more like anandamide. - So you said anandamide is high affinity, low efficacy. - Yeah, so THC is the same. THC is actually only a partial agonist. It's not even a full agonist at CB1.

- But it is high affinity. - It's high affinity, so it has the ability. So, 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. - Blocking the effects of 2-AG, but does it block the effects of anandamide?

- THC and anandamide, I would kind of, 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 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. - That's a very interesting point that we should highlight. So there are drugs that now exist that can block the breakdown of anandamide, make more available, presumably by disrupting some enzymatic breakdown, and therefore lead to more binding of the now elevated levels of anandamide that are available to CB1, and you see no psychoactive effect.

People are not aware that they- - Yeah, you can do, no one can guess. Yeah, no one can guess. - What is it used for? - 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 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. 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, and that drug didn't work that great to begin with. So it was maybe some issues with the trial, but it essentially killed the development of the drug from that point on, because everyone's like, oh, it's not gonna work. So it kind of shelved for a while.

A colleague of mine, Marcus Heilig and Leah Mayo, Leah is now a colleague of mine in Calgary, but at the time she was a postdoc with Marcus in Sweden, and they were able to get access to this molecule right before COVID, essentially. And they did a trial in just healthy controls with it, which again, this is kind of jumping the gun on some of the other stuff I'll talk about, so I'll tether back to that.

But what they did was they dosed people for 10 days on this drug, and then we looked at stress and fear, because this is something that I study, this is something that they were interested in. And we did find that boosting anandamide with this drug over 10 days was sufficiently capable of dampening stress-induced autonomic responses.

So like looking at heart rate or skin conductance. I think skin conductance was the measure we did in there, but it's a proxy for like adrenaline release. So it blunted that, and it blunted subjective feelings of stress as well, so people had lower levels of saying they actually felt stressed.

And it kind of helped remove this conditioned fear memory that they had trained people to do. And so I worked with them on kind of doing the biochemistry of this to make sure the drug was working properly. But it was very interesting because we did see in that situation where elevating anandamide produced kind of like a reduction in stress perception, a reduction in stress physiology responses, and kind of helped kind of reduce fear.

And so that is kind of an interesting outcome because it tracks with some of the stuff we know about cannabis. And I'm sure we'll talk about some of the PTSD stuff and anxiety later. But so that's kind of one of the things. The drug has not really been used that widely yet.

It's still, it's one of the frustrations I have as a scientist who does a lot of translational work and with clinical partners like Leah, is that getting access to these molecules is not easy when they're not kind of wide, they're not like out in the market. So you can just go and get them.

You really have to try and get access from the drug companies to be able to do trials with them. And so we are in the midst of trying to do that. We did just complete a trial that Leah and Marcus ran that I worked with them on as well, that was on PTSD.

And so there are various potential indications for this. I mean, Johnson & Johnson developed one as well, and they looked at it in social anxiety disorder. They had some moderate efficacy in their trial. So I'd say the jury's still out on exactly what we're gonna do with these, but they have some potential.

I think in certain clinical settings, we just have to figure that out exactly. But I think going back to where we started this from, they're not psychoactive. And so, I mean, when Pfizer first made the drug, they were actually initially concerned that it wasn't getting in the brain because no one could tell they were on the drug.

I mean, this was the Wild West at this point. No one had any idea what endocannabinoids were actually gonna do. People were basing it on what we knew about THC. So the assumption was people would have psychoactivity, but they didn't. Pfizer then actually had to do, they did a sleep study to show that it did have some effects on sleep cycle, the same way THC does.

And then they also did like an in vivo pet binding study to show that they could displace a radioactive molecule that would bind to the enzyme in the brain. - Seems like a lot of gymnastics to basically confirm what they already knew, which is that even greatly elevating the anandamide by blocking this enzymatic breakdown of anandamide leads to, at least from what I'm understanding, vastly different subjective experience than ingesting or smoking THC, which brings us back to THC and cannabis.

Like, you know, it seems that this thing that we call cannabis and THC are overlapping with the endogenous effects of anandamide. But here you're not talking about endogenous normal levels. You're talking about pharmacologically greatly increasing anandamide, no psychoactive effect, no euphoria, no munchies, you know, et cetera. Then people smoke or take an edible of THC or cannabis and you get a vastly different set of effects.

So maybe we could talk about THC and the CB1 receptor. And since we're here, we might as well talk about CBD and the, I think you're going to tell us, the lack of interaction with CB1 receptor, right? And what is cannabis doing at the level of these receptors? Because it makes me wonder whether or not these receptors are the whole story or whether or not cannabis is, you know, as you mentioned, you know, 70 plus active molecules in there, terpenes and a bunch of other things that may modify their action.

But this thing we call cannabis has many more actions than just mimicking the endogenous cannabinoid system. - 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.

So-- - They evolve to do that. - Yeah, so there's going to be, and I think like, it's very clear that like anandamide, for example, is not active at every synapse that has CB1. And so when we boost anandamide signaling by inhibiting its metabolism, all we're doing is amplifying anandamide signaling at the synapses it already exists.

Whereas THC, when you consume it orally or inhalation wise, and it gets into your blood and into your brain, it's just blanket activation. You're just carpet bombing the whole system indiscriminately, and so-- - You're introducing the ligand, the thing that binds the receptor. This is far and away different than say like the actions of amphetamines, which are disrupting the normal biology in a way that's giving you an amplification of an endogenous mechanism, right?

If that was all just nerd speak for those listening. It's one, in the context of amphetamines, what you're doing is you're taking an endogenous system, a naturally occurring system, and you're greatly amplifying the amount of dopamine, the amount of norepinephrine that's available. With what we're discussing today, the endocannabinoid system seems to be producing a set of effects that might overlap with the THC effects, but THC is doing a bunch of other things, and that's because THC, and we'll talk about CBD, but at least THC is acting as the ligand.

It's in some sense, we don't wanna say replacing, but it's masking the effects of anandamide. - I think the problem is when you just blanket activate all the CB1 receptors in the brain indiscriminately, like you do when you consume cannabis with THC, the resulting effect is the intoxicating state, and it's probably because there's a lot of CB1 receptors in the cortex, and those are gonna be differentially regulated at different times by endocannabinoids, whereas when THC hits them, all of them are gonna get affected at once, and if you think of the way that I had described how cannabinoid receptors work by essentially, I mean, at 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 gonna change the way that information processing and perception occurs, and I think as a consequence of that, that's what produces the intoxicating state, not that THC is like a super-duper version of an endocannabinoid or that it's boosting endocannabinoids.

It's kind of like just indiscriminately activating all the receptors as opposed to a system that's very finely tuned to do very specific things at very specific times. - That's very helpful. So the analogy that I was considering using coming in here, like the difference between endogenous testosterone or estrogen versus pharmacologic testosterone or estrogen given as a therapy is very different because that's a levels issue.

This is a levels and an extent issue. - Yeah, this is a lot more to do with just, yeah, the nature of how it hits everything, because like, so for example, if we talk about feeding, we know it's been established at this point that, for example, if an organism doesn't eat for like a day, so you fasted, at that point in those feeding circuits in your brain, like the arcuate area where these AGRP neurons and stuff are, you'll start seeing elevations in endocannabinoids.

So endocannabinoid levels start kind of going up and up following kind of fasting periods. And part of this is because they're trying to engage that feeding circuitry now and they're shifting the activity of those neurons to promote food-seeking behavior because an organism is basically like 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. 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. 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. Yeah, some of it's gonna be the intoxication, but in tandem, you're gonna hit the CB1 receptors that are in those feeding circuits as well. And the consequence of that is gonna be, I mean, the way I kind of analogize it to people, as 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.

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 that their food circuitry is responding, in the brain at least, seems to be similar to what would happen if they'd been fasted.

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. 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. 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 that hits.

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 you, then yeah, you go into food seeking behavior mode. - Super interesting. Well, I have to imagine that there are many people who use cannabis not to stimulate appetite, but for other reasons.

They either like the euphoria or to adjust their anxiety. What are some other known mechanisms by which cannabis can change people's psychology? Let me focus in on one particular aspect of subjective experience, which is focus. Do you think that some people use cannabis because it allows them to focus better?

And I raise this specifically because I think that in the past, cannabis has had a bit of a reputation for making people spacey. Now you use the word stoned, kind of out of it. And yet I've heard of some potential uses for enhancing focus. - 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. I mean, there's some things, 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. - My understanding is that people who use cannabis have poor, certain forms of memory, but not necessarily poor memory across the board. Is that correct? - 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? - 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.

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. 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. But even in regular users, the impact on memory processing is usually not super robust. It's still there. I mean, I think 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.

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. 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. And so- - I should just say this point has often been confused by undergraduates and others to assume that just because one can gain proficiency at a task while under the influence of a substance does not mean that you have higher proficiency at that particular task while under the influence.

In fact, the way it was presented to me when I was an undergraduate was incorrect. I remember the lecturer said and later corrected himself. I won't call him out here 'cause that's unfair. He's not here to defend himself, but it happens in lectures that people who studied drunk would be better off coming to the exam drunk.

That is not true from what I understand. - 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.

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 relatively well-established. Most people would agree that acutely intoxication with cannabis does impair memory processes in some capacity.

What explicit form of memory? I don't think I could speak to comfortably just 'cause I'm not a memory researcher and I know there's very specific things of like episodic and declarative and whatnot. So 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.

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. - Thanks for clarifying that. And also thank you for clarifying the discrepancy between endogenous cannabinoid binding and affinity for CB1 versus THC.

I really appreciate that because that's something that you and I discussed in light of the solo episode I did about cannabis, and now you've made it clear that THC does not bind with much higher affinity. It's just, as I think your words were, assuming high THC levels in the cannabis carpet bombs all the networks as opposed to binding more with higher affinity at particular receptors.

- 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. - Is that right? - I mean, you look at edibles, for example. I mean, this may be an interesting segue into root of administration stuff, 'cause I think it's an important point that a lot of people don't recognize, is the difference between someone inhaling cannabis versus someone orally consuming cannabis is like a different game.

- Yeah, let's talk about this, 'cause I know that you and I arrived at different understanding of the fastest, typical, and slowest routes of entry for THC into the system, to arrive at the brain, right? The numbers I gave in the previous discussion about this were related to how quickly inhaled smoke moves from the lungs to the bloodstream and crosses the blood brain barrier.

- Which is very fast. - Right, which is very fast. - 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. - Okay, so it may be that it is the same as nicotine. It may be that it's faster, but importantly, it can be fast.

But typically, how fast is the onset of the subjective experience of, okay, somebody takes a hit off a joint or a bong hit and they start to experience the subjective effects of euphoria, et cetera, how quickly after? - 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.

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. - I've seen some people not titrate it very well. - Depending again on how you're, 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. - Yeah, I mean, that's not just a fair amount. I mean, if we were talking about alcohol concentration.

- It's beer to vodka. Yeah, basically you're talking about a beer or a wine to a spirit. - And there are aquavit varieties, so to speak. By the way, I think when people hear me talk about any kind of a drug that can be used recreationally or alcohol, I think some people assume that, you know, I'm ultra anti all these things.

I'm actually not, right? I'm not an alcoholic, so I can drink a little bit and I have, I just don't tend to. And we could discuss cannabis in a different venue. But the point here is we're not trying to frame this as what people should or shouldn't do. We're just trying to inform people.

I want to be very, very clear about that. So, but when I hear about, you know, 20 to 30% concentration, as opposed to 5% concentration, that's significant. - 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. 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, you can't use commercial cannabis. And 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, 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 like Mississippi that was essentially funded by NIDA to produce cannabis.

- Lucky farm. - And 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." 'Cause it reflects cannabis that I would say is more from like the seventies or eighties.

So it would be like five to 9% kind of THC cannabis. Now, 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.

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 a hundred nanograms per mil of THC, give or take.

That seemed to be where it was. Now, because of the way that the, you can legally study cannabis in the States, 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 'cause 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. 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." So there's a group in Colorado, so 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, in kind of an ecological setting, let's say.

And so they created what was called the Canavan. 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, 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, I think this was a great advance in the field 'cause 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.

- I love this. I mean, as somebody whose lab has done a in-laboratory VR-based experiment on human anxiety and fear, and then compared that to a clinical study that we did sort of in mass, where people were at home doing specific respiration practices. You have many more subjects, but of course they're reporting back their effects.

Well, you can monitor them by device, look at HRV, look at heart rate, et cetera. I think having the ability to compare and contrast in-laboratory and ex-laboratory data is extremely valuable. - Yeah, 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.

- Yeah, for people that have never been to a laboratory or tried to find a parking spot at a university, that's an anxiety-inducing experience in and of itself. - A novel experience while someone's intoxicated with cannabis can also create a very different altered state. - I would wanna 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. 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 mil using this relatively lower potency cannabis. When Kent 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 100 nanograms per mil because people are really good at self-titrating. Now, where things fall apart is with the concentrates. So then you go into things like dabs or these 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%. So you can get really, really- These are tinctures? Distillates, 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.

And so when the Colorado group looked at those, their blood levels were closer to 200 to 300 nanograms per mil. So with cannabis plant, there does seem to be this ability for people to relatively self-titrate. And then my buddy Ryan McLaughlin, who's also at Washington State, he was really one of the ones that pioneered these vape chambers in rats and created this really cool model of self-administration, which was 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 'cause they found it quite aversive.

But when you let rodents actually titer their ability to get vape hits, they will, like, work for this, the same way they will other reinforcing drugs. 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, and 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. And if you gave them the high-potency product, they would actually take less vape hits off of that than they would off the lower ones. And again, all their blood levels tended to cluster in the same range because they titrated.

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. 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. So does that mean that cannabis use rarely leads to tolerance of cannabis use? 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. 'Cause 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. - Yeah, it sounds like those are precarious.

That somebody who thinks they have a lot of experience or God forbid, no experience, takes a concentrate and is, what, no longer getting the euphoric experience that they anticipated, but instead are getting, what, a paranoid anxiety attack. - 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 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.

- This is a very important point, and I'm going to highlight it because I think it's very, very, very important. Although you're making it very clearly already, which is, these days we hear a lot about the "problems" with high THC containing cannabis as relative to what was present in the '70s and '80s, and presumably '90s as well.

I was a teen in the '90s, so maybe I'm alluding to something there. But what you're saying is that unless one is talking about concentrates, that people, and animals in the laboratory, will self-regulate the amount of intake in a way that leads to approximately the same blood levels of THC.

So it may not be as much of a concern, at least in light of the concerns about, oh, these levels are so high that people are overwhelming their system with THC. Basically, this could be stated in real-world terms as people are taking fewer tokes of the higher concentration stuff that allow them to match blood levels that were present in the person taking many more tokes in the '70s.

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. So the advantage that existed from a titration perspective was with '70s weed, there's a large window to titrate.

So people could take small amounts and not over-consume, let's say, because there was a much lower concentration of THC in the plant. So they're able to consume, 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 over-consume 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.

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. 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, but, you know, 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 gonna put my efforts into kind of like, you know, 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 gonna come with them than I would about the cannabis flower myself.

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 the 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 flower, that's a concern.

Like, I think that's where problems start arising because then you're gonna 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 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. - Yeah, usually it's the life destruction that thwarts their progressive increase. Seriously. - Or the cost. I mean, the sheer cost. - Another form of life deterioration.

- 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 as Meg has said to me many times, the guys that come in her studies, these are very heavy users, and then they will use this relatively low potency product and still get high off of it.

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, we definitely see, like if we look at some pet imaging studies, chronic cannabis users do have some down-- - Sorry, I have to interrupt.

- Pet, positron emission tomography, not pets. Although people get their pets high and we don't know what those pets think about that. - Not good, don't get dogs high. - If also high, one can assume a lot of things about what your pet is thinking while also high. Sort of half joke there.

But yes, positron emission tomography is one way to assess the binding of drugs within the brain as well as activity of endogenous neurotransmitters, neuromodulators, such as anandamide, dopamine, et cetera. - Yeah, so a typical pet study and 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. 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 there might be a lot more receptors there than we necessarily always need or are always using, let's say.

So we might be downregulating a component of this, but maybe not all of the ones that are required to produce the psychoactive effects 'cause 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.

And again, surely I think as a response to the biology of hitting the system that heavily with that much THC as it comes in 'cause they can't titrate it the same way. - It makes sense. Yeah, these concentrates sound like something to at least pay attention to as a potential problem.

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I may have made this joke in the previous episode I did on cannabis. I've known a lot of chronic cannabis users and none of them admit to being addicted. It's not my place to challenge them on that, but they do seem, in my experience, this is not an experiment, but in my experience, more irritable when they don't have access to what they call their "medicine." So that speaks to a dependence or something, but then we need to be careful because in the classic sense, addiction, I've defined and others in the field of addiction have defined it as a progressive narrowing of the things that bring you pleasure, such that it causes disruption to other areas of life.

Your life becomes maladaptive. - Yeah, 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.

- But that's the nomenclature now that people are using, alcohol use disorder, cannabis use disorder. This is what you start to see now instead of saying being addicted to pot or being addicted to alcohol. - 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? How does that relate to other substances of abuse?

I mean, certainly the outcomes associated with it are gonna be slightly different than someone, something like opiates or alcohol, because that's a totally different beast, because you have a fatality potential. There's a whole bunch of other health consequences. 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. 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, you know, 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. 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%. 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.

- So, I just wanna make sure I'm understanding clearly. For people that use cannabis weekly, the propensity for developing cannabis use disorder is on the order of about 30%. - Yeah, I'd say in that neighborhood, they would probably qualify as meeting criteria for cannabis use disorder. - 'Cause weekly doesn't seem like that often.

- No, I mean, it depends again on how you vary this. Like, 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. 'Cause I think a lot of people, 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. - 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. I think some of them certainly would fall into the criteria of cannabis use disorder.

'Cause if you start looking and say, well, you know, if you travel to like Egypt, are you gonna go put yourself at risk of going to jail to get access to cannabis? 'Cause you can't function without it. If you do, then yeah, you know, you've got cannabis use disorder.

You know, are you going to burn relationships? Are you gonna start failing at meeting responsibilities or getting things done on time because you're preoccupied with cannabis? Yes, you're gonna 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.

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, 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. 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. And 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.

- That's interesting. I was under the impression this has really changed over the last, you know, five, 10 years. You know, growing up, it was, I mean, I think there are still people in jail now because of possession and sale of cannabis. And then of course there are stores not far from here where people are selling cannabis.

- Ironic, yeah, sadly. 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, you know, 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. 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. 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. 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. So people view it very differently. And I think it's an interesting thing because I feel like, 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 as legal, that means it's safe.

- Is the legalization of cannabis leading to more cannabis users or fewer and/or incidents of people going into the emergency room, suffering from cannabis-induced psychosis, something that I hope we can also talk about. - 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 use. - More cannabis use. Now granted, their baseline was quite low pre-legalization. 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 one 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 use has come from.

Definitely the young adult population, like 20, 24, that group has definitely seen increased use as well. - Does it split male, female? - Historically, cannabis tended to be more male biased. I'd 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. 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.

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.

So I think like that's obviously an important demographic to have tracked. This was one of the concerns with legalization was you'd prove, you know, increase access. Teenagers would get it from their parents and whatnot, or had just, you know, other siblings and stuff. And so you'd 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. So we did an interesting rollout in Canada. 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 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. I actually know somebody whose child accidentally ate THC containing gummies. Fortunately, the child was fine, but there are actually pretty serious ramifications for this.

The parents actually are quite susceptible to legal action if this happens, right? So this is something to like really keep in mind. I mean, there are a million other health-related reasons why this is probably- - I don't know if that's true in Canada the same way, but in the States, yeah.

- Yeah, like if your kid gets into a stash of THC containing gummies and ends up in the emergency room, there will also be, most likely, there'll be a police visit to that emergency room also, and it doesn't bode well for the parents. It's a very serious issue. And again, this was highlighted to me by someone that I know who didn't anticipate any of this, but, you know, kids are good at finding candy.

And if that candy contains THC and they end up in the emergency room, serious issues. Nonetheless, if your kid is acting strange 'cause you think they ingested THC containing anything, take them to the emergency room anyway. - 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. And so people are, once cannabis was legal, people were more likely to actually go into the ER because the consequences were different. - I see.

- And so, sure, some of this is availability, and some of it is just like, okay, I'm not as concerned now about something happening because I've taken my kid in. Like, I'm not gonna 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.

That's, 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 'cause kids find them. - So as long as we're talking about edibles, is there any fundamental difference between the dose regulation that you talked about earlier of inhalants versus, excuse me, versus edibles?

Meaning earlier you said that even if it's high THC containing cannabis, people will self-regulate to achieve the same, approximately the same blood concentrations. But with edibles, I imagine you eat half a cookie, a quarter of a cookie, and you can end up in a vastly different place than you expected.

- 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.

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 mg gummy or two 5 mg gummies or four 2.5 mg gummies, you get it. So you couldn't, in one package, have more than 10 milligrams of THC.

Now for people who are, 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. Some will even feel it at 2.5 mg. Most people will feel it at five. Virtually everyone will feel it at 10.

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. - Right, before you said 100. - Yeah, so this is dramatically lower. And so also the time course of this is fundamentally different.

So in oral consumption, you're looking at a minimum of 30 to 45 minutes for onset of intoxication. 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. And then like 15 minutes later, it starts hitting them. And then like once it fully kicks in, it's just like a steamroller.

- I've heard of this happening. - 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? 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 that was create this idea of standardized dosing units, so that people have an, like we do with alcohol, where we say, one beer is the equivalent to one glass of wine versus like a shot of tequila or something, so that there's some comparator that people understand how many drinks are, you say two drinks you do, you're going to hit legal limit kind of thing.

- Yeah, it seems very important. - Yeah, and so this is very difficult to do with cannabis because the dosing with oral consumption is just a different ball game 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 seems to be a bit more potent than THC is in terms of its ability to activate the receptor. So, and 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. 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. Versus inhalation is just this like spike. So you get this very rapid, 'cause 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. 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.

- As long as we're on the topic of time course, you know, based on what I was able to find, I believed, and tell me if I was wrong, that cannabis can stay in one system for as long as 80 days. The reason I brought this up previously was there are a number of people who have used cannabis are going to take a drug test and want to know how fast it can clear from their system.

But based on conversations we had offline, sounds like that 80 days might be a bit too long. - I mean, you could still fail a drug test at 80 days. I would say, I feel like, I think the way it was worded more 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. - So abstinence for 30 days. - 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 to store, it doesn't like the blood.

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. And it can essentially kind of slowly leak back as it, 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. I mean, some of this, again, it's gonna 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 gonna be somewhat reflective of people's body fat content.

Although talking to colleagues who do this, they say not always. But we do know, you know, certain things like exercise, for example, anything that's gonna trigger adrenaline, 'cause 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.

- Or lost weight. - Yeah, or they've lost weight. And anything that's gonna 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.

And so this is where something like, and this is what I mean by standardization of regulatory issues become very complicated, was I remember right when legalization happened in Canada, all these kind of chemists were like talking to me about they're gonna 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.

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 gonna 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 mil of THC in their blood.

- But you're talking about this metabolite that can come from the edibles that doesn't come from inhalants that can have a much more potent effect. - You get a bit of it from inhalant, but not nearly as much as you get from edibles. - So it's a different, it's sort of a different situation altogether.

- 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 gonna be like five nanograms per mil, let's say, but it would be like that for a long time.

Whereas the a hundred nanogram per mil from smoking is like for 20 minutes and then it starts dropping. 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.

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 can have someone who's dead sober 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. - Well, I guess it sounds like the drug tests either have to be revised or discarded. And it also sounds like if somebody is going to take a drug test for cannabis and they have used cannabis in any form in the previous 90 days, let's say, going for a run right before your test is going to liberate whatever the THC resides in the fat stores.

- Potentially, yeah. So I mean, it is complicated. - A lot of people are writing this down. Along the lines of what's known and not known, I'm curious what is known and not known about the effects of cannabis THC in particular on hormones. I've seen studies that cite increases in testosterone from cannabis use.

I've seen studies that cite increases in estrogen from cannabis use, and they argue for increased aromatization of testosterone into estrogen as the mechanism. I've also seen studies that say the exact opposite. So is there any global takeaway message yet, or is it just highly variable or depends too much on dose and individual age, et cetera, that we just really can't- - I would say there's nothing that's super clean cut.

I mean, I know in the previous podcast, you talked about a prolactin thing. - Right, well, there's, and this is where I think it's important that people understand that, on this podcast, we cover science and studies, but we also pull from common experience that people want explained if we can.

And one of the experiences that is talked about a lot in certain, let's just say online communities, is the experience of people who had no preexisting gynecomastia, male breast development, will smoke marijuana, do we call it marijuana these days? - We'll go with cannabis. I actually got someone, I got a lot of comments that said marijuana is an inappropriate term.

Okay, smoke, we'll go back to that. That was new to me, I didn't know, so forgive me if I didn't know. - No, no, no, I mean, I understand it, but yeah, a lot of people don't know that. - Okay, so will smoke cannabis and experience gynecomastia, or in females, so males and females both have breast tissue, but in males, it's typically, it's not hypertrophied, but they'll smoke cannabis and get gynecomastia, growth of the male breast tissue.

That's sometimes reversible, sometimes not, presumably through the aromatization of testosterone into estrogen, which then acts on the tissue, makes it grow, as well as reports of breast tissue tenderness after cannabis use in females. So that was sort of the origin of that discussion around does cannabis impact aromatization of testosterone into estrogen, and you can find a little bit of evidence for that, but you can also find evidence to the contrary in the scientific literature.

So I'm just curious your thoughts on this. - It's super mixed, so I mean, you're talking 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. - Interesting, because dopamine is one of the main ways that prolactin is suppressed, they're kind of in a seesaw, they work in somewhat seesaw fashion. - And it 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, 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. Now, whether that's a pre-existing thing-- - Is there any reason to think that would be the case?

- 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 this is from my previous life, because my undergrad and graduate supervisor, he was a neuroendocrinologist who focused much more on sex hormones and reproductive hormones.

So we've written a few reviews, so I've done reviews on this area, and I know the literature somewhat. 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. 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. 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, so maybe they're subbing in and having estrogenic effects. I don't know how valid any of this is. - Yeah, it seems a bit, I mean, there are phytoestrogens in tons of different plants.

The sort of attacks on soy and the attacks on, this I think grew out of the kind of the soy versus meat communities and plant-based versus carnivore. This podcast has always been agnostic with respect to nutrition and is really, if we encourage anything, it's that people consume unprocessed and minimally processed foods.

As the bulk of their food intake, there seems to be enough data on that, but whether or not people choose to be vegan and eat a lot of plants or carnivore and eat just meat, we've essentially stepped out of that debate because let's just say it's as futile as about any other debate.

You're just never gonna, it's completely circular. You end up right back in Twitter. - 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. - So this seems to be something that purportedly occurs on a backdrop of elevated androgens, meaning in puberty or a backdrop of some other form of androgen increase.

- Like someone who's on steroids or something. - Yeah, but that's not the community I'm referring to. It seems that because transient gynecomastia during puberty is actually fairly common because of there's just so much androgen being produced in puberty that some gets aromatized. And that the idea, I'm not stating this as fact, is that it may exacerbate that.

In any case, it sounds like the takeaway from this is that there aren't a lot of conclusive studies about the effects of cannabis on testosterone or estrogen or aromatization in any direction. - I don't, I mean, I'd say like, yeah, enough studies to suggest that you might see transient drops in testosterone from cannabis, and it seems to be relatively short-lived.

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. - There it is again, it's homeostatic, just like the endocannabinoids. - 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, all 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, 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. - Are those positive or negative changes? I'm assuming that the studies you're referring to saw disrupted what they call sperm quality, which has to do with motility, et cetera. - 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. So I have like- - As we say this, I'm just chuckling to myself 'cause anytime this conversation comes up about a substance and sperm quality or egg quality, I always get a barrage of comments of people telling me how many children they conceived while under the influence.

No one is saying that you're going to be infertile, but if people are having challenges conceiving, it might be something to think about. - 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.

So for some, you know, 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 or their sperm capacitance, their ability to maintain fertility. And for the bulk majority of men, I'd say it's probably not the case.

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. - Along those lines, I saw kind of a jaw dropping statistic and I'm not sure I still believe it, but you tell me what you know about this, which is that up to 15% of pregnant women in the US have used cannabis during pregnancy.

That just seems, that number just seems too high and yet, you know, it exists out there. - 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.

- No, I mean, so I've heard as low as two and I've heard as high as 20. - Okay, two sounds like, okay, that I could imagine, but as high as 20. And do we know what the effects on the developing fetus are? - There's a lot to unpack there.

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? 'Cause 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.

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 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, and I think also the number that carry on through the entire gestational period is gonna 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.

Now, anecdotally, I have heard women say, with the history of things like thalidomide and other anti-nauseant drugs that had profound traitogenic 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 thalidomide effects that happened.

- Thalidomide effects are malformation of the limbs and other bodily structures in fetuses. It was an absolute tragedy of medicine that this occurred in even one birth. But yeah, it's the reason why thalidomide is now, I believe, banned as a drug for use during pregnancy. - 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. But 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.

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 frustrate you. 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.

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?

And this is- - You're talking about the irresponsible that the dispensaries would say that? - Yeah. - It's irresponsible that the study was carried out that way, because it's a little bit of- - Entrapment. - 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, which is 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.

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's 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 it was a thing in Canada. - Bartenders in the US put in the comments on YouTube, do you have to undergo training about alcohol to be a bartender? - Like anything, even if it's just like an online quiz.

But like, so I, 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.

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.

I'm an executive director of an organization called the Canadian Consortium for the Investigation of Cannabinoids, the CCIC. And it's, 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 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, 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.

- You're certainly doing your part to provide the public education about cannabis now. So we all appreciate your highly informed and broad distribution of this information. Because this is also an issue with psychedelics, which currently don't have legal status in the US. This is an ongoing process of whether or not it will.

Right now, things are really on the teeter totter with MDMA, where we await the decision from the FDA, but the early recommendation to the FDA was to not approve MDMA as a treatment for PTSD. That's sort of today and mid to late June, 2024, we'll see what happens. But this is also the case for ketamine, which has legal status, but many people are accessing ketamine not through a physician, but through online sources.

So what you're speaking to here is a much larger issue. And I absolutely agree with you. I mean, I think most people are probably not aware, except by experience, positive or negative in some cases, about the differences in blood concentration as it relates to number of tokes versus concentration versus edible.

I mean, these are critical themes, especially for where we're gonna go next, which is all the discussion about high THC and psychosis. - 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 have conversations.

And I mean, some of the, our system, at least, is somewhat provincially regulated. So like, our organization has worked with like the Ontario group that deals with cannabis distribution, 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 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.

- It sounds like the take-home message is proceed with caution, you know, low and slow. - I mean, that's the, yeah, the- - Like don't ingest too much too quickly. Like really, you know, if one is going to explore this legally, of course, you know, take a little bit, wait, take a little bit, wait, because otherwise you're gonna get the, what was the reporter?

- Oh, I think it was Maureen Dowd, but I- - Right, you're gonna- - I don't know, actually, when I say that- - Is she still on the floor in a Colorado hotel? - She may have recovered by now. - Reporting from the floor in Colorado. - But like, yeah, it can become very frustrating at 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.

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, that just kind of goes through, 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 gonna use, these are the different ways to engage in harm reduction. You know, like, obviously, oral consumption has, you avoid the issue of lung damage that you could get from smoking. 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?

Can people self-regulate their THC concentration in the blood by vaping as well as they can by joint or bong or other forms of smoking? - 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.

So in those situations, that's gonna really heavily depend on what the concentration of THC in that product is. 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.

- In a big bag. - 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 by-products. 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. Pre-legalization when cannabis in Canada was only under medical authorization. Because of the reduced harm associated with vaporizing the plant matter versus smoking it, that is, I would say, a safe guideline for harm reduction that if you're gonna try and avoid, there's still gonna be some issues that happen with vaporization of plant matter, but it's not the same as combustion.

So you avoid some of the other issues that come out. When we're talking about oil-based vapor products or whatever they're in, they're usually in some kind of oil-based solution. Who knows? I mean, we don't have the research on this. We just don't know. I mean, we certainly know there have been some pretty big errors of the things that happen in the States.

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 a by-product, I believe, of them adding like vitamin E acetate or something into the... Because again, everyone just assumes it's inert, but then when it combusts through the vaporization process, it creates a massive irritant on lung tissue.

And so that was just, you know... 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'd have to go through testing. It's kind of the Wild West you get down here.

Every state has its own rules. People, there's not really a lot of regulation of things. - But if you go overseas, it's even more wild. I mean... - 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, the product is. - No, I mean, we're going to be doing episodes on stem cells and you've got people flying out of country to do stem cell injections. People were getting them down in Florida who went blind from the injections of stem cells into the eye in an attempt to save what little vision they already had.

Probably don't want to get me started on that one. I'm in total agreement with you, by the way. I want to make sure that I ask about psychosis and paranoia. I've previously said, and I was sort of, I wasn't joking, but I have observed in my history that when people started to experience some degree of anxiety or paranoia when smoking cannabis, that sometimes the message they would receive back is to take more, to just adjust the subjective experience.

I think that's a terrible idea, terrible idea. - I am baffled that you heard that. I have no idea. - Well, 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.

- Well, usually the advice of people in terms of, that was recreational drug taking, is rarely excellent advice. - Yeah, no, no, no, that's, so, yeah. 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 'cause that will just like grease the wheels going downhill, for sure.

- Yeah. I also am aware that there are some very high profile papers that have been published in the last, really five years or so, pointing to potential increased risk for psychosis of lasting duration, even after the effects of cannabis have worn off in high THC cannabis users, in particular high THC cannabis users that initiate that cannabis use young, and this might be preferentially impacting males.

I want to make clear that what I just said is not a statement of absolute fact. It's my understanding of the conclusions of these papers. There are other conclusions in these papers also, but that particular conclusion seems to be important enough that they place it in the abstract and it's reached major press headlines.

So I guess the simple question, which probably doesn't have a simple answer, is does THC cause psychosis? - So yeah, there's not a simple answer to that. And I think that also is a question over whether you're talking about acute drug-induced psychotic episode versus the development of a chronic psychotic disease like schizophrenia.

So the first arm of that is just, can people acutely have a psychotic episode to THC or cannabis? And the answer to that is yes, it's not common. I would say in terms of adverse events that happen with people consuming cannabis, it's on the rarer side, but it definitely can happen.

- So less than 5% of people that- - Much less than that. I mean, it's certainly, I mean, if something like this was happening at a regular frequency, it would be very well-known. - What about anxiety attack? - 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, or does it carry the same set in setting considerations that, you know, psychedelics like psilocybin have? - Both. So I think there's some contextual component to it. There was like, I mean, back in the '70s when they did more, let's say, interesting studies, there's one where basically they dosed people on THC and then had them undergo oral surgery, which seems like, in hindsight, a very bad idea.

And I think virtually everyone in that study had a panic attack. So it really potentiated the stress of what they were undergoing. And had they been given that same dose in a different setting, I'm not sure it would have evoked that kind of response, but there is definitely a dose effect to this in terms of like, you know, the kind of classic low-dose aspects of THC or cannabis, like that are usually considered more of the positive, pleasurable responses that are why people use, like it reduces anxiety, it relaxes, blah, blah, blah.

That is more of like a low-to-normal-ish dose, let's say, of what someone consumes to produce those responses. If they start going upwards, though, it's not like it's graded, it's like a full flip. Like, it's not linear at all. It's almost like it goes in the opposite direction. So, you know, someone can use cannabis to reduce anxiety, but then cannabis can also trigger anxiety in other people, and even in the same person if they consume too much.

And a lot of this, at least we think, has to do with the ability of it to regulate both excitatory neurotransmission and inhibitory. And so for reasons that we don't totally understand, there's like way more cannabinoid receptors on inhibitory neurons than there is on excitatory neurons. But in the early days of creating the genetic lines, Giovanni Maricicano and Beat Lutz were over in Europe, created like deletion of CB1 only from excitatory neurons or only from inhibitory neurons.

- Okay, so to just clarify for people, these are laboratory mice that are genetically modified so that they contain or lack specific receptors on particular neuron types so that researchers can parse the effects of THC on what we're referring to as inhibitory neurons, which quiet other neurons versus excitatory neurons, which excite other neurons and so forth.

And in doing so, to understand some of the network biology, which is basically impossible to do in a typical mouse, what's called a wild type mouse or a human, because when one ingests the drug or when the mouse is given the drug, it affects any site in the brain, potentially any site in the brain where the CB1 receptor is expressed.

- If you do like a full body deletion of CB1 and you give a mouse THC, doesn't respond to it at all, not surprisingly. - That's a comforting experiment. You want to see that result. - Yeah, exactly. So that's how we know CB1 drives all the kind of psychoactive effects of THC.

So if you delete CB1 off of inhibitory GABA neurons, even though that removes like 70% of the CB1 receptors in the brain, those animals look just like wild type. They still get, like they still exhibit all the classic signs of intoxication in terms of how they would respond to like pain sensitivity or locomotion or these other like assays we use in mice to tell if they're high.

If you delete the CB1 only off of excitatory neurons, the glutamate neurons, then you see what looks like the full knockout. So now the animals don't seem to get high. So even though the majority of CB1 receptors seem to be on these inhibitory GABA neurons, it's the CB1 on the glutamatergic excitatory neurons that mediate most of the classic signs of what we would consider intoxication from THC or cannabis.

But what's interesting is, Beat worked with the Spanish group 10, 12 years ago. Then they showed, they're looking at anxiety, that if you delete CB1 only off of excitatory neurons, you lose the anti-anxiety, anxiolytic effects of THC, but you still have the panicky, anxiogenic effects of high dose. If you delete CB1 off of only the inhibitory GABA neurons, you still have the low dose anti-anxiety effect, but now you don't have the high dose anxiogenic panicky effect.

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

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

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

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

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 'cause we can't know. But based on what we've seen in animals, that's 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 'cause 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. I mean, that's just a strange thing.

But I mean, that's kind of the precedent of when you start going into the psychosis 'cause obviously paranoia would be a big component of that. Someone once asked me a question about, what happens in the brain, like imaging-wise, when someone's having like a psychotic episode from cannabis? And I was kind of thinking like, how would that study get done?

- Probably on accident because somebody takes cannabis, is in the scanner and then starts having a psychotic episode but chances are they're going to try and get out. For those that don't know, these, I don't want to scare people out of doing MRI or fMRI, but you're typically told to stay extremely still.

There's sometimes even a bite bar. This is a very controlled environment, not an environment that you would want to be in during a psychotic episode. - No, 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 gonna have an answer to 'cause 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. 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. - And there's also the issue of polypharmacology, which is simply when people take one drug, then there's often the tendency to take another drug, either because it's available in those conditions or because their threshold to saying yes is a little bit lower.

Do most people who take cannabis and achieve the high have a tendency to do other drugs? It doesn't seem like a drug that people combine with a lot of other drugs. - 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. 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 that are usually purely due to cannabis. Like it's not necessarily due to some kind of drug interaction there. 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 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. I think we're talking about a whole different ball game 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 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. 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 a greater risk of schizophrenia.

Essentially, 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. - Is there a bias towards males developing psychosis? I know there may be a bias initially toward males in schizophrenia that could confound this.

So we wanna be careful. - 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, the popular, like just in general, what people talk about.

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. So if there's an individual who has schizophrenia, we know for certain that cannabis can lead to the onset of 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. Like you shouldn't be using cannabis if you have schizophrenia. I think that's a risk across the board. - What about a first relative who has schizophrenia? Because there's a strong genetic component to schizophrenia.

- So I was gonna say, then the next question is knowing who's gonna 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, 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. And there is a camp of people who have looked at this literature and definitively believe that cannabis causes schizophrenia. And they attribute a proportion of people who have schizophrenia to only having that schizophrenia because of the fact that they used cannabis.

And I think you'd had some discussion about this in the last podcast. I can't remember exactly the way that you described it. - Yeah, I was looking toward some of the recent studies in Lancet, JAMA Psychiatry. I believe we can provide links to these again. And now more recently, there's been a lot of, let's just call it mainstream media coverage of this potential, I think is the right way to refer to it, potential linkage between adolescent teen and young adult use of high THC cannabis and lasting psychosis.

But the more I hear you talk about this, the more I'm wondering if that idea is being amplified more than perhaps we ought to let it be amplified. - I mean, I think this is what happens when you have, I mean, obviously you're familiar with this. In science, there's different, 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. 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 adolescence and the development of schizophrenia. 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, 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.

- As I recall, and I may have this incorrectly, but as I recall from my undergraduate years, what you just said is also true for military service, for people that have a predisposition to develop schizophrenia, that active military duty can exacerbate it as well. - 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, 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. 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. 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.

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. 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, 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. 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, and somewhere around 5%-ish are probably using almost daily.

So we have a 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.

And I mean, the rate use rates there are probably under 5% globally for teenagers, like probably closer to two 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.

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?

- Yeah, I hear your point loud and clear. I seem to recall that there is a higher incidence of schizophrenia independent of cannabis use closer to the poles and less so at the equator. I don't know if those statistics still hold up, but- - I have no idea. - Okay.

- I don't know. - It'd be interesting for us to look into that because then it would argue that since we're comparing very Northern locations to less Northern locations, that perhaps cannabis was sort of exacerbating- - Yeah, I mean, you could probably use Greece or Italy. I mean, they're gonna have cannabis use higher than Scandinavian countries, but it's gonna be way lower than North America still.

'Cause it's just- - What is it about North Americans and cannabis use? - I have no idea. I mean, I think it's just part of the culture here. It's just evolved totally differently. I mean, I think- - The Grateful Dead. No, I'm just kidding. I'm not picking on The Grateful Dead.

I like The Grateful Dead. Rick Rubin convinced me to start listening to them again 'cause my sister used to listen to them, and there's some great songs, and they're from Menlo Park, Palo Alto. So I've done my duty to listen. There's some great songs, so I'm not picking on them.

But- - 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 who are teenagers to drink. Alcohol is just much more of a cultural thing as well. And there are just differences.

I mean, it's the same thing. You look at like the opioid crisis that we're going through. 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. - Do you see differences between United States and Canada with respect to either cannabis or opioid use?

- I don't think dramatically. I think we're pretty comparable from, 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. 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. So they're not wildly different at all.

And again, even if you talk about climate, a lot of the U.S. is a lot warmer than Canada and you guys are certainly closer to the equator than we are. So I mean, we know like you do see higher rates of schizophrenia in urban settings than you do in rural settings.

And so, I mean-- - It's a stressor argument. - 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. I mean, no one's really, I think, sussed out a mechanism to explain why you see that. But 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 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 look at this from a somewhat, let's say, unbiased perspective where they see, you know, there's some, 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. 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. - 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. - I've spoken to many psychiatrists in an effort to find someone expert in ADHD.

We've done two episodes on ADHD, focusing on everything from behavioral to nutritional, but also prescription drug treatments for ADHD. And what's interesting is that all of them have relayed the fact that many people, not just young people, but adults with ADHD will often use, not necessarily abuse, but will use stimulants like coffee and other forms of stimulants to a high degree.

And then of course you can say, well, perhaps the stimulants are causing ADHD, but they actually argue for the opposite, which is that people are attempting to self-medicate. And then it's perhaps no surprise that most, not all, but most of the medications that are approved for the treatment of ADHD are variants of amphetamine or similar.

So it's another case where, depending on whether or not you look through the lens of the drug leading to the condition or through the lens of the condition leading to the use of the drug, you can end up in two very different places, but it looks exactly the same through each lens, so to speak.

- I think you, 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, 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, you know, the medications that they're provided to manage the disease are 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 they don't like engaging in stuff. There's some anxiety, some depression, some social withdrawal. And 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.

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 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, it would have this big effect in terms of reducing schizophrenia rates.

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, 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.

Like, I can't actually understand any other model that could explain this. - Yeah, no, the way you're explaining it now makes perfect sense. I do want to make sure that we distinguish between schizophrenia, like psychosis, or schizophrenia itself induced by cannabis, and manic bipolar episode. So people who have a predisposition or full-blown manic bipolar, sometimes called manic depression, but there's still a lot of nuance there.

We did an episode about this that people can also find linked in the show note captions. But in any case, is there any evidence for the fact that people who suffer from or have a predisposition to manic bipolar conditions like bipolar depression, for instance, should avoid high THC cannabis?

- So, well, first of all, I mean, in like hereditability family trees, for example, where you look at something like bipolar schizophrenia, the two do kind of track together. - Sure. - 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, but Glenn Close was one of the- - The actress.

- Yeah, she was one of the public speakers and she had talked about schizophrenia in her family tree. And she kind of put up this family tree of like, you know, her family and the one, the previous relatives in her family and showed like the individuals who had schizophrenia and bipolar as well.

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 hereditability 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.

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 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 of it smells stronger, it's more potent cannabis. That's not really true 'cause THC doesn't dictate the odor. That's, as I was saying, more of a terpene thing, but certainly I'm sure some of the skunk cannabis they were 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. 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? 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. 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, where it's not a country that has high cannabis use rates. And in an era when cannabis was hovering in a two 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.

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. 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. Nowadays it's higher potency cannabis. - Or maybe they seek out lots of different forms of recreational drugs and cannabis just happens to be one that they land on.

Which raises the other question, which is it's hard to imagine that these people who develop psychosis who happen to be using cannabis are only using cannabis. 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 rate. - Which is known to stimulate dopaminergic and other path. - There could be other reasons. 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? 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. - I think it enhances cognition in everybody. It just carries certain health concerns. And by the way, it doesn't enhance all forms of cognition, but there is a nice body of work to support the idea that nicotine delivered in any number of different forms can improve cognitive function to some extent.

But I don't suggest people run out and do it. And in fact, it's one of the more quickly abused drugs nowadays because of the non-smoking delivery routes that are becoming really popular, pouches and things. In fact, I was chewing a little bit of Nicorette gum to kind of do an experiment.

I liked it a lot. And then I decided to stop completely recently because it just, it wasn't having the same effect. And I found myself reaching for more and that's the time when I usually back out. - Well, yeah, no. Nicotine's a whole other thing, which I, yeah. - We'll have you back to talk about nicotine.

- No, I definitely do not know enough about that to have any kind of informed conversation. 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 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. And I think in the longterm, it will likely make the prognosis of the disease worse. So if you were a psychiatrist in a clinic and you consistently see patients presenting saying, I didn't have psychosis, I used cannabis, 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.

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 topic of conversation.

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 like, I'm in this fun position where I get hate mail from both sides. 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 gonna try and answer things as best as I can with that. And to me, that's the perspective I've maintained. 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.

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, 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.

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, 'cause it's gonna cause 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. - You know, I think it's because of these very high profile papers and the way those were picked up by traditional media. And this seems to be something that every couple of years, there's a resurgence of this idea.

Clearly people are curious about it. And so I just want to say, thank you for clarifying what is now to me obvious that it could be that there's a relationship there. It's clearly not the case yet. And it may never be the case that there's a causal relationship there.

And it could just as well be that people who have a predisposition to schizophrenia are seeking out cannabis use and engaging in cannabis use. And I think that's a very important principle for our listeners and viewers to just hear and understand anytime we're talking about a substance and a condition.

- Yeah, and I mean, I think, again, this is, again, no endorsement that that doesn't mean that it's safe and that that'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.

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.

- Yeah, absolutely. Let's talk about strains of cannabis. I've spoken before about the sativa versus the indica strains. And certainly there is a lot, a lot, a lot of subjective anecdotal descriptions about differences in the "effects" of those as reported by users. When I talked about this before in the cannabis episode, I leaned on a paper that took those subjective reports of arguably many, many people, pushed those subjective reports through what was known about the strains they claim to have used.

So this is, you know, people are reporting their use. We assume honestly, but you always have to assume that there, I guess people could be lying about which strains or misinformed. But, and then using machine learning to couple their subjective experiences as they report them to indica versus sativa strains.

And then by looking at the chemical composition of those different products, because these were products that they had consumed, trying to tap chemical composition to strain, in this case, that mainly the indica sativa discrepancy to subjective experience. And I know that you and presumably others in the field of cannabis research take real issue to that sort of approach.

And perhaps I have the feeling this is what you're gonna say, rest on the idea that we, at least at this point in time, really can't say anything about the different biological effects of sativas versus indicas. And yet at the beginning of the episode, you said that there are many, many different cannabinoid compounds in cannabis.

So three questions, and I'll keep these very short. One, do you think that there are different subjective effects of different strains of cannabis that can be attributed to the different strains, right? Not just to individual differences in experience. And then the second is, do you think that there will ever be a time in which we can understand this plant flower, right?

To the extent that we can engineer it to provide specific subjective experiences, perhaps more positive than negative, et cetera. And then there's a third question, but I'll hold off. - Okay, so, yes. So going back to just the idea with the indica sativa thing. So the indica and sativa names, at least from everything I've understood from everyone that I talked to and being in this field, is those are botanical terms that largely refer to shape of the plant, the way the bud grows, blah, blah, blah.

They do not track with chemical composition in any way. In fact, Nick Jacobus has done like a lot of analysis of like thousands and thousands of 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 that 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.

And there is no such thing as a chemical profile that exists in something that's a sativa versus something that's an indica. - Is it possible that there's a chemical profile that relates to the most common indicas or most common sativas? - 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, well then that immediately to me negates the sort of premise of this paper that I was referring to that divides according to indica sativa. And yet the paper is also trying to distinguish among all the different types or products of cannabis. Meaning, is there some other feature of the cannabis plant that does relate to these different subjective effects?

Because people do seem to get different subjective effects from different products that relate in some way to things other than the concentration of THC. - Yeah, I would, my honest opinion is this is expectancy bias. This is all expectancy bias. I mean- - I see. So they purchase something that they think is gonna make them calm and it makes them feel calm.

- If 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 cannabis is like this whole area is so ripe with these expectancy biases that people have about what they assume.

If you go, someone goes into, you know, and a bud tender tells them, "This is a sativa, it's gonna energize you." There's no way to remove that expectancy bias from what you get. 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 gonna do to them.

I mean, and a lot of- - It's pretty wild. It speaks to, you know, I did an episode on the placebo effect. - Yeah, it's similar. - And a lot of people hear placebo effect and they go, "Okay, well, then everything's a placebo." The placebo effect is amazing. There's dose response to the placebo effect of nicotine on cognition, dose response.

If you're told you got a high dose when you actually got a low dose, you will exhibit the high dose neurocognitive enhancement effect. And by brain imaging, it shows a high dose-like enhancement of the relevant brain areas. In other words, the expectancy drives changes in brain activity. - 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. Like people say this. I mean, the issue has been, and I just asked Ryan Vandery this. 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 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 gonna influence it. There's no way around it. And so people kind of lean into this and 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. 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. - Do you think this also explains the lore or perhaps it's real that different alcohols produce different drunks?

You know, I mean, I've heard of, I've got friends who will swear that whiskey makes them feel aggressive and vodka is mellow and white tequilas feel different than the other tequilas. And for people listening to this, they go, okay, well, that's not science. I agree, that's not science. That's just anecdote.

And yet, you know, the chemical composition of these different drinks is different, but ultimately we're talking about alcohol, right? Different sugar contents, you know, different hangover propensity. - I mean, I have to believe the majority that's an expectancy bias. I have a hard time believing that these things are really driven by fundamental biological differences within, 'cause anything else that's, I mean, that's the thing like, sure, 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 terpenes or minor cannabinoids may influence that effect. That is a theory. 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.

There's some stuff that's starting to come out now, like Ryan Vandrie 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.

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, 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 the second most abundant terpene, I think, from Nick Giacomas' work. I think myrcine may have been the highest prevalent terpene across all types of cannabis. Beta-caryophyllene's 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. 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? 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, I mean, it's how someone personally experiences it. 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, given the amount of terpenes and the amount of combinations at different levels, how overwhelming this could become. 'Cause 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, 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 like different chemovars or what people call strains of cannabis could do different things subjectively.

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 introduce this, that was, again, I think like one of the issues that I took with the other podcast was because as you've said, I understand the thought process you went through.

Like you had this paper where people were reporting subjective effects. There's some neuroimaging data that's been done with cannabis. So you kind of said, okay, this is what that was. And that was what Sativa did and versus this is what Indica did. So I think it's important that you explain that.

'Cause I do think that like- - Well, that's what the data pointed to. But now what I'm realizing is that anytime we're talking about cannabis, because of the 70 plus cannabinoids present that could modify or join, so work in parallel with the effects of THC, we're really talking about polypharmacology.

It's not a pure subject. It's not like giving anandamide or it's not like adjusting levels of endogenous anandamide. This raises, I think, an equally important issue for us to resolve, which is CBD, which we didn't talk about earlier. When Nolan Williams, who's a psychiatrist, he's one of these phenoms, triple board certified psychiatry neurology, colleague of mine from Stanford School of Medicine, who mainly works on Ibogaine and transcranial magnetic stimulation.

But we talked about cannabis a bit when he was on the podcast. And he mentioned a strain of cannabis that is available in Colorado, which is pure CBD. I think it's called Charlotte's Web. And the parents of children who have epilepsy will move there or go there just to get this strain because it seems to help their epileptic seizures.

- 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. - Yeah, so the questions are, could you tell us a little bit about the biology of the CBD receptor, mainly as it relates to CB1 or not?

Does it bind CB1 as well? If not, how is it working? And you mentioned that people will not report any subjective effect of taking a pure CBD compound, so lacking THC. But it sounds like it may have some usefulness for treatment of epilepsy. And what are some other established, meaning clinical trials and/or lab data to support the use of CBD for any type of either psychiatric condition, pain, et cetera?

- 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. - You mean there's no CBD in there? - 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. 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. 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.

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 again, it's just, it's, I mean, I think in the analysis that Nick Jachomas 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. And in Canada to get a CBD rich strain, you have to basically explicitly buy it because it has to be bred 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. And now I think like 90 to 90 something low percent of all cannabises that are out there are type one. Like they're all high THC 'cause that's what's been bred. There's a few that have been mixed.

And so are kind of equal proportions, but you're never gonna get high equal proportions. So like a high THC cannabis is like 20 to 30%. If you go for type two, which is mixed, they're both gonna fall around 12%, maybe a little more, but in that range. And then same if you've got a type three, it's high CBD, it's gonna be 20-ish percent CBD and very low THC.

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 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. 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 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. Elizabeth Thiel 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, five? What is it, class? - CBD? - Yeah, like CBD. I mean, given the availability of CBD everywhere in gummies and drinks. And I mean, you can get it in a convenience store.

- 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, but essentially what they have shown is that like very high doses of CBD 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.

And so, and I can understand. - Yeah, that's super impressive. - 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. 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 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. So as you had said, like CBD receptor, there is no CBD, like there's no receptor that CBD binds to. - I was under the impression that CBD also bound to the CB1 receptor. - No, I mean, certainly not. - Or that under some conditions, it can modulate the shape of the receptor to adjust THC binding.

But now you're telling me that these two things rarely coexist together. So I guess the question-- - You can dose them. 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. And like, well, if you're using it in a strain, that's simply because the strain of cannabis has less THC. - Right, so it's impossible to separate. - So you 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. - I thought the explanation for that was that CBD can modify the CB1 receptor in some way that makes THC less able to engage with the THC.

- There is some evidence to support that, that like we would call these allosteric modulators. There's some evidence to suggest that CBD may interact with a allosteric site on the cannabinoid receptor that makes THC bind less. - Doesn't sound like you're particularly convinced by that evidence. I'm looking at the look on your face.

For those listening, I'm looking at Matt, and I think he's being generous here. Let me ask it a little differently. - It's definitely more complex than that. - Does anyone know what CBD binds to? - So the most convincing thing that I've seen that CBD binds to is the work that C.C.

Hilliard has done looking at its ability to essentially block adenosine uptake. And so it can inhibit the adenosine transporter. - So that should make people feel more alert. - No, because you're getting more adenosine. So you get an accumulation. It blocks the adenosine transport mechanism. - I see. - So you get an accumulation of adenosine, which is more sedative.

And that, I mean, in the PNAS paper that C.C.'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 the secondary effect by-- - Sort of the opposite of-- - Caffeine. - Of caffeine.

- Yeah, no, if I remember doing-- - The way you're describing this, it sounds like the anti-caffeine. - 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 C.C.'s 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, you know, 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, 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 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.

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.

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 gonna start having hepatic effects. So it's gonna affect the liver, and it's gonna affect the ability of the liver to chew up other drugs.

And there's very specific SIP enzymes, like the cluster of enzymes that metabolize things, there's very specific ones that CBD hits. And so as a consequence, one of them is what chews THC up. So you can get a potentiation of THC by inhibiting its metabolism if you have high enough CBD on board.

- Given the effects on adenosine that you described before, that it's sort of what we're calling, just for sake of discussion, the anti-caffeine, how do we explain the preponderance of CBD added to energy drinks that also contain caffeine? There's like no logic there. - Expectancy bias. - There you go, everything can't be expectancy bias.

I have a feeling it's gonna be interesting to see in the comment section on YouTube. I mean, presumably there's some regular pot smokers listening to this. And the expectancy bias is so strong, as I allude to in the placebo episode and we've been talking about here. And yet it's so strong that I think people will also be convinced that there are real differences between different strains because they've maybe done the non-formal blind, someone gave them their weed and someone else, and then they got a completely different effect, right?

They're not expecting something different necessarily in a particular direction, but they get a very different effect. But that to me just speaks to the idea that, again, cannabis sounds like polypharmacology, 70 different cannabinoids, THC being among the more powerful components, but it's yoked in the sense that, as you said, people self-regulate their intake, provided they're smoking, not ingesting it by edible.

And so it's almost like THC is being held constant. And then there's this constellation of other things around it that are modified. And people eventually veer towards what they like, what they can afford, what works with their lifestyle. And then they come up with a bunch of theories based on packaging, what they're told, but presumably also some real effects of these terpenes, the CBD component, et cetera.

It can't all be just psychological interpretation. - 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 there's a couple of kinds of cannabis that might have a high enough level where you're seeing something.

But 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 sativa versus indica, I think there's a huge bias that's going into there.

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. - This was the big problem with the MDMA trial that happened recently is that people who got the placebo knew they got placebo.

People who got the drug knew they got the drug. It's very hard. You could do a dose response, but it's very difficult. - 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, 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, 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.

And my response to them is, do you know what dose those people are getting? 'Cause this is something that for some reason has not made the transition from science into pop culture. - This is a similar phenomenon with GLP-1. I and other people have pointed to the fact that certain food products or certain drinks or certain activities can increase GLP-1, glucogon-like peptide, which is now becoming more commonplace knowledge because of ozempic, manjaro, et cetera, as very powerful weight loss tools, although there's questions about muscle loss, et cetera.

And then we had Dr. Zachary Knight on, who explained that even a fourfold increase in GLP-1 brought about through a prescription drug or ingestion of a particular food or drink does not lead to any appreciable weight loss. However, when one achieves a thousand fold increases in GLP-1 through the use of things like ozempic, manjaro, you see profound weight loss, meaning that you need enormous effects in order to see the clinically relevant changes in that case, weight loss.

So it sounds like a similar thing with CBD. So if somebody takes a CBD gummy and they feel that they sleep better, you would argue that that's entirely expectation bias. - 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.

- I don't know, I've never taken a CBD product. I know a few years ago, they were all the rage. I just, I was never tempted to do it. And I'm aware, and we'll talk about this a little bit more, that there is evidence, according to Matt Walker, who did a six episode series with us on sleep, that THC does help certain people fall asleep, but it can dramatically alter the architecture of sleep in ways that are probably not great.

- Yeah, yeah. I mean, THC in 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 two 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 megs. 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 kig or whatnot.

So someone my size, so I weigh a bit over 200 pounds, for me to take that dose of CBD, and let's say 20 megs per kig at like 90-odd kilos, I mean, you're talking about me taking- - A liver-damaging dose. - An insane, or maybe I wouldn't say damaging.

It's definitely influencing how the liver metabolizes other things, 'cause it's gonna saturate those enzymes, but you're taking a very high dose. - So if, for instance, you were to take a high dose of CBD and then maybe have a couple alcohol-containing drinks, that could be problematic, right? Because you're talking about the two-hit model.

- Yeah, I can't speak to that, 'cause I actually do not know the metabolism of alcohol well enough. I don't believe so, 'cause that's alcohol dehydrogenase. So that would probably be a separate enzyme pathway than the SIPs. This is more like- - Separate enzyme pathway, but you're challenging the liver.

- 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, and the anti-epileptics funnel into the same metabolic pathway as this THC.

So there's certain things that this would influence. 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 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. 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 routes, we're talking 4%. Like, very, very little. Actually leaves your gut into your bloodstream. 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.

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. - Can see now, it's the steak and CBD, or the CBD with omelet protocol.

I'm just kidding, folks. I'm not suggesting that protocol. - 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, but because you're having benefit from it.

But would I ever recommend someone do this? 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, and there's a couple of receptors people have said, you know, it might interact with serotonin receptor, 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. 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 like, you know, 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.

And now it's like 80 to 90% would know what it is. 'Cause 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 like concoction that people have added CBD, 'cause now it's gonna, you're saying the energy drinks, like it's just, 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, so.

- Yeah, I've never tried any of these CBD containing products. I think a lot of what you're describing speaks to the fact that, you know, people are eager for things that can help them adjust their anxiety and sleep better. You know, which is a large reason why a lot of this podcast has focused on respiration-based tools and other base tools that can help people with anxiety.

I think that many people suffer from just too much activation in their autonomic nervous system. And I would argue there are much better things that are not of a ingestible type, you know, things that one can do that are science supported, right? There are clinical studies, meditation, breath work, any, not so much breath work, I would argue, but certain patterns of breathing, meditation, cognitive behavioral therapy.

There are a whole bunch of different things, as you know. So I don't know what explains the CBD craze, but you certainly have shed light on what is, and mainly what is not known about CBD. And I think it's really important for people to hear. - Yeah, I mean, again, it's, I think from my point of view, it's an ethical thing as well, because like 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, if you're, especially if you're talking about an actual clinical dose, 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.

And I'd say most of the trials that have been done have not found really good evidence of benefit in any capacity. 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.

- So it doesn't sound like CBD is the solution. - I would, I am not convinced by the data that exists that it's really doing what a lot of people claim it's doing. - Except supporting the placebo effect, perhaps, perhaps. - It's a great study of the placebo effect.

- I want to make sure before we close that we touch on some of the potential harms or asserted harms of THC, because I think there's a lot of misunderstanding about this. We talked about psychosis and the lack of evidence for a direct causal effect. You give a beautiful description as to how we should think about all of that based on the current literature.

But cannabis and driving is a potential hazard, right? And some people will laugh. They'll be like, oh, driving too slow, as opposed to, you know, driving drunk or driving too fast. Okay, we can talk about that. We talked about the potential for addiction and the evidence potentially for and against that, right?

There's also this, the big black or gray box of, you know, all the things we don't know about what regular cannabis use could do. And yet I know a lot of people who've used cannabis for years, mainly as a replacement for alcohol, at least that's how they describe it.

Well, it's not as bad as alcohol, but you hear that a lot, okay? But what are some actual, if any, what are some actual harms of cannabis use that people need to take into account and just weigh against the fact that every compound, caffeine, even water can kill you if you drink too much of it.

And then let's make sure that we touch on this issue of cannabis and driving or operating machinery. But I think the machine most people are thinking about these days is driving. - 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.

- Because people are smoking less of it or there's just fewer carcinogens in there. - 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 a hundred percent sure, but I know he was in California.

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.

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. 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 gonna 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. 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. 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 it was. - Can this potential, I wanna highlight potential, relationship between cannabis use and cardiovascular issues be bypassed, no pun intended, by using edibles, not inhalants, or is it related to THC itself?

- I would probably guess, and this is a guess, that the, you know, 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 gonna have some vascular effects to some degree on the system.

So I imagine it would make it worse, 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.

And so this is not uncommon to happen to people and with edibles as well. So it's not just from smoking. 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 shift in gravity that happens.

And so not enough blood perfuses the brain and they go down. And that can be transient. They'll come to a minute or two later, but it happens. But as a consequence of the vasodilation is it triggers tachycardia, which is an accelerated heart rate. And so that's a very reliable physiological response for a lot of people who use cannabis.

And so 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. 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.

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, 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, you know, vascular stiffness that can evolve over time. 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, it's just obviously the timeline of this.

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 forties and the thirties and stuff, and people started living longer, you started seeing a lot of these effects of cigarette smoking emerge because- - And yet it took a while for the medical community to adopt the idea that cigarette smoking was bad.

- Oh, I know. It's wild- - Physicians would smoke in clinic, there were ashtrays in the doctor's office. - 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 was kind of wild to hear that stuff when you think of how cigarettes are viewed nowadays. But 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. And I would also say, if anyone has cardiovascular issues, they should avoid cannabis. Just 'cause that's more of like, I would say a being safe, 'cause 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. So I would, 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.

We've seen this in Canada a bit more now with legalization, again, 'cause 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 puking and they can't stop it. And it's like this intractable vomiting that they get into.

And then bizarrely, one of the things that seems to cure it is a hot shower, which is, I can't even begin to understand this. I mean, there's also-- - I'm chuckling at the example 'cause you are so very clearly rooted in science, but that just came out of nowhere.

Like, okay, cool, a hot shower, deliberate heat exposure, folks. There it is. - I have been trying to understand how this was-- - I'm not enjoying it because it's deliberate heat exposure, but it just speaks to the fact that we're talking about smoking being a regular part of the medical community's behaviors up until a few decades ago.

And then a hot shower being the treatment for this chronic vomiting. And it speaks to the fact that with science and medicine, we do know a ton. It's amazing how much we've progressed this, especially in the last 100 years, last 25 years even. But it's also astounding how these seemingly surprising antidotes to uncomfortable conditions can hold up over time in the absence of any randomized control trials or mechanistic data.

- I mean, I really struggled to understand, 'cause 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 'cause they're like vomiting on themselves.

- Probably. - I inadvertently realized 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. - So something about activation of the heat, thermal-- - It's something with thermoregulation, 'cause 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. 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?

'Cause I mean, it is again, surprisingly counterintuitive because one of the medical uses that people have used cannabis for is as an antinauseant, especially in the context of chemotherapy. And so something that typically has antinauseant qualities suddenly triggering a vomiting syndrome is kind of a paradoxical. - And yet we started off today's conversation with you explaining beautifully how activation of these CB1 receptors are homeostatic in some sense, the thermostat analogy.

And maybe after chronic use, there's some, the seesaw sort of gets flipped to one side and gets stuck. - I think that's how most people have tried to kind of conceptualize what's going on is maybe like, and it seems to involve the insular cortex, at least the antinauseant effects of cannabinoids are involved through the insular cortex.

And so maybe you like have burned out those receptors from chronic use. And so that endogenous mechanism isn't working or it's somehow flipped in the other direction now in that circuit becomes sensitized, 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. 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, so a hot shower. - Yeah, so apparently if it happens, hot shower is what people claim. So yeah, so for me, I would say the main harms that people need to be aware of are 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.

Those are the main, I think genuine bonafide health issues associated with cannabis that people should be aware of. I mean, I know we're not gonna 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 good studies that have been done in any capacity that have really definitively told us if cannabis has like really bonafide medical benefit.

- Yeah, I was gonna ask you about that. It's always nice to end on a positive side and we don't wanna demonize cannabis, nor do we wanna glorify it. But the examples that I've heard of medical uses for cannabis include appetite stimulation. We talked about that. For glaucoma, lowering eye pressure and glaucoma, the age and age-related increase in eye pressure are two of the major risk factors for glaucoma, which is the most common blinding disease, second to cataract.

More than 70 million people suffer from it. Everybody, regardless of age, get your eye pressures checked. There are drops for this, but okay, cannabis can reduce eye pressure and glaucoma. Nausea, you mentioned, and then anxiety. It sounds like if people get the dose right and it's right for them, that in some cases it can help them with their anxiety.

And the reason I raised that one is because it seems that most people who decide to use cannabis regularly are using it as perhaps for its euphoric effects, but as kind of a mild sedative, a way to relax in the same way that they would use a glass or two of wine.

What are your thoughts on that? Because I think this is the most common use case. - Yeah, 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 as pain. So chronic pain. - The 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. And 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. 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. 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 that component of it. And I think you alluded to something like that in the previous podcast. You'd said something about how it's changing the emotional state of pain.

- And we know from the biopsychosocial model of pain that emotions and interpretation of the sensation of pain is a huge component of what people refer to as chronic and acute pain. - 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 smoked cannabis and found small signals of benefit. But so anxiety is an interesting one. 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. 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, we figured the same was gonna 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. Now, whether that would hold weight in a clinical trial is a different story.

There is some old evidence from like, I'd say the '70s, early '80s, where they were using synthetic forms of THC, like nabalone, 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.

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.

It gets a little bit more complicated 'cause 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 done by the Canadian military. First, they did one version of it that was an open label.

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, 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. And there does seem to be some suggestion that because they're remembering it and maybe changing the details 'cause 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. 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 re-consolidation and the sensitization of the disease that happens over time in this kind of sleep state can make it worse.

And so, 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 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, soon as they put people on Nabilone, this synthetic version of THC, it vary in like a large proportion, I think like 85% of them almost stopped having these nightmares.

And this was like a treatment-resistant population that was pretty severe. So, this was a big benefit. So, they then took the 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.

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 Nabilone at one point, it was switched. They didn't know which one they were on.

Because they're taking it right before bed, maybe that will remove some of the subjective bias. Again, you can't totally remove it, but like if someone's taking it within an hour or so of going to sleep, they may not feel high the same way. But even under the double-blinded conditions, they found a very effective suppression of the nightmares and the re-experiencing.

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. 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, 'cause that was the primary outcome of the study.

But, so I thought that was interesting, 'cause 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 a kind of, I wouldn't maybe call it a sleep aid, because it's really more of a modulator of the dream state.

And I think this is- - Presumably, because it's reducing the amount of rapid eye movement sleep you're getting, which most people will probably hear and interpret as bad. But you know, REM deprivation is actually one treatment for depression. So there are certain case conditions where dreaming and REM is not advantageous.

- Yeah. - And you're describing one. - 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. 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 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. You know, 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. 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, the fall inhibitor that elevates anandamide levels.

So Johnson & Johnson did do a trial on social anxiety disorder. It's published, I think, from a few years ago, '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 'cause they kind of underdosed the patients a bit.

And so 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.

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 largely anandamide signaling. And I mean, 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.

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 it's kind of tonic housekeeper, keeping things in that homeostatic range, 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. 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.

- That's extremely interesting because it squares with my, again, non-laboratory observation that a lot of people use cannabis to deal with their anxiety, right? So what you're saying is that, you know, there's a range of kind of, let's just say, baseline circuit activation within the amygdala and related structures in mice, in humans, presumably in other animals also.

If people take a compound that adjusts the sort of homeostatic level of what's considered low, moderate, and high activation of those circuits that include the amygdala, then perhaps they're bringing their anxiety into range. In a way that perhaps is different than with alcohol, which is more acute, you know, people have a couple of drinks, they'll feel relaxed, but then there's this phenomenon of anxiety, you know, the next day, feeling a little anxious when they're not drinking.

Whereas it's interesting that many people who use cannabis for this purpose are not using it all day long. They are perfectly able to wait until the nighttime or evening. And of course people can wait for their happy hour for a drink as well, but it's far and away different than the way we envision something like alcohol use disorder where somebody discovers that alcohol really helps with their anxiety and then they're drinking, you know, maybe one at lunch, maybe a couple at dinner, and then in the evening to fall asleep at night.

I'm describing extremes here, but I find your hypothesis to square really well with the real world observations. And it's an interesting one. - 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. So this was done in mice and they basically, but one of the questions was is, so A, does like, you know, 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. 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, maybe for some people, this is if this, 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.

And that again, may be very different than someone who is like, you know, very anxious for different reasons or has normal endocannabinoid function or something else might be at play there. So- - Very interesting. - Yeah, I think I could explain some of the heterogeneity that exists out there for sure, yeah.

- So perhaps genetic differences in sort of baseline levels of anxiety, perhaps map to endogenous levels of anandamide and might predict propensity for THC use. - Yeah, I mean, we have definitely found in human populations through work I've done with a lot of clinical collaborators and others, like, you know, 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.

And we have found relationships between peripheral endocannabinoid levels and mood states, both anxiety and kind of depressive measures, which does, you know, 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.

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.

- Fantastic, and I really appreciate that you're able to share some of what your laboratory is working directly on now and looking into the future. And I want to thank you for what has been an incredibly clear, precise, and in many cases actionable, whether or not it leads to a yes or a no, actionable information here, because cannabis and CBD, as you pointed out, are kind of everywhere around us.

And people are making decisions about cannabis and CBD. And I also want to thank you because what initially started off as a bit of a confrontation online, which I alluded to in the introduction that I gave, has now evolved into a collaboration that I'm certain based on the exquisitely clear and generous information that you've provided has led to better education, more clarity, and therefore better informed choices for all the people listening and watching.

So I really, truly appreciate you coming out here, sitting down with me, discussing these issues, clarifying points that were unclear before, and also pointing to the fact that this is a complex system, a complex biology. There are a lot of things about psychosis, about negative effects, about potential positive uses of cannabis that just are not yet clear.

And thanks to excellent researchers like you are likely going to be clarified in the years to come. So thank you ever so much for your time, for your research, and for your attention to the public health education effort around cannabis. - 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, 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, 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 in that area as well, yeah. - Yeah, if somebody who is expert in a particular area takes issue with something specific and can substantiate it with something that can foster better understanding, without fail, I'll reach out to them.

Now, how quickly we're able to get them here, et cetera, is always an issue. Sometimes we can put an addendum to a podcast. Nowadays, that's easier using what's called dynamic insertion, where we can go back and actually make a correction. But listen, the best situation is always when this podcast can mimic the real world of research science as you and I both know it to exist, where if we had been in a meeting and you presented data, I presented data and we disagreed, what we would probably do would be to head, well, traditionally it would be to the bar, but we'd grab a cup of coffee or go for a walk and we would talk about it, hash it out, and then potentially bring it up again at the next meeting.

So in some sense, what we've done here over the last month or so, and certainly during today's podcast, is to do something to that effect. - 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. - Yeah, likewise. And it's certainly within the spirit of the podcast. In no way, shape or form do I purport to get everything right and where I've made mistakes, I really strive to correct them.

And listen, it's been a real honor and privilege to have you out here. Thanks for coming all the way from Canada. And I do hope to have you back again as the research evolves and we can learn more about these topics and more. So thank you so much, Matt, appreciate you.

- Great. - Thank you for joining me for today's discussion about cannabis with Dr. Matthew Hill. I hope you found the discussion to be as informative as I did. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. Please also subscribe to the podcast on both Spotify and Apple.

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I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled "Protocols, An Operating Manual for the Human Body." This is a book that I've been working on for more than five years, and that's based on more than 30 years of research and experience.

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