Dr. Matthew Hill: How Cannabis Impacts Health & the Potential Risks

Welcome to the Huberman Lab podcast where we discuss science and science-based tools for everyday life. 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 Huberman Lab. He also took issue with some of the specific points made within 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. 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 Indica versus Sativa's 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. 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 other 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. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is 8 Sleep. 8 Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity.

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I also drink element dissolved in water during any kind of physical exercise I'm doing, especially on hot days if I'm sweating a lot and losing water and electrolytes. If you'd like to try Element, you can go to drinkelement.com slash Huberman, spelled drinklmnt.com slash Huberman, to claim a free element sample pack with the purchase of any element drink mix. Again, that's drinkelement.com slash Huberman to claim a free sample pack. Today's episode is also brought to us by BetterHelp.

BetterHelp offers professional therapy with a licensed therapist carried out entirely online. There are essentially three things that make up great therapy. First of all, great therapy consists of having good rapport with somebody that you can really trust and talk to about the issues that you're dealing with. Second of all, that therapist should provide support in the form of emotional support or directed guidance.

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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 going to 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. And 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 tetrahedric cannabinal or what we call THC.

And that really is what dictates the psychoactive and intoxicating properties of the plant. The amount of THC that is within the cannabis plant will influence the, you know, how high a person's going to get when they consume it. There are probably 70 to 100 in some odd other cannabinoids that are within cannabis. Most of them are pretty trace levels like, and they vary from different types to cannabis from one another.

But the other one that's had a lot of attention is cannabis dialer, what we call CBD. CBD is structurally looks pretty similar to THC, but doesn't behave anything like THC. It's not intoxicating at all. I'm not sure I would probably say it's not psychoactive in the sense that people can't tell if they're on it or not. But I would, some people still say it's psychoactive because people claim, you know, it can affect anxiety state or mood state or other things.

So in that context, maybe psychoactive is still somewhat appropriate of word to use. And then there's a whole bunch of other things like cannabinole, cannabageryl, and these other minor cannabinoids, most of which we really don't understand any of the biology. 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, you know, 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 limiting, which, you know, gives some cannabis kind of a citrusy odor or flavor to it.

Pining, which gives things more of like a earthy tree kind of smell, beta-carioffling, mercine, 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 terpen or one other minor cannabinoid and seeing how it influences things. 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 distal it 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.

Fascinating plant. You mentioned the psychoactive effects. Some people listening to this and watching this presumably have experienced the 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 he would 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 they I mean, people often refer to it as they're being some euphoria or some positive mood.

Not on the same order is what people 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, you know, other aspects in terms of changes in feeding behavior. People might find things funnier than they found things that 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 somebody 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 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 that people get someone high, they just kind of use a what we call a visual analog scale, which is like a 100 or something or 0 100 and say, do you feel high?

Do you enjoy this? Would you say you feel you fork 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 higher not from it. And this is why when people do studies with something like a placebo cannabis or a very low to see 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 a thing. 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 the drug.

And they pay you now. Yeah, I think that 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 that 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 because 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.

But 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 of past and 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 impidients but it might be in rodents that's looking at like temporal ordering and they give animals cannabinoids and that's kind of a cleaner way of seeing because they are very good at learning like if I wait 10 minutes and then I engage in a behavior I get a reward. 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 going to really understand the mechanism of it that would probably be the way to go but I'm not super familiar with the work as 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 of effect makes people hungrier obviously but we hear again in.

Kind of recreational terms of people getting the munchies you know 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 get a step back actually 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 are acting at this one receptor for the most part that's widely expressed to the brain called the cannabinoid type one receptor CB one yeah CB one is the shorthand for it and I think you know as people tend to create analogies to describe what receptors are for those you don't know it's most people use like a lock and key analogy that like a receptor would be a protein that's 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 and some capacity. And so THC acts on the CB one receptors which are very widely expressed in fact outside of like kind of ion channels that are expressed in the brain the CB one 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 didn't 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 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 going to 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 CB one and there is also a CB two receptor it's not really expressed in the brain since some of the immune cells in the brain and maybe maybe some limited distribution in actual brain cell neurons where we're in the body is mostly immune cells so you'll see CB two is mostly on like macrophages.

Or other kind of immune cells cells that gobble up debris yeah and that basically you know regulate inflammatory processes and so the main role of CB two 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 in the brain and behavior we're talking almost entirely about CB one.

And so both the CB one and CB two receptors like I said don't exist because nature was like humans are going to find cannabis though this wall worked together now so there are molecules our body produces which we call endocannabinoids and they are kind of funny little molecules because they don't really behave like certainly in the brain they don't behave like a normal neurotransmitter so.

I mean I assume most people who listen to your podcast are relatively adept with the basic idea of how neurons work so you have neuron a what's called 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 you know jack that neurons activity up or it can scale it down and that affects you know brain wide patterns of activity and we call that and terror grade because it moves from neuron a to neuron B which is kind of the general flow of things and how we usually think about it so endocannabinoids are kind of this you know.

Little bit of an oddity in the sense that they could do the reverse and so endocannabinoids are actually made in neuron B on the posts synaptic 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 so they were talking about some really excitability so if neuron A is dumping out something that excites neuron B like glutamate which is an excitatory neurotransmitter as neuron B gets too excited it's going to start releasing it.

And it's going to start releasing endocannabinoids to go back and tell neuron A to stop driving it so sort of a homeostatic scale and 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

canabinoid 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 that's probably why the CB one 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 because we're talking about retrograde signaling but ultimately you don't want runaway excitation yes that looks like epilepsy exactly and you don't want runaway in addition because that looks like suppression of yeah ability to think move etc.

Okay so you want to keep things in the in where they should be it so you want neurons to get excited but you want them you don't want them to get over excited so endocannabinoids and kind of a very prototypical sense act is 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 presenaptic 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 is to more excitation.

I usually like in it to basically take in the breaks off of a car while you're going downhill kind of thing like you're you know you'd use your breaking system to keep things in check but if you want to go faster you take the foot off the breaks 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 hard wire 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 CB one receptors are found on virtually every single kind of neuron in the brain except one I think you'll find this interesting because it's dopamine

and dopamine neurons are basically the only neurons in the brain that don't really at least as far as we've been able to characterize the date expressed can abnoid 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

search and ergic receptors system I wouldn't say that can abnoids don't affect dopamine because what we understand in the ventral tegmental area which is kind of a hot spot 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 or there's an

opportunity for indirectly exactly so what you have is those neurons that regulate the dopamine neurons are very rich in can abnoid receptors this is actually kind of similar to how you opioid receptors work for things like morphine or heroin

and essentially what the can abnoid receptors will do is when they're activated they'll turn off that inhibitory control and that allows dopamine neurons to kind of move into a state where they're more prone to go into burst firing and have big dumps of dopamine

whether or not that relates to you know the positive affect or the euphoria I don't think anyone has cleanly demonstrated that I mean obviously dopamine is very complicated in terms of its relation to endpoints and whether it's reward or motivation

but can abnoids 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 can abnoid 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 something 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 plus this video 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 and

it's a very terrible way and it diversifies at the level of a receptor so serotonin has like 15 receptors or 20 or something now dopamine has at least 5 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 of the reverse not only do they work backwards across the synapse and working 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 then at the receptor which is the same as the one that is regulated by two molecules so the diversification happens more at the level of the molecule then at the receptor which is the

different molecules 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 a kind of a funny name because it comes from the Sanskrit word anand for bliss and so

Rafi Mishulam who was in Israel when he discovered the molecule you know 30 odd years ago wanted it to reflect inner bliss and so he named it an and amide so it's like inner bliss with an amide bond is kind of the joke he had for it and so he discovered an and

amide and decided to call it bliss because he had familiarity with cannabis or because he took an and amide as a direct experience and he takes a lot for a scientist to discover a molecule but then for scientists to discover a molecule and then name it bliss

for a particular reason you have to speculate that they they had some familiarity with with the caravan. Rafi Mishulam was also the guy who who isolated and discovered THC so I mean he has a very he's kind of the grandfather of a whole canabinoid 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 birth date of the first THC paper was 420

1964 well now that now that potential myth is definitely going to propagate but yeah so he had he had 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 an and amide is being the first molecule that activated the receptor

and dodgingously and so it was kind of yeah I think it was a little tongue in cheek that he named it the way it is a few years later the second molecule which is just called to a rack of all glycerol or what we call 2 AG that was discovered kind of in tandem both again by Mishulam 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 a nandamide 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 an and a mind or required to actually bind the receptor but once it binds its ability to stimulate a biological response in that neuron is 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 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 intercellular signaling response and so

why we have to 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 of the circuit that they're working in or this idea that maybe a nandamide 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 an andamide might just be kind of made by neurons on an ongoing basis and just released and its job may be to kind of keep the steady state of a brain circuit and a desired range so that under resting conditions it's not too active or too quiet your thermostat analogy is perfect here so in that context it kind of is like just the thermostat of the house

whereas 2a g is like let's say the pinch hitter who gets brought in to do the heavy lifting and so 2a g during a situation like let's say something like even like a seizure is an extreme example we have a huge amount of neural activity those neurons that are getting heavily activated during you know massive amounts of neural activity start dumping out huge amounts of 2a g and that acts as the okay we really need to turn off this circuit very quickly in this situation

and 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 is going on most of that is driven by 2a g signaling and so you know all these forms of like turning things up or down in an and a kind of rapid on demand manner that's mostly 2a g

most people who study like neurophysiology and like record activity and neurons and look at endocannabinoids they're almost entirely talking about 2a g when they play with stuff so yeah that's kind of one of the ways we do it we say that an and a might may be more tonic and 2a g might be more phasic and like brought online when needed but doesn't do a lot

there is some evidence that 2a g may also have a role to regulate some circuits under kind of resting conditions as well and there's certainly are some situations where an and a might 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 2 up so we kind of have these 2 molecules

they end of the day do the same thing they're regulating or transmitting 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 2a g is activity dependent so as that neuron becomes more active it's going to make 2a g to regulate its inputs

so yeah you have this very complex system and it's really widely distributed in you know it's everywhere as an cannabinoid receptor is the endocannabinoid molecules are in the cortex they're in the hypothalamus and strutum the hippocampus the cerebellum all over the brain except the one area where it's really interesting actually where you don't really see much receptor is in brainstem populations that regulate you know kind of unconscious cardiac and respiratory function

so this is one of the things that really differentiates cannabis from opiates because a lot of the signaling mechanisms between opioid receptors and cannabinoid receptors are quite similar

but as it's been well established people can overdose 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 cardio respiratory 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 they 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

whether 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 it's 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 fissionado 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

the pomep on 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 in feeding are a really interesting thing because proto like if you ask people like kind of the prototypical responses to consume 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 and yeah we just had an episode with Zach Knight from HHMine UCSF we talked about like the agrp neurons and different neurons of the hypothalamus we can link to that in the show no captions

nowadays a rich understanding of the neurons that stimulate food seeking craving and 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 dis inhibit 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 an andamide for example this is you know Steve Mallor and Kent bearish did this work years ago where they just put an andamide into the nucleus of comments 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 PNS 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 sour or I don't know if they did umami in that one but it was a 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 palm cina runs

those kind of both sides of that in the in the arqueot nucleus to regulate multiple components of feeding but a big question is like my labs 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 you know what is it that because it's not just food seeking and it's not just you know like there's want to consume something there's there's a maintenance of eating and so we know from humans and animals you can satiate them you can make someone fall and then get them high on cannabis and they'll reinitiate eating

so that's an interesting thing in and of itself because that means you're disrupting either the ability of the brain to detect satiety or you're messing with a process we call reward devaluation and so reward devaluation is like you know if you have an eating for a day and you see like a picture of a pizza or someone brings a pizza in front of you it just looks delicious

and that first slice tastes amazing it's salty it's fatty it's delicious you eat five of those slices it feels greasy and nasty 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 a lab where you'd get the animals and either satiated in advance where they have already devalued the food and under a normal state they won't eat 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

it's head of like a little hot box it's probably the best way to this because it's essentially a kind of a locked airtight box that the rack goes in and it gets like vapor puffs and it fills up and then they inhale this and then it clears out and they get another puff and then it fills up and we do this for like 15 minutes and we've tight-treated all this to get exactly blood levels of THC that you would achieve in someone who's you know consuming cannabis through smoking

and so we get them to that point and then give them access to food and they will you know go gangbusters they eat food doesn't matter what you give them you give them playing 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 them stoned they will re-initiate eating again and you make them work for it where they have to like lever press

and you get them stoned and they will go to town on that and they will work 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 well I mean and at least we're at St Cassie more have done this at Hopkins as well they've shown similarly using what we call progressive ratio which is essentially a thing where it's like the first time you press a lever

you immediately get a sugar next time you got to hit it twice they got a pellet then you have to hit it four times yeah then you got to hit it 16 and then they're 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 the at one sugar pellets she really wants it so you can really kind of goose up their motivation to eat and so this clearly a rewarding aspect of this because they're motivated to engage enough

and 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 condition 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 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 to you and so that could be a complex process that either involves changes in the reward circuitry this could be something that's like from the orbit of frontal cortex which is a very important part of the brain that scales reward and kind of assesses

how much someone wants to work or an organism wants to work to achieve a reward at the end 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

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 it 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 works through again populations in the arqueot nucleus and changes the way those neurons function to drive food seeking behavior and we know there's a shown previously that you know if you elevate endocannabinoids you can override that and actually one of the mechanisms by which leptin seems to

suppress feeding is actually by turning on the metabolism of endocannabinoids so that their levels decline and so as you lose that endocannabinoid function the animal is less interested in eating and so you can prevent these anorectic effects of leptin by like

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you're talking about increasing endocannabinoid activity and we've set 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 CB one 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 a 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 two AG 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 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 and no cannabinoids by the way that'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 an anandamide that can bind to CB1 receptors because what you're talking about is a super physiological condition

yeah it's i mean you don't really actually need much THC in the brain to produce psychoactivity like it's 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 intercellular response it's much lower than 2a g it's actually more like an anandamide so you said an 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 that 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 outcompete 2a g but because it's a lower efficacy agonist than 2a g in that sense it's almost blocking the effects not amplifying them blocking the effects of 2a g but does it block the effects of an anandamide you know a 2a THC in an 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 an 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 an anandamide that's a very interesting point that we should highlight so there are drugs that now exist that can block the breakdown of an anandamide

more available presumably by disrupting some enzymatic breakdown and therefore lead to more binding of the now elevated levels of an anandamide that are available to CB1 and you see no psychoactive effect people are not aware that they can do 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 austere-thritic knee pain trial that was like even in that trial the positive control of naproxen barely worked but because the fawn inhibitor which is take a step back, faws the enzyme that choose up an anandamide so the drug that is developed inhibits that enzyme

so you prevent the enzymatic breakdown of an anandamide so we just call them fawn inhibitors so this drug will boost an anandamide levels quite high and an 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 n-sade just like adville basically a leave 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 always not going to work so it kind of shelved for a while a colleague of mine Marcus Hylig and Leah Mayo, Leah is now a colleague of mine in Calgary

but at the time she was a postdoc with Marcus and Sweden and they were able to get access to this molecule right before COVID essentially and they did a trial and just healthy controls with it which again this is kind of jumping the gun on so many other stuff I'll talk about I'll tell their back to that but what we did what they did was they dozed 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 an 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 there but it's a proxy for like adrenaline release so I blunted that and it blunted subjective feelings of stress as well so people had lower levels of saying that actually felt stressed and it kind of helped remove this like conditioned fear memory that we had 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 an anandamide produced kind of like a reduction in stress perception or reduction in stress physiology responses and kind of help kind of reduce fear and so that is kind of an interesting outcome because it tracks with some of the stuff we know about cannabis 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 one of the frustrations I have is 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 markets 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 Leon 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 and 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 still out on exactly what we're going to do with these but they have some potential I think in certain clinical settings we just have to figure that out exactly

but I think going back to where we started this from 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 going to 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 need 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

so it's 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 an 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 so I think it seems that this thing that we call cannabis and THC are overlapping with the endogenous effects of an anandamide

but here you're not talking about endogenous normal levels you're talking about pharmacologically greatly increasing an anandamide no psychoactive effect no euphoria no munchies and you know etc. then people smoke or take an edible of yeah THC or cannabis and you get a vastly different set of effects so maybe we can 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 these receptors are the whole story or whether or not cannabis is you know as you mentioned 70 plus active molecules and there are terpenes and a bunch of other things that may modify their action that 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 evolved to do that. Yeah so there's going to be and I think like it's very clear that like an anandamide for example is not active at every synapse that has CB1 and so when we boost an anandamide signaling by inhibiting its metabolism all we're doing is amplifying an anandamide signaling at the synapses it already exists.

Whereas THC when you consume it or earlier inhalation wise and it gets into your blood and into your brain it's just blanket activation you 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.

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. In some sense we don't want to say replacing but it's masking the effects of an 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. It's probably because there's a lot of CB1 receptors in the cortex and those are going to be differentially regulated at different times by endocannabinoids whereas when THC hits them all of them are going to get affected at once.

If you think of the way that I had described how cannabinoid receptors work by essentially, I mean in its simplest form, what cannabinoid receptors do is they change the way that tunerons talk to each other. So you're changing all the network simultaneously. So if you hit a whole bunch of networks simultaneously you're just going to 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 anodocannabinoid 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 the nature of how it hits everything because like so for example, 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've fasted. At that point in those feeding circuits in your brain like the RQ at 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 to do this and PY is another one and Grelin 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 and 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. Yes, some of it's going to be the intoxication, but in tandem, you're going to hit the CB1 receptors that are in those feeding circuits as well. And the consequence of that is going to be, I mean, the way I kind of analogize it to people is I say it's almost like tricking the brain into thinking that you've been fasting.

Because you're now activating receptors that are normally activated following kind of a fasting state. 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've been fasted.

And the thought is that's why when people, you know, when someone gets stoned, they're not like going to 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 at 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 raised this specifically because I think that in the past cannabis has had a bit of a reputation for making people spacey. I just 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, you know, a lot of the stuff that's been done is usually more like kind of acute memory tasks, like a working memory or recall or something like this as opposed to explicitly studying focus.

And 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 Kerry 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, you know, 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 lecture said and later corrected it himself. I won't call him out here because 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. 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 much less experienced user. That being said, I think it's relatively well established. Most people would agree that acutely intoxication with cannabis doesn't pair memory processes in some capacity.

What explicit form of memory? I don't think I could speak too comfortably just because I'm not a memory researcher. And I know there's very specific things of like episodic and declarative and whatnot. So 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 the monetized well, 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 it 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 that 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 because 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 because I know that you and I arrived at different understanding of the fastest typical and slowest routes of entry for THC into the system into to get to arrive at the brain.

Right. The numbers that 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, 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.

So there may be 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, you know, somebody takes hit off a joint or a bomb 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 times and understand this. I've seen some people not titrate it very well, depending again on how you saw again, this can vary.

So like, you know, cannabis from the 70s was like, I don't know, 5% to say, 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 highly clear. But so it's gone up a fair amount. Yeah, yeah, I mean, that's a, that's not just a fair amount. That's, I mean, if we were talking about alcohol concentration vodka.

So basically you're talking about a beer or wine to a spirit. And there are a lot of varieties, so to speak. By the way, I think when people hear me talk about any kind of 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, it'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, make Haney, Harriet DeWitt, this cluster of researchers around the country, Ziva Cooper, 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 pre even like the state by state legalizations hasn't changed this. So if you are doing cannabis research in humans and you're funded by like NIDA, which is National Institute of Drug Abuse, you get all your cannabis sourced. I mean, this may be changing. I think there are some shifts that are happening, but historically and 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. Well, the cannabis that came out of it though, and this is one of the reasons a lot of the clinical stuff people have kind of been like, oh, I don't know how representative this is because it reflects cannabis that I would say is more from like the 70s or 80s. So it would be like 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 talks, 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 are 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 100 nanograms per mile 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 because they're like, why wouldn't you study what we're using.

But because of the legal aspects of this, you couldn't bring those products into the lab. They'd never been standardized. 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 used the cannabis that's sourced from NIDA.

So there's a group in Colorado, Ken Hutchinson and Angela Bryan and Simon Bidwell have kind of, I would say, became very creative actually to figure out how to study cannabis that's being used, I call it in the wild, like, and kind of an ecological setting, let's say. 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.

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 and 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 because it was this huge innovative approach that allowed us to start comparing what we've learned from lab based settings with this kind of old school weed that was coming from NIDA with what is being used on the street.

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, you know, 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, you know, look at HRV, look at hardware, etc. I think having the ability to compare and contrast in laboratory and X laboratory data is extremely that. 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 university, that's an anxiety inducing experiencing of itself. And novel experience, well, someone's intoxicated with cannabis can also create a very different altered state. I would want to be stoned in a laboratory. I'll tell you that much. I feel like there's pluses and minuses to both sides, but I think the data together is very compelling. And that's where we get a lot of advance in the field.

So what Kent and Angela and cinnamon did with the can of and was kind of create the situation that allowed this research to occur. And what we found fascinating, I'm ever talking to Meghani about this because all the people in her lab studies tended to always hit around 100 nanograms per mail 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 mail 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 like high potency products that are now like, because cannabis itself realistically, from what I understand from the botanist that I've talked to you, you can't really grow a plant that's going to exceed more than 25 to 30% THC just by sheer biology. So it taps out there that's about as high as it's going to go. Concentrates can go up like 90, 98%. So you can get really, really tinctures.

Distillets 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, 300 nanograms per mail. So with cannabis plant, there does seem to be disability 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 and rats and created this really cool model of self administration, which was like a very important thing to actually establish because it was very challenging to get rodents to self administer.

Cannabis if you're doing like an IV approach or something else because they found it quite aversive, but when you let rodents actually tighter their ability to get vape hits, they will 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 what's called medium and then a high.

And what you ended up with, you look at the data is the one the rats liked the best was the medium potency product. And if you gave them the high potency product, they would actually take less vape hits off that than they would off the lower ones.

And again, all their blood levels tended to cluster in the same range because they titrated, like even at the 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 leg to occur. And then they can probably exceed the levels they intended to and consume too much and then have a 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 because I would say if we're talking about a harm reduction thing, that's more where we need to focus a lot more is this idea of these high potency products. Yeah, sounds like those are precarious.

Yeah, that somebody who thinks they have a lot of experience or got 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 I think you're 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 fledger system on a regular basis, the biological changes from that are going to be very different. Then what you get if again, you're titrating your 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 it's very very very important, although you're making it very clearly already, which is these days we hear a lot about the quote-unquote problems with high THC containing cannabis as relative to what was the same.

In the 70s and 80s and presumably 90s as well. I mean, 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 toaks of the higher concentration stuff that allow them to match blood levels that were present in the person taking many more toaks in the 70s.

So the joke I always make to people is I say go watch a Cheach and Chong movie from the late 70s. Look at the size of the joints that they smoke in movies like that relative to what you would see someone on the street consuming nowadays.

It's just, I mean, so the advantage that existed from a titration perspective was with like 70s weed, there's a large window to titrate. 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, you know, even if they were doing it relatively fast because of how little THC was coming into the system, it was a little easier to scale that.

So there certainly is the propensity for people to 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 toaks 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 too strong. And if there's someone who's kind of more an R.A. Drainch 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.

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 going to 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 going to come with them. Then 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 and humans. And I think the real world, the ecological studies that the Colorado group have done have been very informative in this sense because, yeah, if the blood levels of THC you achieve from concentrates are double to triple of what you get even from higher potency flower, that's a concern.

Like I think that's where problems start arising because then you're going to start seeing a lot higher degree of tolerance. I mean, there used to be more of a debate in the field as to whether people develop tolerance because 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 usually it's the life destruction that that towards their progressive increase seriously. Yeah, or the cost. I mean, the sure cost. Another form of life life life deterioration.

And that is required to be able to maintain that but with cannabis, it seems like there is some degree of tolerance that people exhibit it varies from person to person but you know as like I've you know as make has said to me many times you know the guys that come in her studies these are very heavy users and then you know they will use this relatively low potency product and still get high off of it.

And so it's not to say that there's no tolerance. It's just it's not as profound as I think we see with a lot of other drugs and this is probably due to the fact of just like you know we definitely see like if we look at some pet imaging studies chronic cannabis users do have some down. 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 their binding of drugs within the brain as well as activity of endogenous neurotransmitters and remodulators such as an endomide, dopamine, etc. Yeah, so typical pet study in a human looking at this they'd give a molecule that's radio labeled that will bind to CB one receptors.

You can scan them and then look at the emission rates of the radiation again the 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. There could be some, I think there's a lot of evidence that there's some degree of a reservoir of CB one receptors that there might be a lot more receptors there than we necessarily always need or always using let's say.

So we might be down regulating a component of this but maybe not all of the ones that are required to produce the psychoactive effects because there's clearly some maintenance of the system that allows someone to continue to get intoxicated. 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 because 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 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 quote unquote medicine.

Yeah. So that speaks to dependence or something, but then we need to be careful because in the classic sense addiction, I've defined 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 and 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 it, 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. That's the nomenclature now that people are using alcohol use disorder. So cannabis use disorder is what you start to see now instead of saying being addicted to potter 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, it's definitely a thing. It's 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 going to be slightly different than someone something like opiates or alcohol because that's a totally different beast because you have fatality potential.

There's a whole bunch of other health consequences. 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 9 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 than the rates of people who would qualify as having cannabis use disorder probably go higher. So I just want to 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%.

And in that neighborhood, they would probably qualify as meeting criteria for cannabis use disorder. Because 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. Because I think a lot of people, you know, again, regardless of anyone's opinion of alcohol.

I 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 uncle. I don't think so. 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 and frequently 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 because if you start looking and say, well, you know, if you travel to like Egypt, are you going to go put yourself at risk of going to jail to get access to cannabis because you can't function without it.

If you do, then yeah, you know, you've got cannabis use disorder. You know, are you going to burn relationships? Are you going to start failing at meeting responsibilities or getting things done in time because you're preoccupied with cannabis? Yes, you're going to hit the criteria for cannabis use disorder. If it's someone who's kind of just intermittently using it the same way that a lot of people casually use alcohol, I would say a lot of them probably wouldn't hit criteria.

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're 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 I'm 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 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 with this 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. Yeah, yeah. Because of possession and sale of cannabis. And then of course, there are stores not far from here where people are selling. Ironic, yeah, yeah, sadly. It's a very, I mean, obviously a big push for legalization is not endorsement of the safety of cannabis.

It's more the harms associated with prohibition of outweigh the harms associated with legalization. I think that's generally the public health perspective. That's certainly what motivated it in Canada. And there was a, you know, some attempts, let's say it 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 dad 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 minorized communities. They get, 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 potentially it's all that. So I can understand the legal framework behind why there would 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. It across the board in terms of harms to the individual harms to society. It's, 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 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, you know, despite the fact that some people hate the government and hate the way that it regulates their life, there's this weird, passive belief that like if the government dictates something 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.

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, 10 to more cannabis use. Now granted their baseline was quite low pre legalization. So if you look at a full 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 increase 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 like more females used and 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. Yeah, interestingly we don't have a lot of actual indication that teenagers have used more. So like 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 in the states both hover you look at a 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% or 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 legalize a slight dips in 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 we get it from their parents and whatnot or had just you know other siblings and stuff.

And so you get this big boost in consumption, but we don't seem to see that in terms of raw numbers of teenagers who are using cannabis. So so that's good ER visits. So we did an interesting role letter in Canada. We legalized flower 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 with you know a lot of these look like gummies and candies. People are buying them not storing them properly. Kids would find them and eat them and like become very intoxicated. I want to make mention or something on those lines. Actually know somebody whose child accidentally ate PhD containing gummies. Fortunately, the child was fine.

But they're actually pretty serious ramifications for this. The parents actually are quite susceptible to legal action if this happens. 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 that's true in Canada the same way. But I think the state. Yeah, like if you if your kid gets into a stash of TFC containing gummies and ends up in the emergency room, there will also be most likely.

There'll be police visits to that emergency room also and it doesn't bode well for the parents. So 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. Yeah. And if that candy contains TFC and they end up in the emergency room serious issues. Nonetheless, if your kid is acting strange because you think they ingested TFC 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 under age, it's not the same ramifications as if your kid used in illegal substance underage. And so people are when someone 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 going to have my kid taken away from me or whatnot. So there is, I mean, both those factors, I think, have contributed to it. But we definitely see the majority, at least of kids ending up in the ER is almost all based on edibles. 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 because 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 T.C. 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-megame or two five-megame or four 2.5-megame, 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. You know, some will even feel it at 2.5-megames. Most people will feel it at 5, virtually everyone will feel it at 10. Now, if you look at the blood levels these produce, we're now talking blood levels of 2 to 5 nanograms per mill. So folds lower than what you get from inhalation.

Before you said 100. Yeah. So this is dramatically lower. And so also the time course of this is fundamentally different. So an oral consumption, you know, 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 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 steam roller. Like I've heard of this happen. 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 on a chocolate bar or some like 50 or 100 milligrams and spent like the weekend on the floor of a hotel room being like this was the most a versus 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 I was create this idea of standardized dosing units so that people have an like we would alcohol like we always say one beer is the equivalent to one glass of wine versus you know, like a shot of tequila or something so that there's some comparator that people understand how many drinks are, you know, you say two drinks you do you're going to hit legal limit kind of seems very important.

Yeah. And so this is very difficult to do with cannabis because the dosing with oral consumption is just a different ballgame than it is with inhalation.

But what happens with oral consumption is like it kind of very slowly leaks out of the GI track. 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 it's efficacy at least at driving a response through CB one receptor 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 got 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 because it goes right through the lungs into the blood goes into the brain, but it also clears out. And so yeah, people will start feeling intoxicated two to five minutes. The peak high is like 15 to 30 minutes maybe from consumption and then they'll start to come back down 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. I mean, you could still fail a drug test in 80s. 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.

And 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, but that abstinence for 30 days after abstaining for 30s. 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 out long. That'd be surprising.

The thing is, THC is a lipophilic molecule. It's fat so it's fat so it's fat so it likes the storts. 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 you know,

THC concentrations in the blood would reduce. THC, it's in the fat. We'll 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 going to be depending on how much cannabis someone's used, how much THC they've consumed, how long it's been in their system for.

I would have thought this was going to be somewhat reflective of people's body fat content, although talking to colleagues who do this, they say not always. But we do know certain things like exercise, for example, anything that's going to trigger adrenaline because adrenaline is lipolytic. So adrenaline causes fat to metabolize and release stuff that's inside it.

So there are plenty of cases I've heard from people where they were testing themselves and were negative and then went for a run or went to the gym and then tested positive or lost weight. Yeah, or they've lost weight and anything that's going to cause the the lepolysis 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 happening Canada, all these kind of chemists were like talking to me about they're going to create like a breathalyzer for cannabis.

Because this way they'll be able to do roadside detection the same way they could do with alcohol. And I kept trying to say to them, I'm like the rate limiting step here is not the science of detection thresholds. It's the biology of how the body processes cannabis and you're never going to get a test that works because you can take someone who is eating an edible and is profoundly intoxicated and they will have possibly under five nanograms per male 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. You don't have to come in hailing but not nearly as much as you get from edibles. So it's a different 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 boldness that hit you at once you get a high blood level.

With edibles it's like the time course. So I mean it's going to be like five nanograms per meal let's say but it would be like that for a long time. Whereas the hundred nanogram per meal from smoking is like for 20 minutes and then it starts dropping. 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.

So the total 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 you let's say your cutoff was five nanograms per meal which is for some of the stuff detection thresholds would hover around that area.

So you get to 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 test 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 THC resides in the fat stores. Potentially. Yeah. So I mean it is it is called people 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 site increases in testosterone from cannabis use.

I've seen studies that site increases in estrogen from cannabis use and they argue for increased aromatization of testosterone in 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 etc that we just really can't say. I would say it's there's nothing that's super clean cut. I mean I know in the previous podcast you talked about a prolactin thing.

Well there's and this is where I think it's important that people understand that you know 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 pre existing kind of comastia male breast development. I mean I mean I understand it but yeah I have a lot of people don't know that.

Okay so we'll smoke cannabis and experience going to comastia or in females. So males and females both have breast tissue but it's typically it's not hypertrophied but they'll smoke cannabis and get a gun a comastia 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 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. It's super mix so I mean you talk about something like prolactin for example that is another one that's obviously involved in in this whole cascade stuff.

Generally I would say the bulk of the literature actually says that cannabis with suppressed prolactin not increase it that's the majority of the literature is dopamine is one of the main ways that prolactin is suppressed or kind of in a seesaw they work in somewhat seesaw fashion.

And it probably I mean the road 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 but so typically I would say more often I mean the studies with inhalation and IV that have generally found reduced prolactin and in chronic canvas users they find somewhat lower resting states of prolactin that's been found in one study it came at a year.

testosterone gets a little bit more complicated because there are a lot of studies that find a to begin with. Can't miss users may have higher levels of testosterone just at rest now whether that's a pre existing anything that would be the case I don't know I yeah I mean that being said a lot of the stuff now granted this was mostly done in the 70s.

And like this is from my previous life because my undergrad graduate supervisor he was a neuroendocrinologist focused much more on sex hormones and reproductive hormones so we've written a few reviews so I've done like reviews on this area.

And I know the literature somewhat it's mixed but generally from the 70s studies what they would often see is that if they would look 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.

And then I think that's the kind of change 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 hypergenadil or would lead to something like kind of comasti at least from a testosterone deficiency side in terms of the balance between testosterone and estradiol.

And I know as much about the aromatization side of it again I'd say it's pretty mixed I mean I don't think the kind of comasti is stuff is I mean certainly people online might be talking about it and there might be some other components this I've also heard and again this isn't like science this is just the same kind of stuff you see on a random.

Internet communities people talking about oh well you know it has plant estrogen so maybe they're subbing in and having estrogenic effects I don't know how valid any of this is.

Yeah seems to be on I mean there are photoestrogens and tons of different plants that the sort of attacks on soy and the attacks on it 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.

Unprocess and minimally process 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 just meat you know we've essentially stepped out of that debate because let's just say it's as futile as about any other debate you just never going to 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 don't I've not seen any compelling evidence for it so I can't I certainly don't know what I'm going to say.

I certainly wouldn't say that it's a typical side effect that men would experience is like developing breast tissue in response to can because 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 I'm a curve purportedly occurs on a backdrop of elevated and regions meaning in puberty or a backdrop of some other form of androgen in the community I'm referring to it seems that because transient going to

be a kind of a mixture during puberty is actually fairly common because of there's just so much energy being produced in puberty that some gets aromatized and that the idea I'm not saying it's stating this is fact is that it may exacerbate that in any case it sounds like to take away from this is that there aren't a lot of conclusive studies about the effects of cannabis on testosterone or estrogen or a romanticization in any direction.

I don't I mean I'd say like yeah this enough studies to suggest that you might see transient drops in testosterone from cannabis and it seems to be relatively short lived. 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 again it's homistatic just like just like the end of cannabino.

Yeah so and that's the thing I mean testosterone fluctuates across the day anyway so there's a lot of things that fluctuate it's like cortisol these hormones have cycles so as long as you're in this normal range there really shouldn't be any kind of like behavioral like in terms of sex drive for testosterone or like physiological like gynecumasty 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 not.

I'm assuming that they're 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 could have some effect on sperm so I have like as we say this I'm just.

Chuckling myself because anytime this conversation comes up about a substance and sperm quality or. Equality I always get a barrage of comments of people telling me how many children they can see to all under the influence no one is saying that you're going to be infertile but you know 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 the 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 their sperm capacity and so their ability to maintain fertility and for the bulk majority of minutes that'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 it kind of a jaw dropping statistic in.

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 it's very I mean I've heard high in the research later so I've heard higher numbers so I'm on the low end of the list.

I've heard as low as two and I've heard as high as 20 okay two sounds like okay I that I could imagine but as high as 20 and do we know what the effects on the developing fetus are there's lots of impact there so first thing going back to the the levels that's challenging because again this depends on are you talking about self report or are you talking about verified blood levels because those varied so some of the higher numbers actually come from blood levels where they've taken blood samples and I'm not sure if that's the right thing.

And blood samples and found to HC but the women have reported not using cannabis and so there the idea that it's like the self report numbers tend to come in around two or three my guess is the real numbers probably somewhere around 10% but that also is going to 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 well pregnant.

So the majority I would say the overwhelming majority of people once they learn their 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 going to be a lot less I would guess now the motivations for this quite often are more in the capacity of the kind of anti nauseant and 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 you know with the history of things like thalidomide and other anti nauseant drugs that had profound try to genic effects on the fetuses women have said that they would rather use cannabis than one of these other compounds because they're less concerned about the impacts of cannabis than they are because of the you know

the effects that happened in the limousine effects are now formation of the limbs and other bodily structures in the fetuses it was a absolute tragedy of medicine that this occurred in even even one birth but yet the reason why the lydamide is now I believe banned as a drug for you stirring pregnancy

yeah I would 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 redisense 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

so many things just frustrate you it's where they actually decided to call this was done in Colorado with a 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

you're talking about that irresponsible that the dispensaries would say that or 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 I mean you can you can bulk it 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 yeah that's kind of the the cloak wheel term that people will use for someone who sells cannabis at a dispensary we see this in Canada and I've heard the threat of the states as well I personally have been a huge advocate for the fact that I think so you know 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 weekend course

essentially called like serving at right or some other terminology we 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

or 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 and 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 and 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 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 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 you're 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 taught with MDMA where we await the decision from the FDA but the early recommendation to

to the FDA was to not approve MDMA as a treatment for PTSD that's a so today and you know mid 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 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 talks versus concentration versus edible I mean these are critical themes especially for where we're going to go next which is you know all the discussion about

high THC and psychosis yeah yeah exactly so I think that I I just wish I mean again even if this was just like an online course that wasn't that much but at least had some consensus of information that was the basics about how to you know have conversations and I mean some of the our our system at least is somewhat provincially regulated so like you know our organization has worked with like the Ontario group that deals with cannabis distribution the

like the OCS which is anterior cannabis stores and help 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 some like edibles how long you should wait just stuff like this like it sounds like the take home messages proceed with caution you know low and slow I mean that's the yeah like don't 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 can get the what was the reporter I think it was more endowed but I right you're gonna I don't know actually when I say that she's still on the floor in a Colorado herself she may have recovered from the floor in Colorado but like it yeah it's it can become very frustrating it just the kind of lack of

understanding that exists in the 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 in lines it's called the lower risk cannabis use guidelines

that 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 going to use these are the different ways to engage in harm reduction you know like obviously oral consumption has you you avoid the issue of

lung damage that you can 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 T. H. C concentration in the blood by vaping as well as they can by joint or wrong or other form of smoking depend on exactly what you're vaping so and 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 going to really heavily depend on what the concentration of T. H. C. in that product is now the other way 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 T. H. C. in the canabins big bag yeah like a volcano 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 product so people don't like exhale carbon monoxide of 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 in Canada 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 going to try and avoid you're you know there's still going to be some issues that happen with vaporization of plant matter but it's not the same as combustion so you avoid like some of the other

issues that come out when we're talking about oil based vapor products or whatever they're in they're using some kind of oil based solution who know I mean we don't have the research on this like we just don't know I mean we certainly know like there have been some pretty

big errors of like the things that happen the states like there was that problem where all this people developed kind of popcorn longer that lung inflammation where several people died from vaping products which seem to be like a byproduct I believe of them

adding like vitamin E acetate or something into the because again everyone just assumes it's a nerd but then when it 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 you would not see that on a federal landscape because you'd have to go through testing like people it's kind of the wild west you get down here every state has its own rules

people is not really a lot of like 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 you know we're going to be doing episodes on stem cells and you get people flying out of country do some cell injections people were getting them down in Florida

who went blind from the injections of stem cells into the eye and attempt to save what little vision they already had probably don't want to get me started on that one I mean total agreement with you by the way I want to make sure that I ask about psychosis and paranoia

yeah 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 it's a terrible idea terrible idea that you heard that I have no idea let's just say I did more than hear it yeah see I've observed it I cannot even understand that that is the strangest thing I've ever heard but okay well usually the advice of people in terms

of that was recreational drug taking is is rarely excellent advice yeah I mean I agree with you on that point for sure that you should not be consuming more of your having a bad reaction to it because that will just like grease the wheels going downhill for sure yeah I

also I'm aware that there are some very high profile papers 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 a cute 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 teach your cannabis and answer 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 certainly I mean it's 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 does it overboard or does it carry the same set and setting considerations that you know psychedelics like psilocybin 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 dose 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 like so it really patentiated 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 like of THC cannabis like that are usually considered more 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 normalish 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 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 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 Marsecaino and B.E.Lutes were over in Europe created like deletion of CB one 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 type 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 CB one expressed

if you do like a full body deletion of CB one 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 CB one drives all the kind of psychoactive effects of THC so if you delete CB one off of inhibitory

and inhibitory gabin neurons even though that removes like 70% of the of the CB one 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 CB one 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 CB one receptors seem to be on these inhibitory gabin neurons it's the CB one on the glutamaturgic excitatory neurons that mediate most of the classic signs of what we would consider intoxication from THC or cannabis

but what's interesting is be outworked with the Spanish group 10 12 years ago then they showed they're looking at anxiety that if you delete CB one only off of excitatory neurons you lose the anti-anxiety angiolitic effects of THC but you still have the you know panicky angiogenic effects of high dose if you delete CB one off of only the inhibitory gabin neurons you still have the low dose anti-anxiety effect

but now you don't have the high dose angiogenic panicky effect so what that was suggesting was that for some reason CB one like THC will initially hit CB one on kind of glutamaturgic neurons and essentially the thought is this will reduce excitatory transmission and probably quiet down circuits and if we're talking about some of the amygdala this is probably how it's reducing anxiety

whereas as dosing starts to increase and you start to saturate the CB one on the gabin 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 angiogenic 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 like biology of exactly where the CB one receptor sit on excitatory or inhibitory neurons relative to all the machinery that regulates transmitter release

I mean Biot lutes has definitely done some stuff looking at the ability of cannabino receptors to evoke signaling responses in a cell and on glutamate neurons they're much more sensitive than they are in gabin neurons so there's probably a dose threshold

so it does look like this kind of you know 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 the higher dose starting to saturate on the inhibitory neurons now we obviously can never test something like that in humans because we can't know but based on what we see in animals that's my theory of kind of how this is working and why we see these kind of classic by phasic effects so

yeah too much THC not a good thing because then you start maybe disinhibiting things like the amygdala and producing these kind of panicky anxio genic 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 strange things so but I mean that's kind of the precedent of when you start going into the psychosis because obviously paranoia would be a big component of that

someone wants to ask me a question about you know you know have you know 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 like probably on accident because somebody takes cannabis is in the scanner and then

having a psychotic episode but chances are they're going to try and get out like for those that don't know these I don't want to scare people out of doing MRI or FMRI but you know you're typically told me that you know I'm not really told to stay extremely still there's sometimes even a bite bar you know like this is a very controlled environment not not an environment that you would want to be in during a psychotic

I can't actually even imagine how that would go down so I'm like where this is something I don't think we're ever going to have an answer to because I don't think 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

what'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 it's not common I could not give you an actual number but it's 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 they're 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 part 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 it's there is clearly a population of people that use cannabis is 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 you know 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 they are usually purely due to cannabis

it's not 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 I 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 ballgame here and this is an area that is I mean I think it's an important thing to discuss in the context of science because you can't establish causality like in my view it's 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 use hypotency 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 in 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 want to be careful

to be honest and all the research I've and 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 and 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 you know 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 you know increases in positive symptoms like hallucinations and delusions and a full-blown psychotic episode

so I think the first thing to say which is very clear is in my view if someone has schizophrenia cannabis is contraindicated 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 going to say then the next question is knowing who's going to develop schizophrenia obviously we don't know this and as you say the only real predictive variable that we know of is a first degree family member that has schizophrenia means that you have a higher risk of developing schizophrenia so again same with bipolar I would say if there's bipolar or schizophrenia in a family 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 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, Jamestock, Chiatry I believe we can provide links to these again and now more recently there's been a lot of what's just called 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 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 and science is different there's 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 this is relationship between cannabis use especially in adolescents 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 we'll make it kick in faster and harder so

if there is a genetic vulnerability for for developing schizophrenia 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 in the 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 is 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 is one of the drugs that was part of the repertoire of what people use recreationally until like the 60s so unlike alcohol which is like been there for centuries

we have a little bit of a before and after what we can look at the grateful debt yeah so now granted we don't have like really good prevalence that of what schizophrenia was in the era prior I mean even nowadays our prevalence that is not perfect but if cannabis as a solitary variable was driving the genesis of schizophrenia denovo 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 that to challenge our 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 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 sweet

or any of the Scandinavian countries where cannabis is like not a thing certainly not at a recreational level not teenagers and I mean the rate use rates there are probably under 5% globally for teenagers like probably closer to 2 or 3%

so you have 2 countries that have pretty similar social structures and other capacities of things were both western countries and yet our schizophrenia rates prevalence wise are relatively comparable and yet in Canada and the states are cannabis use rates and 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 polls and less so at the equator I don't know if those statistics still hold up but I have no idea

yeah I don't know if you're interested in looking to that because then it would argue that you know since you know we're comparing very northern locations to less northern locations that perhaps cannabis was you know sort of exacerbating the probably use Greece or Italy I mean they're going to have cannabis use higher than Scandinavian countries but it's going to be way lower than North America still because it's just 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 grateful dead no I'm just I'm not picking on the great but I like the great well that Rick Rubin convinced me to start listening to them again and because 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

done my duty to listen is there's some great song so I'm not picking on them 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 where teenagers to drink out 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 it's sure it's there to some degree in Europe and it's nothing like it is North America we are just a different beast for a lot of drug use 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 the 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 used in some other parts of Canada and you guys probably in some southern states maybe or a bit different than other states so I I don't know about that but again overall at a federal level I think the which is

where most of the most of the data aggregates I would say that they're pretty comparable with each other so they're not they're not wildly different at all and again even if you talk about climate a lot of the US is a lot warmer than Canada and you guys are

certainly closer to the equator than we are so I 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 stress or argument is other 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'm no one's really I think sust out a mechanism to explain why

you see that but so there are 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 I 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 I can think about the top of my head that I could

do some of the other recommendations down for for sure after this that do look at this from and 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 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 are 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

patients that are approved for the treatment of ADHD are variants of a infetamine or similar so it's another case where you know depending on whether or not you look through the lens of the drug leading to the condition or the condition leading 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.

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. Anacdotally from having done work in the community and talk to individuals who have schizophrenia who use cannabis what their perspective it on 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, hallucinations, solutions 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 they don't have 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 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 to know vote 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. No, the way you explain 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 so a lot of nuance there we did an

episode about this that people can also find linked in the show no 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 have weighed high T. H. C. cannabis. So well first of all I mean for in like heredibility 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're at that meeting Glenn clothe was one of the public speakers and she talked about schizophrenia and 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 it's been seen a fair amount is there is some co relationship in the way that these track at a heredibility level and so I don't know that area really well enough to to be able to comment on and from the cannabis perspective bipolar is definitely much less study studied and focused on the schizophrenia is but I think also to the

HC 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 on 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 at the UK at least was much more that it's this

high potency kind of scunk 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 people make the assumption of it smells stronger it's more potent cannabis that's not really true because T. H. C. doesn't dictate the odor that's so same more of a turpene thing but certainly I'm sure some of the scunk cannabis they're referring to is high potency cannabis and so the analysis on this if you actually go back to those

papers and read is they often use like hash or low potency cannabis is 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 gets a little bit more of a literature everything goes back to this one 1987 Lancet paper 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 60 70s early 80s so we're talking about Sweden and cannabis where it's not a country that's high cannabis use rates and in an arrow in cannabis was hovering in a 2 to 5%

THC range that was the initial finding that provided this association between it and yet the cannabis in that study that they would have been referred 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 in his 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 and Sweden that would have been 2 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

of schizophrenia use they smoke a lot of cigarettes I mean that's also that's well as much higher than the general population rates which is known as stimulate dopamine and other path and there could be other reasons you know again there may be some reason why they like it and I think this is something that I think we just don't understand it's a very challenging thing to figure out why it is that individuals that have certain diseases may like certain

substances is it is it helping them I mean some people have argued that perhaps nicotine for example might enhance cognition in individual with schizophrenia and that may be why they like it I think it enhances cognition and everybody it just carries certain health concerns yeah and by the way it doesn't enhance all forms of cognition but they're

there 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 and out days because of the non smoking delivery routes that are becoming really popular pouches and yeah and things and in fact I was chewing a little bit of nicarac 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 nicotine's a whole other sharing which I have yet we'll have you back to talk about I would definitely don't not know enough about that to have any kind of

informed conversation but so I don't know I would say to me at the end of the day if I put all the data together what I would kind of the perspective that I have on this is for some reason be it genetic architecture biological predisposition individuals who are

prone to develops 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 long term it will likely make the prognosis of the disease worse so if you were a psychiatrist and 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 a tributed 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 fund 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

the other and I'm very you know want it this way or want it this way when at the end of the day I'm just like no I just like data so I'm like I'm going to try and answer things as best like end 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 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 this 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 am 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 of so many uses it because it's going to cause them to become schizophrenic I am just kind of shocked by so this is clearly

permeated you know the general population that there's a widespread belief of this you know I think it's because of these very high profile papers in 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 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 have a pre disposition is 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 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 who are 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 and 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 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 quote unquote 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 push those

subjective reports through what was known about the strains they claim to have used so this is you know people reporting their use we assume honestly but you always have to assume that there's some I guess people could be lying about which strains were misinformed yeah but and then using machine learning to couple their subjective experiences as they report them to indica versus the tiva strains and then by looking at the

chemical composition of those different products because these were products that they had consumed trying to attack 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 the feeling this is what you're going to 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 sativa 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 etc. 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 it's those are botanical terms that largely refer to shape of the plant the you know the way the bud grows blah blah blah they do not track with chemical composition in any way in fact nicochomas has done like a lot of analysis of like thousands and thousands of

different kinds of cannabis cannabis that have been submitted for kind of biochemical analysis to understand tccbd terpenes minor cannabinoid content and essentially his 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's no 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 indica's or most common sativas. I mean I think in nixon allis there was like a couple of terpenes that may have loaded on a little bit on the 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.

Yeah 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 going to make them calm and it makes them feel calm.

So many 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. And this has been I think one of the most common things with with cannabis is like this whole area is so ripe with these expectancy biases that people have about what they assume if you go someone goes into you know an a bud tender tells them this is a sativa it's going to energize you.

And then you can remove that expectancy bias from 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 going to do to them. I mean and it's pretty wild.

The speaks to you know I didn't episode on the placebo effect it's a lot of people here placebo effect and they go okay well then everything's a placebo effect is amazing there's dose response the placebo effect of nicotine on cognition.

And is your 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 it a high dose like enhancement of the relevant brain areas in other words the expectancy drives changes in brain activity.

And then the first the board I mean it's again this is not unique to cannabis in any way it's just cannabis is so ripe for this because of the like myth like the lore that it just exists like people say this I mean the issue has been.

And I just asked Ryan van der Rees as far as I know I don't believe this actually ever been a clinical trial that has blinded people and given them sativa's 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 it's going to it's going to influence it there's no way around it and so.

People kind of lean into this and I 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 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 lower or perhaps it's real that different alcohols produce different drunks. You know I mean I've heard of you know I've got friends who will swear that whiskey makes them feel aggressive and bottom you know is mellow and white tequila's feel different than yeah then the other tequila's and you know for people listening to this they go okay well that's not science I agree that's not science that's just anecdotes yeah 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 because 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 the

drug or influence this is called like I think I said this before the entourage effect this idea that THC alone might do one thing but then layering in other. Turpin's or minor cannabinoids may influence that effect that is a theory that's not a thing that we know definitively in any way in in fact there's virtually no research that's ever been done to test this.

Some stuff that's starting to come out no like Ryan van dery at Hopkins recently published a paper where they kind of in a dose dependent manner added limining which is one of these turpines like I said I think gives it like a citrus you to into the THC and did find that 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've gotten there but limiting 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 deliminin I don't know but it really was one of the first demonstrations that adding in a turpin could actually influence a component of the intoxicated state in a in a blinded manner I think is interesting and Ziva Cooper who's here at UCLA is doing some work with beta carry off a lane which is probably.

The second most abundant turpine I think from next to comis is work I think mercy may have been the highest prevalent trip in across all types of cannabis beta carry off lanes probably the second and limiting 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 carry off lane is 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 us to told you that this strain is better for pain and the problem is these are all subjective end points I mean this is like pain sleep anxiety these are all in someone personally experiences it 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 their 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 the amount of combinations of different levels how overwhelming this could become because maybe you know there's a few that you need

in there the 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 acted the cannabinoid receptor which none of them seem to so this isn't like you've got things that

are being regulated how T. H. C. is binding to CB one if they're doing something else it's probably through an interaction with another in our chemical system that's influencing what T. H. C. is doing so I'm not against the idea that like different chemo bars or what people call strains of cannabis could do different things

I just am remiss to believe this until I see some blind data because I think outside of that we know how powerful an expectancy biases 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 said I understand the thought process you went through like you know you had this paper where people reporting subjective effects there's some neuroimaging data that's been done with cannabis you kind of said okay this is what that was and that was what

sativa did versus this is what indica did so I think it's important that you explain that because I do think that like well that's out that's what the data pointed to but now when I'm realizing is that any time we're talking about cannabis because it of the 70 plus cannabinoids present that could modify or join so work in parallel with the effects of T. H. C. we're really talking about polypharmacology it's not a pure substance it's not like giving an

Andamide or it's not like you know adjusting levels of endogenous and Andamide you know this raises I think an equally important issue for us to resolve which is CBD which we didn't talk about earlier when No one 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 I began in trans cranial

magnx 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 Charlottes 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 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 CB one or not you know does it bind CB one 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 you know psychiatric condition pain etc. So I mean the first thing that's interesting that I think a lot of people don't understand about CBD is CBD like 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 has largely been bred out of the plant for quite some time.

And so this I always find it interesting that this is this community that's like oh well THC is the recreational cannabis and CBD is the medical cannabis and most like that's bizarre because historically there's always been like THC is better than that.

And 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 CB one driven CBD is this other molecule that we can go to the farm college unit second but again it's just it's I mean I think in the in the analysis that makes a coma state 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 has been

added 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 cumulative our distinction I think you did a

little bit of this last time which is the type one type 2 type 3 so type 1 is high THC type 2 is like somewhat balanced and type 3 is high CBD and now I think like 90 to 90 something low percent of all canabases that are out there are type 1 like they're all high THC because 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 going to get high equal proportions so like a high THC cannabis is like 20 to 30% if you go for type 2 which is mixed they're both going to fall around 12% maybe a little more but in that range and then same if you get a type 3 it's high CBD it's going to be 20% 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 Charlottes Web which was popularized by I think Sanjay Gupta and CNN and like 2012 or something it was a while ago but that was what got a huge movement going around this idea of CBD and yes so the Charlottes Web was I believe that was what they had named that kind of cannabis that they'd extracted it from and it was this it was a tincture that they were using that was very high

very high CBD content that they were finding was controlling pediatric seizures and kids now this has actually been studied pretty effectively most of it's come out of Boston Elizabeth Teal 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

scheduled or changed and scheduling down to a what is it five what is it class like what do you be the 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 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 in and it was very specific it was a very specific form of pediatric epilepsy called CBD

pediatric epilepsy called Dravace syndrome now I 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 and some kids it's profound like in some kids you're talking about kids that we're having dozens of seizures

and so I can understand I mean yeah that's super important from a grassroots perspective I can understand if you are a parent who had a child with a disease like this that was largely

intractable and not that well controlled from the medications there 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 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 said like CBD receptor there is no

receptor that CBD binds to I was under the impression that CBD also bound to the CB one receptor no I mean certainly not or that 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 certain amount of THC and people do go for those and there's this I mean one of the arguments people make is they so introducing CBD reduces the

adverse effects to THC and Mike well if you're using it in a strain that's simply because the strain of cannabis has less THC now is possible so you've breaded 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 CB one receptor in some way that makes THC less able to engage with the

substance 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 can have a receptor that makes THC bind less doesn't sound like you're particularly convinced by that I mean like the look on your face with those listening I'm looking at Matt it and he's I think he's he's being generous here let me ask it a little differently it's definitely

no one knows what CBD binds to no and so the most convincing thing that I've seen that CBD binds to is the work at CC Hillard has done looking at its ability to essentially block a denocene uptake and so it can inhibit the adenosine transport so that should make people feel more alert no because you're getting more adenosine so you get an accumulation of blocks the

adenosine transport mechanism I see so you get an accumulation of a denocene which is more sedative and that I mean in the P and A paper that CC's lab had from 2006 they showed that that also mediated it was the adenosine I think two a receptor that drove the anti inflammatory effects of CBD so it was a secondary effect by sort of the

opposite of caffeine of caffeine yeah I know I've I'm not really describing this it sounds like the the anti caffeine that's kind of how I described it people have they ever ask me for what the pharmacology of CBD is I'm like that's not the only mechanism but the thing that was important in CC studies that I think is relevant is that it was not super high

concentrations of CBD that caused that so you could get this adenosine accumulation at 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 like yes there's evidence for it and it is convincing evidence it's just the

dose range in there you're kind of like who's getting hit with CBD at that level where you're getting these effects and more so when they've done the blinded work like when Ryan van der Hockens 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 amplify some of the effects of THC and this was something we learn from the pediatric epilepsy world was that when you start giving CBD it 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 maybe 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 they're at the clinical level you're going to start having hepatic effects so it's going to affect the liver and it's going to affect the ability of the liver to chew up other drugs and there's very specific sip enzymes like the cluster of enzymes that metabolize things is very specific ones that

CBD hits and so as a consequence one of them is what choose THC up so you can get a potentialiation of THC by inhibiting its metabolism if you have high enough CBD on board.

Given the effects on an identity that you described before that it's sort of the 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 everything everything can't be expected to be I have a feeling it's going to be interesting to see in the comment section on YouTube I mean presumably there's some regular pot smokers listening to this and you know the

expectancy bias is so strong as I alluded 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 you know non-formal blind you know someone someone gave them their 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 cannabins THC being among the more powerful components but it's 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 veered 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 etc it can't all be just psychological yeah I mean so what you're saying is like what we said is the entourage effect and I think that is a theory

that is held by a lot of people that this exists I mean the reality is these terpenes and minor cannabinoids exist at such low levels that like there's a couple of kinds of cannabis that might have like a high enough

level where you're seeing something but 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 and people got the drug knew they got the drug it's very hard you could do a dose response but 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 taking 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 because this is something that for some reason has not made the transition from science into pop culture this is a similar phenomenon with GLP1

I and other people have pointed to the fact that certain food products or certain drinks or certain activities can increase GLP1 Google gun like peptide which is now becoming more commonplace knowledge because of ozempic monjaro etc as very powerful weight loss tools

although there's questions about muscle loss etc and then we had Dr. Zachary Knight on who explained that even a fourfold increase in GLP1 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 thousandfold increases in GLP1 through the use of things like ozempic monjaro you see profound weight loss meaning that you need enormous effects in order to see that 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 wise.

I think that's a placebo effect and I say that because majority of gummies are about like two migs, five migs, 20 migs. I've never taken a CBD product. I know a few years ago they were all the rage.

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, I mean THC and sleep is definitely a whole other thing.

Sure. But sure a lot of people report this with CBD but again so most CBD addibles or things that people take that are sold through commercial markets are in the range of two to 25 migs of CBD. So then I say to them, so you were aware that in the pediatric epilepsy studies the dose ranges are like 1,500 to 2,000 mA.

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 mostly things are done, well they'll say 20 migs per keg 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 migs per keg at like 90 odd kilos, I mean you're talking about me taking a liver damaging dose.

And insane, well maybe I wouldn't say damaging. It's definitely influencing how the liver metabolizes other things because it's going to saturate those enzymes but you're taking a very high dose. So 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 then you're talking about the two-hit model. Yeah, I can't speak that because I actually do not know the metabolism of alcohol well enough.

I don't believe so because that's alcohol dehydrogenase. So that would probably be a separate enzyme pathway than the SIPS. 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 warferin and blood thinner. Blood thinner.

In the anti-apilaptic 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 effective 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. And the thing is actually every done the pharmacokinetics on the list. 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 fine 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 like fatty environments. And for some reason having fat in the stomach and then the gut seems to promote its ability to get into the bloodstream. You can see now it's the steak and CBD where the CBD with omelet protocol. I'm just kidding folks. I'm not suggesting that protocol.

But yeah. And so because of this it's like you're taking very lotuses 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 to 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 what might interact with the serotonin receptor. Do 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 because everyone you can't walk down a street in any city in North America. And not see CBD products, whether it's some kind of cream or like a shake or some random like concoction that people have added CBD. Because now it's going to, you're saying the energy drinks, like it's just, it's bizarre to me how much this is 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. They can help them adjust their anxiety and sleep better. Which is a large reason why a lot of this podcast has focused on respiration based tools and other based 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, 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 that 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 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. 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 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.

Yeah. Except supporting the placebo effect 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.

Yeah. 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. And we talked about the potential for addiction and the evidence potentially for and against that. Right? There's also 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 have used cannabis for years mainly has a replacement for alcohol. At least that's how they describe it. Well, it's not as bad as alcohol that you hear that a lot. But what are some actual, if any, what are some actual harms of cannabis use that people need to take into account and just way 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 are just fewer personagens 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 a UCLA, I'm not 100% sure, but I know he was in California. He did like very long term studies tracking cannabis smokers and basically did not find associations of 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. But I think more likely it's because most people who smoke cigarettes at least that were the relationship with lung cancer where people who are 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 going to have damage there. There's no question about that. So again, harm reduction perspective would be oral roots 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 and some capacity.

The data is not entirely clear in this in this sense yet. I mean, we don't see again, it's not like super clean relationships like we're seeing that we're there when we they're 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 want to 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 end, 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 going to have some vascular effects to some degree in the system.

So I imagine we may get 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 hypertension.

So sometimes when what that is is if you stand up in 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 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 shifting 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 tacky cardio, 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 cardiac sensitivity or issue, the tacky cardio 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 to drop in blood pressure.

And do 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 to fix cardiovascular function. There are occasionally people who have reported having like elevated blood pressure. I mean, some of that also could be from an anxiety state or what not coming around. But the typical response, and this is usually driven by collaborative receptors that are in the

cardiovascular 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,

cardiovascular 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 is 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 40s and the 30s and stuff and people started living longer, you started seeing a lot of these effects of cigarette smoking emerge because a while for the medical community to adopt the idea that cigarette smoking was bad. I know it's wild physicians smoke and clinic. They're ash trays in the doctors office.

My grandparents grew up in Belfast. They had smoked for years and they even said like when they were younger doctors would say, I have a cigarette after meal at promotes digestion. So it's 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.

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 because that's more of like, I would say, a being safe because I don't know how to actually explicitly say what I would say the harms associated with it are.

I think there is something there I've seen enough evidence that's like starting to coalesce into a story that's like the 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.

And that kind of disease in this world, it can't help more now's legalization again because people are going in the ERs more where it's this somewhat strange phenomenon where it's usually people who are pretty excess cannabis users. They just start like puking and they can't stop it and it's like this intractable vomiting that they get into. And then bizarrely. of things that seems to be sure it is a hot shower, which is, I can't even begin to understand this.

I mean, I'm chuckling at the example because you are so very clearly rooted in science, but that just came out of nowhere. Like, okay, cool, hot shower, deliberate, deliberate heat exposure folks. There it is. I have been trying to understand how to do this. I'm not enjoying it because it's deliberate heat exposure, but it just speaks to the fact that we're talking about, you know, smoking being a regular part of the medical community behaviors up until, you know, a few decades ago.

And then, you know, a hot shower being the treatment for this like chronic vomiting. And it speaks to the fact that like with science and medicine, we do know a ton. It's amazing how much we progress, 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 with in the absence of any randomized control trials or mechanistic data.

I mean, I really struggle to understand, because certainly I don't think it was doctors that figured this out. This was people, I think, who were experiencing this. And then they started telling doctors this. And then I think, and I could only imagine I'm like, maybe they're going in the shower because they're like vomiting on themselves. Probably. And then 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 benefits. Something about activation of the thermal regulation. It's something of thermal regulation because the other thing that seems to have shown some benefit is propanol, which again, would suggest some kind of sympathetic, which is 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 thermal regulation. 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? It is again, surprisingly countertuitive because one of the medical uses that people have used cannabis for is as an anti-nauzeeant, especially in the context of chemotherapy.

And so something that typically has anti-nauzeeant 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 homestatic in some sense, the thermostat analogy. And maybe after chronic use, there's some, the seesaw gets flipped to one side and gets stuck there.

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 anti-nauzeeant effects of cannabinoids are involved through the insular cortex. And so maybe you 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 on that circuit becomes sensitized, but it is a very bizarre but very real thing that seems to happen.

And again, this isn't common. I've heard a couple of people I've met describe it, but it's not like it's happening to every 10 to 20th person or something. It's a little more and free going, but it's certainly happening enough that we've now captured it at a federal data level. This is a thing that people are showing up in the R4. So interesting. It is. It's a hot shower. Yeah. It's a hot shower. It's like people are playing.

So yeah, so for me, I would say the main harms that people need to be aware of, the schizophrenia bipolar, possible cardiovascular effects. And then this is one of these syndromes that can come out of it as well as possible lung damage from smoking. Those are the main, I think genuine, bona fide health issues associated with cannabis that people should be aware of. I mean, and if you, I mean, I know we're not going to probably go into depth with it.

On the other side of 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 of cannabis has like really bona fide medical benefit. Yeah, I was going to ask you about that. It's always nice to end on a positive side. And you know, we don't want to demonize cannabis in order we want to glorify it.

But you know, the examples that I've heard of medical uses for cannabis include appetite simulation. We talked about that. For glaucoma, lowering eye pressure in glaucoma that 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 in 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 a kind of a mild sedative way to relax in the same way that they would use a glass or two of one. 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 pain is, I would say the number one. So pain is certainly the one that there's the most amount of evidence for. And thank you. 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 anal gzick. It's that cannabis, it has some anal gzick 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.

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 anal gzick properties to it, to some degree. But it really seems to be much more of that component of it. And I think you alluded to something like that in the previous podcast you'd said, something about it, it's changing the emotional state of pain.

So, 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. Yeah. So, so the pain thing, I think, is the central one. And that's one of the only ones that there's a little bit of actual research on. Most of it, see that it was isolated to you. I think there's one or two studies that have actually looked at smoke cannabis and found 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 in 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 going to be true for stress and anxiety, which to some degree it is.

But it's very complicated because it can be like I said before by phasic where some, you know, lower doses or 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, let's say the 70s or early 80s where they were using synthetic forms of THC like nabalone, which is some of you can get in Canada or Marinal or Dr. Nabalone, 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 diazopam or something. Exactly what the comparator they'd used 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 because obviously PTSD has an anxiety component to it, but there's a lot more to it as well. And again, there's very little research in this space. There was one really, really small study 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 is 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 because they're in a dream-scape space that they reconsolidated 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, as soon as they put people on navelown, this synthetic version of THC, it very in a large proportion, I think, 85% of them almost stopped having these nightmares. And this was 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 sample 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 navelown 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 won't move. 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 they overall PTSD score. They only reported or really focused on the nightmare component of it, because that was the primary outcome of the study. So I thought that was interesting, because if you look at the anecdotal, that and PTSD, that's where a lot of it is focused on, is using it as kind of, I wouldn't maybe call it a sleep aid, because it's really more of a modulator of the dream state.

I think this is presumably because it's reducing the amount of rapid eye movements that 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, and you're describing one. 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, right? At least certainly for PTSD, I would imagine, in terms of the context of the nightmares, that's providing some benefit. Other or not, 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 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 doubt 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 mentioned earlier, the fawn inhibitor that elevates an end to my levels, so Johnson and Johnson did do a trial on social anxiety disorder published, I think, from a few years ago, 21 or something, I can pull up the reference of that, where they did find some benefit.

It wasn't huge, and some of this had to do with the design of the study because they kind of underdose the patients a bit. And so not everyone actually showed the elevation in an end of my when they went back and looked, but when they actually isolated the group of people that had higher end of my 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 in end of my 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 an end of my signaling.

And it's that loss of an end of my 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 of an end of my, you know, it's that job as it's kind of tonic housekeeper and keeping things in that homeostatic range. Let's say we're talking about explicitly an anxiety circuit. You know, this 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 and end of my 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 endocannabinide levels and they may go and found lower end of my.

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. Yeah. 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 and 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 the 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 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 night time 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 used to sort or wear 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. Yeah. I'm describing extremes here, but I find your hypothesis to square really well with the real world observations. Yeah. And it's an interesting one. There is some evidence actually spread.

So my buddy, Sach 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.

Okay. 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 endocannabinoid 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 endocannabinoid, giving THC on a background of low endocannabinoid 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, 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, this 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, maybe very different than someone who is like, you know, very anxious for different reasons or has normal endocannabinoid function or something else might be a play there. So very interesting. Yeah, I think I could explain some of the heterogeneity that exists out there for sure. So perhaps genetic differences in or baseline levels of anxiety perhaps map to endogenous levels of an endomide 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 endocannabinides 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 endocannabinide levels and mood states both anxiety and kind of depression 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 for size. 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 every way 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 point into 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. Absolutely. I think it's important. I think it's good that you kind of provided me an opportunity to correct the record. And did so in a very appropriate manner.

I think this was a great discussion for people to understand. Different perspectives. 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 happened down the road, similar things, move forward and you chat with people. I always.

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 present a data, I present a data and we disagreed, what we would probably do would be to head, well, traditionally, you'd 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 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.

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