Welcome to the huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew huberman, and I'm a professor of neurobiology and Ophthalmology at Stanford School of Medicine. My guest today is dr. Matthew Hill. Dr. Matthew Hill is a professor of Cell Biology and Anatomy at the University of Calgary his laboratory studies cannabis and its effects on stress its effects on feeding and its effects on the behavioral impacts.
Of cannabis exposure at different stages of development the origin of today's podcast episode is a bit unique. So I'd like to share a little bit of that background with you previously. I did a solo episode of The huberman Lab podcast about cannabis the biology of cannabis some of its medical applications and uses as well as some of its potential harms that episode came out several years ago now and remains a very popular episode. It's had millions of views and millions of listens several months ago. We posted a clip of that episode.
2x formerly known as Twitter and dr. Matthew Hill responded to that clip on X with criticism about the specific points made with In that clip most notably my discussion of the data that cannabis use can in some individuals cause psychosis. He also took issue with some of the specific points. I Made In that clip related to potential differences in the biology of the effects of different strains of cannabis, most notably Indica versus Sativa strains and a few other points as well now,
As somebody who's been in the field of science for several decades now, I'm very familiar with the fact that every field every single field within science has debates within it controversies and sometimes outright battles and to me that's part of what makes science interesting. It's an evolving process. It's something for which we should all be very curious to try and understand what we know what we don't know and try and get to the real answers. So right off the bat on X, I invited dr. Hill on to 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 talked about th see versus CBD we address the question of whether or not indicas versus sativas have different biological and subjective effects or not. We of course talked about the potential correlation, maybe even causation between cannabis use and psychos.
Isis I think you'll find that discussion very interesting and we talked 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
And biology along the way before we begin I'd like to emphasize that this podcast is separate from my teaching 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 eight sleep aids,sleep make smart mattress covers with cooling Heating and sleep tracking capacity spoken many times before on this podcast about the critical need to get
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Again, that's drink element.com huberman to claim a free sample pack. Today's episode is also brought To Us by better help better help 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 there are apis should provide support in the form of emotional support or directed guidance and third expert.
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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 and cannabis is a plant that has
Been around for some time. It's kind of got like a very rich history of use around the world for different cultures for both kind of medicinal and spiritual and recreational purposes over several centuries. The plant has kind of become I mean in the west it really wasn't a thing mainstream wise until about the 60s and then it became kind of introduced as like a drug of choice that a lot of people started using during the rise of the hippie era and I think that was a lot of the time that cannabis got
popularized and then I'd say more recently cannabis has into the 90s and on has become kind of a very heavily used drug by a large swath of people ranging from teenagers on up in terms of what it is inside it. I mean, it's a plant with a lot of very complex chemistry and biology behind it. So there's a lot of molecules that it carries in it. We call these cannabinoids and they come in a lot of different flavors, but the main one that's the most important one when we talk about cannabis and what drives
Was the kind of intoxicating and what I would refer to a psychoactive effects of cannabis is Delta nine tetrahydrocannabinol or what we call THC and that really is what dictates, you know, the psychoactive and intoxicating properties of the plant and so the amount of THC that is within the cannabis plant will influence the you know, how high a person's going to get when they consume it. There are probably 70 to 100 and some odd other cannabinoids that are within cannabis. Most of them are pretty Trace.
As 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 cannabidiol or what we call CBD CBD is structurally looks pretty similar to THC but doesn't behave anything like th see it's not intoxicating at all. Not sure I would probably say it's not psychoactive in the sense that people can't tell if they're on it or not. But I would some people still say it's like oh active because people claim, you know, it can affect anxiety state or mood.
Data other things so in that context maybe psychoactive is still somewhat appropriate aboard to use and then there's a whole bunch of other things like cannabinol Canada Jarrell 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 two 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 to founds in tons of other plants. So this is a lot of which seems to contribute at least to some of the smell and the flavors of cannabis. So these are things like limonene which you know gives some cannabis kind of a citrusy odor or flavor to it pinene which gives things more of like a earthy tree kind of smell beta carry off lean mersin and these terpenes are also some of which do have known biological activity some don't and they vary quite
We 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 to cannabis. But the reality is we really don't know a lot about them at this point. There's kind of some emerging work that's starting to come out. Now that kind of plays with you know, giving someone THC and adding in one other terpene or one other minor cannabinoid and seeing how it influences things. And so you can imagine with the plethora of molecules that exist in cannabis doing this in a
a piece wise manner could take decades to kind of really get to a point where we understand all the interactive components of cannabis, but people tend to refer to this as like an Entourage effect. That's kind of a phrase that gets used quite widely in the Cannabis world and the idea behind that is that if you took pure THC and so there are some like distillate pens and things that exist out there now in the product Market which are basically isolated THC with Trace levels of anything of other stuff would be very different than if you had th see in
Combination with some of these other molecules and how they might influence how th see itself is working or not. So
fascinating plant, you mentioned the psychoactive effects some people listening to this and watching this presumably have experienced those psychoactive effects others. Perhaps have not how could we described for both groups what the quote unquote psychoactive effects. Are you mentioned the higher the concentration of THC?
See the quote unquote hire. Someone will get right the greater the intensity of the hi what is the high and I know people are probably chuckling sighing, you know, does huberman not know because he's never done it. I mean, that's my own business. I just want people to understand what you mean by psychoactive.
So, I mean the way that people would usually describe the intoxicating effects of cannabis is they would then I mean people often refer to it as there being some Euphoria or some positive mood not on the same order.
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 is referring to somebody a stimulant they're just like oh people feel like they're God. They're like, you know
possibility everyone.
Yeah exactly. Like they're very happy and they're kind of jacked up and I think with cannabis the way people would describe it would be very different. It's like kind of an introspective State you might be more aware of your bodily feelings and states that are going on inside of you your kind of internal state, but you also have like a different perspective on
Internal 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 is intoxicated like the kind of glad worker people get someone high they just kind of use a what we call a visual analog scale which is like a 1 to 100 or something or 0 to 100 and say do you feel high do you enjoy this? Would you say you feel euphoric is your mood elevated? So they're kind of scaling things like that. So I think that's more typical.
In a lab setting how you would Define if someone's high or not from it and this is why when people do studies with something like a placebo cannabis or very low THC cannabis, you'll see kind of a scaling. So even if you give someone a placebo cannabis if they think that they're getting cannabis a lot of people still respond by saying they feel a bit High
that's his 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 me enroll now ya got smokers everywhere running to
look at subject. I think yeah, I don't think you can use drug naive people. I mean, I don't run human clinical lab studies, so I can't explicitly say it but that's my understanding is that someone has to have had even limited like, you know, not much but at least once or twice they have to have experienced the drug before so I don't know if you would take someone who is completely blind because I don't know how they would replicate that state if they're not expecting it.
What about
Out the effects of cannabis on time perception, you know, there's this reputation that cannabis has for disrupting time perception that people will think a long period of time has passed when in fact very little time has passed. Maybe it's sometimes even the reverse is the mechanism by which cannabis can adjust time perception
known I wouldn't say it's well worked out there definitely seems to be some like temporal dilation like you're saying where people think things of you know,
Someone will be high in someone will ask them. How long do you think time has passed they would report usually longer periods of time has passed in actually have I feel like there is some older work I could dig up to see if I could find that is either in like it might even be in pigeons, but it might be in rodents this 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.
Are they kind of no distinct periods of time and if they give them cannabinoids they respond differently. So it's in that context that does still seem to produce some state where there's a 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 is 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
um medical uses of cannabis is in people that are undergoing treatment for cancer in order to stimulate appetite because oftentimes they have very low or even no appetite due to the cancer treatment is the mechanism by which cannabis can stimulate appetite known and if so, what is the general trend of effect makes people hungrier obviously, but we hear again in kind of recreational terms of people getting the munchies, you know becoming exceedingly
Lee hungry is that related to some cannabis induced effect on say blood sugar like insulin or glucose regulation or is it happening at a different level?
I think we almost need to take a step back actually to talk about how cannabis works in the Brain before we kind of go into that through 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 1 receptor CB1. Yeah, CB1 is the shorthand for it and I think you know as people
And to create analogies to describe what receptors are for those who don't know what's most people use like a lock-and-key analogy the like a receptor would be a protein that sits on a cell and a molecule that binds to it like THC is the key that fits in that lock when it activates it it triggers some biological process in the cell and this case a neuron that changes its activity in some capacity and so th see acts on the CB1 receptors which are very widely expressed. In fact outside of like kind of ion channels that are expressed in brain. The CB1 is I think one of the most
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 jello cannabis users everywhere used 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
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 CB1 and there is also a CB2 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 in the body is it's mostly immune cells. So you'll see see b-2s 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 CB2 seems to be much more about like regulating inflammation. So that's kind of a separate role that can certainly impact the brain in different ways. But when we talk about the effects on the central nervous system and the brain and behavior were talking almost entirely about CB1 and so both the CB1 and CB2 receptors. Like I said don't exist because nature was like humans are going to find Cannabis though. This wall work 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 neuro transmitter. So I mean, I assume most people who listen 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 owner on a releases a transmitter and it can be something that excites the neighboring cell there on be 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 axon neuron B and I 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 anterograde because it moves from neuron a to neuron B, which is kind of the general flow of things and how we usually think about it. So endocannabinoids are kind of this, you know little bit of an oddity in the sense that they could do.
Reverse and so endocannabinoids are actually made in neuron be on the postsynaptic side and then they go backwards and act on Neuron a to regulate how much transmitter is released. And so in many ways this is like I kind of liken it to a thermostat model for the most part. Certainly we're talking about some really excitability. So if Neuron a is dumping out something that excites neuron be like glutamate, which is an excitatory neurotransmitter as neuron b gets too excited. It's going to start releasing endocannabinoids to go back and tell Neuron a dad.
Stop driving it
so serve a homeostatic scaling trying to maintain a middle-range.
Yeah, I mean at the end of the day no matter how you discuss it and what system you discuss it. I think the majority of people in the cannabinoid field would agree that the primary physiological role of endocannabinoids is to maintain homeostasis. That's what they do. They keep everything in its happy place. Let's say so like
and that's probably why the CB1 receptor is so widely distributed is that neurons can excite or inhibit each other that is raised or reduce the amount of electrical activity in the
Let's say nearby neuron because they were talked about retrograde signaling. But ultimately you don't want runaway excitation. Yeah, that looks like epilepsy exactly and you don't want runaway inhibition because that looks like suppression of your ability to think move etcetera
exact. Okay, so you want to keep things in the where they should be and so you want neurons to get excited but you want them you don't want them to get overexcited. So endocannabinoids in kind of a very prototypical sense Act is this circuit breaker essentially when they go back and gate how much is coming in and they do this by
through various mechanisms essentially turning off the electrical activity of that presynaptic neuron, so that it stops releasing neurotransmitter. They can also regulate though inhibitory neurotransmitter released 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 excitations actly. I usually liken it to basically taking the breaks off of a car while you're going down hill kind of thing. Like you're you know, you'd use your braking system to keep
In check, but if you want to go faster, you take the foot off the brake and you let things accelerate and so this can be really important for things like forms of synaptic plasticity or neuroplasticity. Let's say where you want synaptic strengthening to happen. So like under a learning event or something you want that synapse to really 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 and okay now,
Avoids 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 neurons are acting on and so they can regulate excitation or inhibition differentially and I mean CB1 receptors are found on virtually every single kind of neuron in the brain except one. I think you'll find this interesting because it's dopamine and dopamine neurons are basically the only
In the brain that don't really at least as far as we've been able to characterize the date Express cannabinoid receptors
interesting if I may earlier, you mentioned one of the potential psychoactive effects of cannabis is Euphoria. Does that mean that the Euphoria associated with cannabis use is independent of dopamine and is more reliant on something like perhaps the opioid receptor system or the serotonergic receptor system. I
wouldn't say that cannabinoids don't affect dopamine because
what we understand in the ventral tegmental area, which is kind of 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 indirect exactly. So what you have is those neurons that regulate the dopamine neurons are very rich in cannabinoid receptors. This is actually kind of similar to how ehome you opiate receptors work for things like morphine or heroin and essentially what the cannabinoid
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 do go into burst firing and have big dumps of dopamine whether or not that relates to you know, the positive effect of the Euphoria. I don't think anyone has clearly demonstrated that I mean obviously don't means very complicated in terms of its relation to endpoints and whether it's reward or motivation, but cannabinoids definitely do have an influence on dopamine transmission. They just don't tend to do it directly and I think that's this.
Very bizarre and interesting component of cannabinoid signaling is why the brain would have evolved in a way to allow every other neurotransmitter system to be actively and directly regulated by endocannabinoids. But dopamine has kind of spared from this so I don't know no one. I mean obviously you can always just theoretically guess as to why some do that. I don't know what the reason for it would be but it is something that has kind of intrigued a lot of people because every other system in the brain is so tightly controlled to some degree by endocannabinoids. And then this one circuit is kind of free of it. So
But yeah, so the main role of endocannabinoids is really to regulate plasticity of homeostasis allow flexibility of circuits to either Goose up their activity or ramp it down if they need to depending on the environment depending on the experience of the organism. So there's a lot of kind of roles that endocannabinoids play in that domain but even within the endocannabinoids, I mean, there's two primary endocannabinoids. And again, this is one of the weird things about how endocannabinoids work because if you talk about things like serotonin or dopamine
You have a single molecule that gets released in the typical anterograde way and it diversifies at the level of the receptor. So serotonin has like I don't know like 15 receptors or 20 or something. No dopamine has at least five and so the different actions that serotonin or dopamine will have is all driven by the diversification of The receptors. It's one molecule. Whereas cannabinoids of the reverse not only do they work backwards across the synapse and work in this retrograde fashion. But really you have one receptor that is regulated by two molecules. So the diverse
Casein happens more at the level of the molecule then at the receptor, which is again very unique and the two molecules that we know are kind of the bona fide endocannabinoids. There could be more they're called an and amide, which is actually kind of a funny name because it comes from the Sanskrit word and for Bliss and so raffy Missoula 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 a name I'd bond is kind of the joke he had for it. And so he discovered an an amide and decide to call it Bliss because he had familiarity with cannabis or because he took an and amide as a direct experience and them because it takes a lot for a scientist to discover a molecule, but then for scientists discover a molecule and the name it Bliss from particular reason, you have to speculate that they had some familiarity with the coffee machine was also the guy who isolated discovered THC. So, I mean he has a very he's
The grandfather a whole cannabinoid field so he has a landmark paper from 1964 which ironically this is one of these weird pop culture things. I don't know if this is true that paper was published on April 20th 1964. And so the joke is is this where 420 came from because the original like birth date of the first THC paper was for 20 1964.
Well now that that now that potential myth is definitely going to propagate
but yeah, so 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 and amide is being the first molecule that activated the receptor endogenous Lee and so it was kind of yeah, I think was a little tongue-in-cheek that he named it the way he did a few years later the second molecule, which is just called to Iraq Donald glycerol, or what we call to AG that was discovered kind of in tandem both Again by machine, 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 an atomized binds the receptor is it's what we would call a high Affinity but low efficacy Agonist or molecule least and what I mean by that is very low levels of an and amide or required to actually bind to 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 to AG seems to require a bit more concentration in the synapse to be able to bind to the receptor.
Scepter so it has a lower affinity for the receptor. But once it binds to the receptor, it's like pretty heavy-duty. So it evokes a very robust intracellular signaling response. And so why we have 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 or the circuit that they're working in or this idea that maybe an and amide might be more of a tonic molecule and what I mean by that is will say it's like a stage Setter so
Like an and amide might just be kind of made by neurons on an ongoing basis and just released and it's job maybe 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 to
quiet. Your thermostat. Analogy is
perfect here. So in that context it kind of is like just the thermostat of the house whereas to AG is like let's say the pinch hitter who gets brought in to do the heavy lifting and so to AG during a situation like
Let's say something like even like a seizure as 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 to Ag and that acts as the okay. We really need to turn off the circuit very quickly in this situation and in most of these forms of like synaptic plasticity, like I was saying earlier where you need to either strengthen or weaken a synapse in response to a change in the environment or in response to an experience or something's going on.
Most of that is driven by two AG signaling. And so, you know all these forms of like turning things up or down in an kind of rapid and on-demand manner. That's mostly to AG. So most people who study like neurophysiology and like record activity of neurons and look at endocannabinoids. They're almost entirely talking about to AG when they play with stuff. So yeah, that's kind of one of the ways we do it we say that an animated maybe more tonic into AG might be more phasic and
like brought online when needed but doesn't do a lot there is some evidence that to AG may also have a role to regulate some circuits under kind of resting conditions as well and there certainly are some situations where an and amide might get brought into play to affect plasticity. But as kind of like an umbrella idea of how we look at it that's often how we divide those two up. So we kind of have these two molecules they end of the day do the same thing. They're regulating neurotransmitter release through retrograde signaling, but what stimulation brings them online or what drives
Our activity May differentiate and we don't really understand all the details behind that outside of the fact that we very clearly no to AG is activity dependent. So as that neuron becomes more active it's going to make to edge you to regulate its inputs. So yeah, you have this very complex system and its really widely distributed in you know, it's everywhere as a cannabinoid receptors in the endocannabinoid molecules are in the cortex during the hypothalamus and the striatum the hippocampus the cerebellum all over the web except the one area where it's really interesting actually where you don't really see much
Each 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 in the way that that tends to happen is when you activate the opiate receptors in the kind of cardiorespiratory parts of the brainstem, it depresses neural.
Tivity, so as the person loses Consciousness, they also unconsciously will start regulating their own heart and breathing and they can it can be a fatal response because cannabinoid receptors don't really exist in those regions. You don't get the same kind of impact in terms of suppressing heart rate and breathing function. And so that's I mean, you know, there's always the saying like, there's never been an account of someone actually dying from a cannabis overdose or a THC overdose. I mean certainly people can do stupid things weather and
executed that result in their death, but in the same manner that someone can die from consuming too much opiates. It doesn't seem to be physically possible to cannabinoids as far as we've seen so far and a lot of that is just because the localization like for some reason it's just not the receptors in that part of the brain. So
very interesting a lot of kind of a aficionado questions about the receptor biology. I'll just spare everyone the details by just highlighting something that you already said Farm.
Eloquently than I will which is I think it is fascinating that this whole system has both atonic like a steady release capability and aphasic, you know, so the ability to spike forgive the pun on the neuroscientist with know what I'm talking about just spiked more activity of this 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.
It 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 there's a few ways, I mean cannabinoids and feeding are really interesting thing because Proto like if you ask people like kind of the prototypical responses to consuming cannabis, most people would usually say Munchies is one of the things that pops up pretty regularly and so
You know, the cannabinoid receptors are very they are expressed in these feeding circuits in the hypothalamus. And you know, there's a lot of complex circuitry there that can regulate food seeking behavior and we just had an episode with Zach night. Yam. Hhmi and UCSF. We talked about like the a grp neurons and different neurons of the hypothalamus. We can link to that in the show notes captions nowadays a rich understanding of the neurons that stimulate food seeking. Yeah craving and
So we know that like cannabinoids they regulate again those inhibitory inputs around a grp neurons for example, and so one thing they can do is dis inhibit those a grp neurons. So they become more active in 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 and and amide, for example, this is you know, Steve Mahler and Kent barrage did this work years ago where they just put an an amide into the nucleus accumbens and that can also stimulate palatable food intake so you also
So have this ability to integrate with the reward circuitry and then there was also this fascinating paper from a Japanese group in pnas, I think about 12 years ago and what they found was they would give a rodent 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.
Are sour or I don't know if they do mommy and 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 a grp neurons as well as the pom C neurons those kind of both sides so that in the in the arcuate nucleus to regulate multiple components of feeding, but a big question is like my lab has become kind of interested in this as well because we
Have a component my lab that studies feeding behavior. And one of my postdocs has been doing these projects for years. Now trying to understand almost like a behavioral mechanism level what the munchies are and what she's been looking at is we kind of started thinking about the idea that you know, what is it that because it's not just food seeking and it's not just you know, like just want to consume something. There's 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
Initiate eating
so that's an interesting thing in and of itself because that means you're disrupting either the ability of the brain to detect satiety or you're messing with a process. We call reward evaluation and so reward evaluation is like, you know, if you haven't eaten for a day and you see like a picture of a pizza or someone brings a pizza in front of you. It just looks delicious now First Slice taste 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.
It's reward salience the grades as you eat and as your brain basically shifts into a thing of we don't need to consume calories in food anymore. We're okay. We're full now and so we've done a series of experiments in the lab where you'd get the animals and either satiated in advance where they have already devalued the food and under a normal State. They won't eat it anymore. They won't work to get access to it. And you get them high on like a cannabis extract. We have these Vape chambers that are like, I don't know how else to describe it outside of like a little hot box.
The best way to this gives 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 titrated 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 go gangbusters. They eat food doesn't matter what you give them.
Even playing Chow, they go to town you give him fatty give him sweet. They love it all but you pre satiate them and they get him stoned. They will reinitiate eating again and you make him work for it where they have to like lever press and you get him 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 weird scene Cassie more have done this at Hopkins as well. They've shown similarly.
I think what we call Progressive ratio, which is a essentially a thing where it's like the first time you press the lever you immediately get a sugar next time. You got to hit it twice. They get a pallet. Then you have to hit it four times to get one. Yeah, then you got to hit it 16 and then thread a 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 our high and she'll do like 300 lever presses the at one sugar Pelt like she really wants it so you can really kind of Goofs up their motivation to eat. And so there's clearly a rewarding aspect of this because they're motivated.
Elevated 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 conditioned taste aversion. So you give them access to a food and then you give them some it 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 nausea. And so the animal no longer likes it. So again same situation get
Almost stoned and it will re-engage in eating that food that it had devalued through being paired with nausea. And so through either satiety or making it kind of a negative Associated flavor because the animal got nauseous before you can kind of override these Effects by giving THC and so that could be a complex process that either involves changes in the reward circuitry. This could be something it's like from the orbitofrontal cortex, which is a very important part of the brain that scales reward and kind of
Assesses how much someone wants to work or an organism wants to work to achieve a reward at the end. So we haven't figured out the circuitry of this and where exactly it's acting but I would say a lot of the stuff that you know, we and others have done kind of supports this idea that a lot of what the munchies is this ability to kind of almost a 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
Others have also done work to show we can block satiety signals. So we know endocannabinoids at least are capable of overriding leptin. So leptin is an anorectic molecule comes out from the fat and usually we release it when we've eaten a lot and it's one of these things it tells your brain stop eating, you know Works through again populations in the arcuate nucleus and changes the way those neurons function to drive food seeking behavior. And we and others have shown previously that you know, if you elevate endocannabinoids you can override that.
Actually, one of the mechanisms by which left and 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 goosing up endocannabinoid
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They'll give you five free travel packs with your order plus a year supply of vitamin D3 K to again. That's drink AG one.com huberman, you you're talking about increasing endocannabinoid activity. And we've said all this in the context of cannabis. So maybe we could talk a little bit about how the components in cannabis THC mainly but also CBD impact these receptors the CB1 and let's just leave CB2 out for the moment because it sounds like it's more of an immune system thing.
Just to make it very clear. Is there a way to increase the activity of endocannabinoids with out ingesting
THC? Yes, I mean they dynamically change all the time.
So but you're talking about you're talking about experimentally or recreationally adjusting their levels, but how does one do that without using THC? So
okay few things there will take a step back. So THC itself isn't going to it does its thing?
NG by acting directly on the cannabinoid receptor not so it sort of mimics the
anandam I'd and and to a g.
Yeah, so THC going back to kind of the pharmacology of this so th see 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 overrides
endocannabinoids either way that's referring the fact that I said that in a previous solo episode about this and there.
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 amide that can bind to CB1 receptors because what you're talking about is a super physiological Condition. It's I mean, you don't really actually need much THC in the
Rain to produce psychoactivity like it's a little bit of a mystery to be honest exactly how it works. I mean, I think the main way that most people in the cannabinoid Theory filled with 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 to AG. Like it's actually more like an and amide. So you said in an amide is high Affinity low efficacy so teach these the same th e is actually only a partial Agonist. It's not even a full Agonist it
CB 1 but it is high Affinity its high Affinity. So it has the ability. So but the tricky thing with that is
It can out-compete to AG but because it's a lower efficacy egg and it's than to AG in that sense. It's almost blocking the effects not amplifying
blocking the effects of to AG, but does it block the effects of Ananda mind
to it teach the in an amide? I would kind of the way I would visualize it as because they seem to have relatively similar affinities and efficacy of the receptor. They might let's say dance around it. So it would be somewhat interchangeable the difference there is and this I think is the big point about what th
HC does versus endocannabinoids because we know now through the pharmaceutical development of drugs that can boost an antibody levels which exists we have Inhibitors that prevent their metabolism can operate them. There's no intoxication and no psycho activity associated with elevating an and amide. That's a very interesting point that we should highlight. So there are drugs that now exist that can block the breakdown of an an amide It more available presumably by disrupting some enzymatic breakdown and therefore lead to more binding of the now elevated levels of and and
My that are available to CB1 and you see no psychoactive effects. Like black people are not aware that they
yeah, you can do there. No, no one can guess. Yeah knowing he has what is it used for? Well, I mean it was developed in 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 arthritic knee pain trial that was like even in that trial the positive control of Naproxen barely work, but because the FAA inhibitor, which is
Take a step back far as the enzyme that chews up and and amide. So the drug that is developed inhibit that enzyme so you prevent the enzymatic breakdown of inanimate. So we just call them Fawn hitters. So this drug will boost in an amide levels quite high and in animal research showed some efficacy in modulating pain and so they put it in a trial and it didn't work against the positive control of Naproxen which is like an NCAA just like Advil 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 I was like, oh it's not going to work. So it kind of shelved for a while a colleague of mine Marcos High leg and Leah Mayo Lee has 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.
And some of this stuff we'll talk about Soul tether back to that. But what we did what they did was they dose 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 are interested in and we did find that boosting and and amide with this drug over 10 days was sufficiently capable of dampening stress-induced autonomic responses. So like looking at heart rate or skin conductance, I think skin conductance was the measure we did in there, but it's a proxy for like adrenaline release so
Blunted that and a 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 make sure the drug was working properly, but it was very interesting because we did see in that situation we're elevating and amide produced kind of like a reduction in stress perception of reduction in stress physiology responses and kind of help kind of reduce fear.
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. It's still it's one of the frustrations I have is scientists do a lot of translational work and with clinical Partners like Leah is that getting access to these molecules is not easy when they're not kind of wide they're not like out in the market so you can just go and get them you really have to
Try and get access from the drug companies to be able to do trials with them. And so we are in the midst of front of do that. We did just complete a trial that Lee and Marcus ran that I worked with them on as well that was on PTSD. And so there are various potential indications for this. I mean Johnson and Johnson developed one as well and they looked at in social anxiety disorder. They had some moderate efficacy in their trial. So I'd say the jury's still out on exactly what we're going to do with these but they have
some potential I think in certain clinical settings. We just have to figure out exactly but I think going back to where we started this from they're not psychoactive. And so I mean when fives are 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 that in a sleep study.
Show that it did have some effects on sleep cycle the same way th see does and then they also did like an in Vivo pet binding study to show that they could displace a radioactive molecule that would bind to the enzyme in the brain
seems like a lot of gymnastics to basically confirm what they already knew, which is that even greatly elevating the in and amide by blocking this enzymatic breakdown of an an amide leads to at least from what I'm understanding vastly different. Yeah subjective experience then T ingesting or smoking THC.
Yeah, which brings us back to THC. So what's it doing and cannabis like you know, so I think it seems that this this thing that we call cannabis and THC are overlapping with the endogenous effects of an animai. But here you're not talking about endogenous normal levels, you're talking about pharmacologically greatly increasing in an amide. 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 could talk about THC and the CB1 receptor. And since we're here we might as well talk about CBD and and the I think you're going to tell us the lack of interaction was sitting on her scepter. Right and what is cannabis doing it the level of these receptors because it makes me wonder whether or not these receptors are the whole story or whether or not cannabis is, you know, as you mentioned, you know, 70 plus
Active molecules in there terpenes and a bunch of other things that may modify their action that this thing we call cannabis has many more actions than just mimicking the endogenous cannabinoids system. Yeah. I mean, I think I would say the main way that we think about this is the difference between endocannabinoids and thc's 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 an I think like it's very clear that lichen and amide for example is not active at
Synapse that has CB1 and so when we boost an endermite signaling by inhibiting its metabolism, all we're doing is amplifying and amide sailing at the synapses it already exists. Whereas th see 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 Lig in the thing that binds the receptor. This is Far and Away different than say like the actions of
amphetamines. Yeah, which are disrupting the normal biology in a way that's giving you an amplification of an endogenous mechanism. Yes, right if that was all just nerd speak for those listening. It's one in the context of amphetamines. What you're doing is you're taking an endogenous system a naturally occurring system and your 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
Lap with the THC effects but THC is doing a bunch of other things. It's and that's because THC and we'll talk about CBD but at least THC is acting as the ligand it's in some sense. We don't want to say replacing but it's masking the effects of an an amide. 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 th see the resulting effect is the intoxicating State and it's probably because there's a lot of CB1 receptors in the cortex and
And those are going to be differentially regulated at different times by endocannabinoids. Whereas when THC hits them all them are going to get affected at once and if you think of the way that I described how can I Bernard receptors work by essentially? I mean it its simplest form what can happen I receptors do is they change the way that to neurons talk to each other and so
you changing all the networks
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 you know, a super duper version of an endocannabinoid or that it's boosting endocannabinoids. It's kind of like just indiscriminately activating all the receptors as opposed to a system. That's very finely tuned to do very specific things at very specific
times. That's very helpful. Yeah. 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 doesn't is very different because that's that's a that's a levels issue. This is a levels and an extent issue. Yeah. This is a lot more to do with just yeah the nature of how it hits everything because like so for example, if we talk about feeding we know it's been established at this point that for example, if an organism doesn't eat for like a day, so you fasted at that point in those feeding circuits in your brain like the arcuate area where these a grp neurons and stuff are the you'll start seeing elevations and endocannabinoids. So
Can I Braid level 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 npy is another one and ghrelin and things like that. So there's a lot of redundancy in these systems, but endocannabinoids are just one of
The molecules that seemed 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 effects 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 days based on nutritional State th see on the other hand. You know, it hits the brain. Yes, some of its going to be the intoxication but in tandem, you're going to hit the CB1 receptors that are
Is feeding circuits as well and the consequence of that is going to be I mean the way I kind of analogize it to people's 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 in their kind of the way their food circuitry is responding in the brain at least seems to be similar to what would happen.
If they've been fasted and the thought is that's why when people you know when someone gets stoned, they're not like going to eat lettuce. They want high calorie food. They tend to like things that are high carb high fat that combo seems to be what people like when they're intoxicated with cannabis and that comes 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 talked about
Pain or stress we can say similar kinds of things are going on is that endocannabinoids normally do one thing but when th see hits the brain, it's still activating these circuits in addition to everything else that hits so you still drive that response that the endocannabinoid system normally physiologically controls, but you're almost like tricking the brain into thinking you're in that state now. And so then you then yeah, you go into food seeking Behavior mode super interesting.
Well, I have to imagine that there are many people who use cannabis not to stimulate appetite.
But for other reasons, they either like the Euphoria or to adjust their anxiety. What are some other known mechanisms by which cannabis can change people's psychology. Let me focus in on one particular aspect of subjective experience, which is focus. Do you think that some people use cannabis because it allows them to focus better and I raise this specifically because I think that in the past cannabis has
A bit of a reputation for making people Spacey. I'll 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 depths. I mean, there's some things, you know, a lot of the stuff that's been done is usually more like kind of a cute memory tasks like a working memory or recall or something like this as opposed to
Mostly studying Focus anecdotally there is certainly a lot of people that report that so
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 wow, someone's intoxicated on cannabis. There is definitely short term effects on memory processing. So people tend to
Effects are in 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 and
Toxicated but they use cannabis somewhat regularly. I don't think there's anything compelling for that. And even in that case like Carrie Cutler who's at Washington State. She's done a lot of this stuff looking at cognitive processing and different kinds of memory tasks in users while they're stoned often and within a person either they have adapted to using it as much as as they do or they've developed some form of tolerance to it. But even in regular users the impact on memory processing
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 canvas 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 an undergrad through alcohol. So like, you know, someone first time they get drunk try
he's 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 test 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 influences of a substance does not mean that you have higher proficiency at that particular time.
While under the influence, in fact the way it was presented to me when I was an undergraduate was incorrect. The I remember the lecturer said and later corrected 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.
Correct, just because they'd had some state-dependent learning. And so I think when we're talking about everything 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 does a memory cross the season some capacity what?
Form of memory. I don't think I could speak to comfortably just because I'm not a memory researcher and I know this very specific things of like episodic and declarative and whatnot. So I can't say that but I'd say it's kind of generally and I mean again, you can replicate this in animals where if you train them on a task while they're under the influence, they don't seem to have been 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 cannabinoids 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 you I think your words were it
assuming high THC levels in the Cannabis carpet Bombs all the networks as opposed to bonding more with higher Affinity at particular receptors. I mean, I don't actually even think it matters if it's high THC in the Cannabis. I think like some people can get very intoxicated off of very very low doses of cannabis. Is that right? I mean you look at Edibles, for example, I mean this may be an interesting segue into route 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.
It's 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. Yeah routes of entry for THC into the system into to get to arrive at the brain write the numbers I gave you in the previous discussion about this. We're related to how quickly inhaled smoke moves from the lungs to the blood stream and crosses the blood-brain barrier, which is very
fast, right, which is very
Fast I don't know if it's different than nicotine. I'm not sure again. I don't know if I would say that but yeah, it's very fast. Okay. So 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 but typically how fast is the onset of the subjective experience of okay. Somebody takes a hit off a joint or bong hit and they start to experience the subjective.
Of effects of euphoria Etc how quickly after 2 to 5 minutes, I would say it's a 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
10. I've seen some people not titrated very
well, depending again on how your so again this can vary. So like, you know cannabis from the 70s was like I know five percent THC. Let's say it was pretty low and nowadays cannabis is a lot of the commercial stuff is between 20 and 30, although whether those are super accurate numbers not entirely clear. But so it's gone up a fair
amount. Yeah. Yeah there that's a
That's not just a fair amount. That's I mean if we were talking about alcohol
concentrated vodka. Yeah, basically you're talking about a beer or wine to a
spirit and there are aquavit variety. 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 a I just don't tend to and we could discuss can't
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 clear about that. So but when I hear about, you know, 20 to 30% concentration as opposed to five percent concentration, it's significant. So I would say this is what 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.
And 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,
Engineer 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 years all that cannabis came from one source, which was I believe a farm in like Mississippi that was essentially funded by Nida to produce cannabis lucky farm and well the Cannabis that came out of it though. And this is one of the reasons a lot of the clinical stuff people have kind of been like, oh, I don't know how
- this is because it reflects cannabis that I would say is more from like the 70s or 80s. So it would be like 5 to 9 percent kind of THC cannabis. Now when you put someone in a lab setting and you get them to smoke two level of intoxication people would take you know, whatever 8 toques. 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 I've 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
Street but they're clearly getting intoxicated from it and it's giving us reliable data. So when they started looking at the blood levels of THC that you achieve it was around 100 nanograms per mL of THC give or take that seems to be where it was now because of the way that the you can legally study Canada 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 don't you study what we're using?
Seeing but because of the legal aspects of this you couldn't bring those products into the lab. They've never been standardized. No one knew exactly what was in them pesticides all this other stuff that could influence it. So from a safety perspective. It was always like no you use the the Cannabis that sourced from Nida. So it was a group in Colorado the Ken Hutchinson and Angela Bryan and cinnamon Bidwell have kind of I would say became very creative actually to figure out how to study cannabis that's being used.
I call it in the wild like and kind of an ecological setting let's say and so they created what was called the canavan and the canavan was a way to study people using products on the street, but not have them come into a laboratory setting where it was complicated. And so what they would do is they would drive the canavan to someone's house, but they be parked on the street and someone would use the product whatever it was on 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 bass 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 many more subjects. But of course, they're reporting back their effects. We can monitor them by device, you know, look at HRV, look at harder than cetera. I think having the ability to compare and contrast in laboratory and X laboratory data is extremely
valued at 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.
82 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 a novel experience with someone is intoxicated with cannabis can also create a very different altered state. I would want to be Stone in a laboratory. I'll say 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 can Angela and cinnamon did with the canavan was kind of create the situation that allowed
This research to occur and what we found fascinating I remember talking to make any about this because sure all the people in her lab said he's tended always hit around 100 nanograms per Mille using this relatively lower potency cannabis when Kenton and Angela and cinnamon started studying this in the people and taking blood despite the fact that these people are now using cannabis that's 20 to 30 percent their blood levels of the same. So they're still coming in around 100 nanograms per mil because people are really good at self titrating now where Things Fall Apart.
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 can't really grow a plant that's going to exceed more than 25 to 30 percent THC just by sheer biology. So 8 apps out there that's about as high as it's going to go concentrates can go up like 90 98 percent so you can get really really short tinctures distillates like yeah various just
In oil based forms that are very very high potency products. Those are incredibly challenging to titrate like they cannot be titrated because the sheer volume of THC that hits the system even from a single hit is so overwhelming and so when the Colorado group looked at those their blood levels were closer to 200 300 nanograms per ml. So with cannabis plant there does seem to be this ability for people to relatively self titrate and then my buddy Ryan McLaughlin who's also at Washington.
State he was really one of the ones that pioneered these Vape Chambers 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 like work for this the same way. They will other reinforcing drugs. So it was a really important finding that you could do this and what Ryan found
He actually did one study where he gave them access to a low potency product will call it medium and then a high and what you ended up if you look at the data is the one the rats liked. The best was the medium potency product just and if you gave them the high potency product, they would actually take less Vape hits off of that then they would off the lower ones and again all their blood levels tend to Cluster in the same range because they titrated like even at the rodent level they're able to titrate because of the lag between inhalation.
And feeling the effects is only on the order of a couple of minutes people can titrate better. I mean not just people it seems like the rodents can as well. So the higher potency cannabis where it becomes a problem is if someone's highly experienced and they consume a whole bunch of it without allowing that time like 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 is Stephen at least some degree of Tolerance and 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 that's more where we need to focus a lot more is this idea of these high-potency products Yes. Sounds like those are precarious. Yeah that somebody who thinks they have a lot of experience or God forbid. No experience takes a concentrate and is what no longer getting the euphoric experience that they can.
So painted but instead are getting what a paranoid anxiety
attack. I think I think you're far more likely to go overboard and have an adverse response. But also, I think the problem is if you're using a product of that potency and that much THC floods your system on a regular basis the biological changes from that are going to be very different than what you get. If again, you're titrating your THC from inhaling plant at roughly the same level whether that's a ten percent 5 percent or 25 percent.
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 present in the 70s and 80s and presumably 90s as well. Yeah. I'm a 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 toks of the higher concentration stuff that
allow them to match blood levels that were present in the person taking many more toxic than the
70s. So the joke I always make to people as they say go watch a Cheech and Chong movie from the late 70's. Look at the size of the joints that they smoke and movies like that relative to what you would see someone on the street consuming nowadays. Like 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 you know take small amounts and not over-consume. Let's say because
Was a much lower concentration of THC in the plant so they are 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 teach see for various reasons, even one or two tokes could be too much for them because at the higher
Potency they 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 of say, oh, you know, I've tried to do stuff too strong and if there's someone who's kind of more in our age range who grew up in an earlier decade where things were a bit different they may be referencing their own experience from when they were younger and what they were able to consume and now they tried doing the same and it hits them like a sledgehammer got it. So it's a little different in that sense. But you know, and I don't think it's the say it's like
Not concerning that cannabis is as high as tht. Is 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 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 in humans and I think the the real world the college ecological studies that the Colorado group of down have been very informative in the
Sense, because yeah, if the if the blood levels of THC you achieve from concentrates or 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 ask Ali the way you would see with cocaine or alcohol where there's very profound tolerance that develops and so I mean
We'll definitely see this in cocaine where people can become tolerant almost immediately. And so dosing start scaling up very fast. They
usually it's the life destruction that the words there. Yeah Progressive increase
seriously, I mean the sure
call another form of life life life life deteriorate.
Yeah 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 Meg has said to me many times
You know the guys that come in her studies, these are very heavy users and then you know, they will use this relatively low potency product and still get high off of it. 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. Don't although people get their pets high and we don't
At those pets think about that not good don't get dogs out. If also High one can assume a lot of things about what your pet is thinking. Well also hi. So I've 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 neuromodulators such as an an amide dopamine Etc.
Yeah. So a typical pet study and a human looking at this they'd
give a molecule that's radio labeled that will bind to CB1 receptors. You can scan them and then look at the emission rates of the radiation to get an idea of the density of receptors that are in the brain chronic cannabis users tend to have less what that means in terms of
The functional outcome is unclear. I mean there could be some I think there's a there's a lot of evidence that there's some degree of a reservoir of CB1 receptors that you know, there might be a lot more receptors there than we necessarily always need or are always using let's say so we might be down regulating a component of this but maybe not all of the ones that are required to produce the psychoactive effects because there's clearly some maintenance of the system that allows someone to continue to get intoxicated and so with cannabis users we do see that but you do see much
More profound tolerance with people using High potency extracts and concentrates and things like this. And again surely I think as a response to the biology of hitting the system that heavily with that much, you know THC as it comes in because they can't titrate it the same way
and makes sense. Yeah, these concentrate sound like something to at least pay attention to as a potential problem. I'd like to take a quick break and acknowledge. Our sponsor inside tracker inside tracker is a personalized nutrition platform the analyzes.
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Dot-com huberman to get 10% off along the lines of use tolerance at cetera is cannabis addictive and or habit forming and I think it's probably important that we distinguish between the two. I may have made this joke in the previous episode on I did on cannabis. I've known a lot of chronic cannabis users and none of them admit to being addicted. It's not my place to challenge them on that.
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, you know that speaks to a dependence or something, but then we need to be careful because in the classic sense addiction, you know, I've defined and others in the field of addiction have defined it as a you know, Progressive narrowing of the things that bring you pleasure such that you know, it causes
Option to other areas of life your life becomes maladaptive. Yeah. I mean I'm not going to play with the definition of addiction. I feel like I have enough friends in the addiction space that it's a very contentious sure field. So, I mean, I will try and not use that word. Although I understand a talking to the general public that's kind of, you know, if you say someone has a use disorder versus an addiction that may not make sense to them. But that's the nomenclature now that people are using alcohol use disorder at Cannabis used to sort it is what you start to see now.
Kept saying being addicted to Potter being addicted to
alcohol. 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. So if we say is cannabis addictive and 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
Only 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 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.
Yes 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 used to developing use disorder. I would say are not entirely clear the kind of old numbers that used to get tossed around were like nine to eleven percent of people that would start initiating cannabis juice would probably transition to develop use disorder the more modern numbers. I would say, you know, if we're looking at people who are ready 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 high.
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% of a and that neighborhood they would probably qualify as meeting criteria for cannabis use disorder because weekly doesn't seem like that off to know. I mean, it's it depends again on how you vary this like and 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.
If with cannabis the way they would view it as very differently because I think a lot of people, you know, again regardless of anyone's opinion of alcohol. If someone told you they had a glass of wine with dinner every night. I don't think people would say you have an alcohol use disorder. I think that's not uncommon. I don't think they would similarly if someone had a Brandy at the end of the night or like, you know, a nightcap to go to bed and they did it 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.
Get that would use it, you know even daily but relatively infrequently and kind of as an end of the day thing. I think some of them certainly would fall under the criteria of cannabis use disorder because if you start looking and say well, you know, if you travel to like Egypt, are you going to go put yourself at risk of going to jail to get access to cannabis because you can't function without it. If you do then. Yeah, you 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 on time?
I'm 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
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 were 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 us, no legal access people still look at cannabis the same way they look,
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 ten years growing up was I mean, I think there are still people in jail now because of possession and sale of cannabis and then of course, there are stores not far from here where people are selling ironic. Yeah sadly. It's a very I mean obviously a big push for legalization is not endorse.
I meant of the safety of cannabis. It's more the harms associated with prohibition outweigh the harms associated with legalization. I think that's generally the public health perspective. That's certainly what motivated 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 data and see that arrest rates related to cannabis or obviously very low compared to what they were that obviously becomes very
Important because there are clearly minorities 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 potentiates all that so I can understand the legal framework behind why they 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 Harm's on a public health level. I mean alcohol stacks of the top it across the board in terms of harm to the individual harms to society. It's a lot cannabis has harms. There's no question on that. It just would fall lower than alcohol. But the way that people view it a lot of people are like alcohols legal therefore it's safe and it's not something to judge people on cannabis at least historically was illegal 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 is legal. That means it's safe
is the legalization of cannabis leading to more cannabis users or fewer and or incidents of people going to the emergency room suffering from Cannabis induced psychosis something that I hope we can also
talk about. Yeah.
Um, so it depends on how you break this down. So what we've seen in Canada is I'd say there's like demographic differences proportionately when we look at the biggest change in use. It's actually elderly communities. It's like 55 plus especially women over 55 tend to more cannabis more cannabis. Use now granted their Baseline was quite low pre legalization. So if you look at a fold change, it looks like a very dramatic increase raw numbers. It's probably not that
That high but I mean it was thick one to two percent or something before and now it's going to placate percent or something. So it's a four-fold increase kind of thing. So we do see the magnitude of that seems to be the biggest in terms of where the uses come from. Definitely the young adult population like 2024 that group has definitely seen increase use as
well. Does it split male-female
historically cannabis tended to be more male biased I would say the gender separation there has kind of narrowed quite a bit.
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 routes of administration vary a little bit based on who someone is but yeah interestingly. We don't have a lot of actual indication that teenagers have used more so like, you know, you look at 14 to 18 year olds that has been now granted our Baseline going in.
Is pretty high as is down here in the states. I mean Cannon the state's both hover. You look like grade 12 hours and you know, it's somewhere between 35 and 40 percent of them have used cannabis now, I mean you even have some that are like probably around five percent are probably almost daily users. So like you do have a pretty high Baseline to begin with in that group, but that has remained relatively unchanged if anything some of the states when they legalized saw a slight dips in in teenage use of cannabis. So I think like that's obviously an important demographic
Tracked this was one of the concerns with legalization was you'd prove, you know increase access teenagers would get it from their parents and whatnot or had just you know, other siblings and stuff. And so you 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 a an interesting role out 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 would you know a lot of these look like gummies and candies people are buying them not you know storing them properly kids would find them and eat them and like become very
intoxicated. I want to make mention of something almost lines actually know somebody who's child.
Accidentally athe 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, right? So this is something to like really keep in mind. There are a million other health related reasons why this is probably I don't know if that's true in Canada the same way but I understand. Yeah, like if your kid gets into a stash.
Of THC containing gummies and ends up in the emergency room. There will also be most likely they'll be police visit to that emergency room also and it doesn't bode well for the parents so this it's a it's a very serious issue. Yeah. 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 THC and they end up in the emergency room serious issues nonetheless if your kid is acting strange because you think they ingested THC containing anything take them to the emergency room. Anyway, well, so this was
The things that also in was influenced by legalization is in Canada, like some of the increase in the ER visits was because of the shift and legalization and the change in policy. And so, you know, if your kid ends up drunk underage, it's not the same ramifications as if your kid used an illegal substance under age. And so people are when someone's cannabis was legal people were more likely to actually go into the ER because the consequences were different I see
See and so sure some of this is availability and some of it is just like okay. I'm not as concerned now about something happening because I've taken my kid in like I'm not gonna have my kid taken away from me or what not. So so there is I mean both those factors I think have contributed to it, but we definitely see the majority at least the kids ending up in the air 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 inhalants versus excuse me versus Edibles meaning earlier. You said that even if it's high THC containing cannabis people will self-regulate to achieve the same approximately the same blood concentrations, but with Edibles, I imagine you eat half a cookie a quarter of a cookie and you can end up in a vastly different place than you expected.
So Edibles are 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 there's a lot of might be changing at least when they first brought it in. No Pat could have more than 10 milligrams of THC in it. So that other men 110 Meg gummy or 25 May gummies or 42.5 made gummies you get it so you couldn't in one package have more than 10 milligrams of THC.
For people who are I would say relatively naive to cannabis or THC even people who might use it in our mentally most people will feel 5 mg. Like they'll feel some form of intoxication, you know, some will even feel it at 2.5 makes most people will feel at five virtues a everyone will feel it at 10. Now. If you look at the blood levels these produce we're now talking blood levels of two to five nanograms per mil so Folds
lower than what you get from inhalation for you said 100. Yeah. So this is dramatically lower. And so also the time course of this is fundamentally different so and 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.
Gummy, they wait half an hour. Like I'm not feeling anything I clearly didn't take enough and then they'll double their dose and I'm like 15 minutes later. It starts hitting them and then like once it's fully kicks in. It's just like a steamroller like I've heard of this app. Yeah. I mean there was that New York, I think was Maureen Dowd or someone went down to Colorado and she ate like an insane amount of THC and a chocolate bar some like 50 or 100 mg and spent like the weekend on the floor of a hotel room being like this was the most diverse of 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 unlike we with alcohol with where we say one beer is 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 know, he's a 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 ball game than it is with inhalation. But what
Happens with oral consumption is like it kind of very slowly leaks out of the GI tract and it also goes through first-pass metabolism in the liver. And what happens there is you get a metabolite called 11 hydroxy THC, which seems to be a bit more potent than THC is in terms of its ability to activate the receptor so and its efficacy at least at driving a response through CB1 receptors seems to be higher than what you would get with just the parent molecule of THC itself and
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 last 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.
Blood goes into the brain but it also clears out and so yeah, people will start feeling intoxicated to 25 minutes. They 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. Yeah previously was there a number of people who have used cannabis are going to take a drug test and want to know how fast it can clear from their system but based on conversations, we had offline sounds like that 80 Days might be a bit too
long. I mean, you could still fail a drug test that 80s I would say, I feel like I think the way it was worded morose like that you made
It seemed like that was the standard. I wouldn't say that was the standard at all. I would say for the majority of people 30 days. Probably after that. They would not pass or they would be able to pass a drug test but do 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 molecules. That's all. Yeah, so it's fat soluble.
It likes the store it so 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 tht concentrations in the blood would reduce th see it's in the fat will start kind of leaking back into the blood still. So Detective Lee you will still have th see for quite some time. I mean some of this again it's going to depend on how much cannabis someone's used how much THC.
You have 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, you know certain things like exercise for example anything that's going to trigger adrenaline because adrenaline is lipolytic. So the 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 where
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 lipolysis to occur. So that it releases that THC. You can certainly all of a sudden test positive again when someone had tested negative previously just because of the fact that there still is some in The Fad 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 happen
In Canada, all these kind of chemists were like talking to me about they're going to create like a breathalyzer for cannabis because this way they'll be able to do roadside detection the same way they could do with alcohol 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 mL of THC in their
blood but you're trying about this metabolite that can come from the Edibles that doesn't come from inhalants that can have a much
more potent Femme inhalant but not nearly as much as you get from edibles,
but the different it's sort of a different situation
altogether it is but it's also the timeline because of the fact that with inhalation. It's like a bolus that 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 milliliter.
Say but it would be like that for a long time. Whereas the 100 nanograms per mil from smoking is like for 20 minutes and then it starts dropping. So but the problem is with the way that you detect it is you can take someone who's a chronic cannabis user and is completely sober and hasn't consumed in a day or two and their basal levels of THC in their blood may be higher than someone who's profoundly Intoxicated by an edible just by the sheer nature of the fact that it would reside in their fat tissue or their brain. It would leak back into the blood and so
You have this issue where you let's say your cutoff was five nanograms per mile, which is for some of the stuff detection thresholds would hover around that area. So you can have someone who's dead sober that test positive and someone who's profoundly intoxicated who test 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 and the
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 tensional. 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 say increases in estrogen from cannabis use and they argue for increased aromatization of testosterone into estrogen as the mechanism. I've also seen studies that say the exact opposite. Yeah. 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 I would say it's yeah, it's there's nothing that's super clean cut. I mean I know in the previous.
Podcast you talk about a prolactin thing. Right? 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 gynecomastia male breast development. Yeah. We'll smoke marijuana. Do we call it marijuana these days?
Go go with cannabis. I got I actually got an I got someone I got a lot of comments is that marijuana is inappropriate term. Okay, smoke will go back to that high. That was new to me. I didn't know so forgive me if I don't
understand it. But yeah, a lot of people
don't okay, so we'll smoke cannabis and experience gynecomastia or in females. So males and females both have breast tissue, but in males is typically it's not hypertrophied, but they'll smoke cannabis and get a gynecomastia growth of the male breast tissue.
That's sometimes reversible. Sometimes not presumably through the aromatization of testosterone into estrogen which then acts on the tissue makes it grow as well as reports of breast tissue tenderness after cannabis use in in females. So that was sort of the origin of that discussion around does cannabis impact aromatization of testosterone into estrogen and you can find a little bit of evidence for that. But you can also find evidence to the contrary in the scientific literature. I'm just curious your thoughts supermax. I mean you talk about something like
Lachlan for example that is another one that's obviously involved in this whole Cascade stuff. Generally, I would say the bulk of the literature actually says that cannabis would suppress prolactin not increase it. That's the
majority of the literature's of dopamine is one of the main ways that prolactin is suppressed and kind of a seesaw. Yeah, they work in somewhat seesaw fashion,
and I'm probably I mean the rodent worked with suggest it's through dopamine that's turning off prolactin because you can reverse some of these Effects by playing with immune signaling so I don't doubt that the
ISM but so typically, I would say more often. I mean the studies with Innovation 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 that came out of jail testosterone gets a little bit more complicated because there are a lot of studies that find a to begin with cannabis users may have higher levels of testosterone just at rest now whether that's a pre-existing
Reason to think that would be the
case. I don't know. Yeah, I mean that being said a lot of the stuff now granted this was mostly done in the 70s and like this is from my previous life because my undergrad and graduate supervisor. He was a neuroendocrinologist focus 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 see really look at testosterone after someone consumed. They would have little dips. Like that wasn't uncommon for them to find it not every study found it that being said that kind of range. The testosterone stayed in was always the normative range like it was never that it went. So low that someone would have classified as being hypo gonadal or would lead to something like gynecomastia at least from a testosterone deficiency side in terms of the balance between testosterone and estradiol.
I don't know as much about the aromatization side of it again. I'd say it's pretty mixed. I mean, I don't think the gynecomastia stuff is I mean certainly people online might be talking about it and there might be some other components this I've also heard and again this isn't like science. This is just the same kind of stuff you see on random internet communities people talking about. Oh, well, you know, it has plant estrogen. So maybe there's subbing in and having extra genic effects. I don't know how valid any of this is. Yeah seems a bit on I mean, they're phytoestrogens and tons of different plants.
Sort of a tax on soy and the attacks on this I think grew out of the kind of the soy versus meet communities and plant based versus carnivore. This podcast is always been agnostic with respect to nutrition and is really if we encourage anything it's that people consume unprocessed and minimally processed foods as the bulk of their food intake there seems to be enough data on that but whether or not people choose to be vegan and a lot of plants or carnivore and just meet, you know, we've essentially stepped out of that too.
Bait 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. 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 wouldn't say that it's a typical side effect that men would experience is like developing breast tissue in response to campus. I feel like if that was the case it would be very known in the scientific Community is something that comes out. So this seems to be something that
Purportedly occurs on a backdrop of elevated androgens meaning in puberty or a backdrop of some other form of Androgen increment but that's not the community. I'm referring to it seems that because transient gynecomastia during puberty is actually fairly common because of there's just so much and regime being produced in puberty that some gets aromatized and that the idea I'm not saying stating this is fact is that it may exacerbate that and
any case it sounds like the takeaway from this is that there aren't a lot of conclusive studies about the effects of cannabis on testosterone or estrogen or aromatization in any direction. I don't I mean I'd say like yeah this enough studies to suggest that you might see transient drops and testosterone from Cannabis and it seems to be relatively short-lived. It doesn't seem too. 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.
Missed out of just like just like the it can happen.
Yeah, so and that's the thing. I mean testosterone fluctuates across the day anyway, so there's all right. I mean there's other things that fluctuate it's like cortisol. These hormones have Cycles. So as long as you're in this normal range there really shouldn't be any kind of like behavioral like in terms of sex drive for testosterone or like physiological like gynecomastia or some change in I mean now there are potentially effects of THC directly on the testes that could affect sperm that could happen.
Independent of changes in testosterone are those positive or negative changes. I'm assuming that they the studies you're referring to saw disrupted what they call sperm quality which has to do with motility Etc. 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 to myself because anytime this conversation comes up about a substance and
Sperm quality or egg quality. I always get a barrage of comments of people telling me how many children they conceived while Under the Influence. No one is saying that you're going to be infertile. But 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 it by than others. So for some, you know, various biological reasons that we don't
have a biomarker for there may be some men that use cannabis and it has a profound effect on their sperm quality of their sperm capacitance their ability to maintain fertility and for the bulk majority of men as 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 and I I'm not sure I still believe it, but you tell me what you know about this.
Which is that up to 15 percent of pregnant women in the US have used cannabis during pregnancy that just seems it that number just seems too high and yet you know it exists out
there. It's very I mean, I've heard hire them in the research literature. I've heard higher numbers because I'm on the low end of no, I mean so I've heard as low as 2 and I've heard as high as 20 okay to
sounds like okay, I that that I could imagine but as high as 20 and do we know what
What the effects on the developing fetus are there's a lot to unpack 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 are varied so some of the higher numbers actually come from blood levels where they've taken blood samples and found THC but the women have reported not using cannabis. And so there the idea that it's like the self-report numbers tend to come in around two or three. My guess is the real number is probably somewhere around
Ten percent 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 while 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 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 nauseam 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-nausea drugs that had profound try to genic effects on the fetus has women have said that they would rather use cannabis then one of these other compounds because they're less concerned about the impacts of cannabis and they are because of the, you know, the thalidomide effects that happened and Delinda my
defects are malformation of the limbs and and other bodily structures in fetuses. It was an absolute tragedy of medicine that this occurred in even even one birth, but
Yeah, that's the reason why I told him I'd is now I believe band as a drug for use during pregnancy. 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 reticence of a lot of people to consider using Pharmaceuticals to regulate nausea because they're uncertain of the consequences of it and they feel that cannabis may be safer now that in and of itself could present some problems in terms.
of that thought process now there was also a study that I thought was like
Some of these things just frustrate you it's where they actually decided to call this was done in Colorado with a called dispensaries and just acted naive and asked what their recommendations were. It was something like 80 to 85 percent of them were actually recommending that people would use cannabis to manage morning sickness. And I thought that was like, it's just one of these disappointing things where you're like, why are you being so wildly irresponsible to kind of promote these things and this is you're talking about
that it responsible that the dispensaries would say that we're irresponsible that the
body 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? But yeah my tenders that's kind of like the colloquial term that people will use for someone who sells cannabis at a dispensary. We Citizen Canada and I've heard this throughout the states as well. I personally have been a huge advocate for the fact that I think so, 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 and Canada you have to do like a like a weekend course, essentially.
Like serving it right or some other terminology. We learn the basics of alcohol harms blah blah blah how to tell if someone is intoxicated when you have to cut them off all these things that you have to do to be able to serve alcohol. I have no idea if this exists in the States, but it was a thing in Canada
bartenders in the US put in the comments on YouTube. Do you have to undergo training about alcohol your bartender? 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
If I think of a misguided thought that people would leverage their Physicians for knowledge about cannabis and was become very apparent is that the overwhelming majority of people talk to the people selling them in 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.
Noise the CCAC 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 or 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.
Nation 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 trainees you're certainly doing your part to provide the public education about cannabis now, so we all appreciate your highly informed and 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
Early on the teeter-totter 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 of today and you know mid to late June 2020 for we'll see what happens. But this is also the case for ketamine which is as legal status, but many people are accessing ketamine not through a physician but through online sources. So what you're speaking to here is a much larger issue, and I absolutely
Absolutely agree with you. I mean, I think most people are probably not aware except by experience positive or negative in some cases about the differences in blood concentration as it relates to number of tokes versus concentration versus edible. 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 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
Basics about how to you know, have conversations and I mean some of the our system at least this somewhat provincially regulated so like, you know, our organization has worked with like the Ontario group that deals with cannabis distribution the interior 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 with some like Edibles how long you should wait just stuff like this. I can
it's 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 weight because otherwise you're going to get the was the reporter. I think it was Maureen Dowd, but I right you're going to I don't know. I actually when I say that only still on
the floor in a Colorado hotel that she may have recording from the floor in Colorado, but like
If 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 Centre for addiction and mental health in Canada, which does a lot of the organization of these things. They did kind of put together what I found to be really useful which again could be leveraged in the states. These are all accessible online. It's called the lower risk cannabis use guidelines. They kind of tried to create a framework that is similar.
How people have done stuff with alcohol that just kind of goes through in 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 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 it can people self-regulate their THC concentration in the blood by vaping as well as
Can buy joint or bong or other form of smoking penned on
exactly what you're vaping so and the state's I've noticed when people say vaping they almost exclusively refer to some kind of oil based product that's in a pain. So in those situations that's going to really heavily depend on what the concentration of THC in that product is now the other form of vaping that I think is a little bit more common in Canada maybe is vaping of the plant matter itself. And so this is where they have like a vaporizer device that heats the Cannabis to a point that
will essentially hit the lift point to vaporize th see in the
cannabinoids big
bag. Yeah. 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 byproducts. 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 is like a medical device pre legalization 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 know 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 we're talking about oil based Vapor Products or whatever. They're in they're using some kind of oil based solution.
Who knows? I mean, we don't have the research on this like we just don't know. I mean we certainly know like there have been some pretty big errors of like the things that happened the states that there was that problem where all those people developed kind of I don't know popcorn lung or that lung inflammation where several people died from bathing products, which seemed to be like a byproduct. I believe of them adding like vitamin E acetate or something into the because again, everyone just assumes it's inert, 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 one. 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
And Netherlands is a little bit of a different situation. They're not legal their 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 got people flying out of country do some cell injections. People are getting them down in Florida who went blind from the injections of stem cells into the eye in an attempt to save what little vision they already had probably don't want to get me started on that one. I'm in total agreement with you. By the way. I want to make sure that I asked about psychosis and paranoia. Yeah.
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 the subjective experience. I think that's a terrible idea. Terrible idea Apple 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. Yeah. Well usually
the advice of people in terms of that was recreational drug taking is is rarely excellent advice. Yeah, you know,
that's so I didn't meet any 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 am 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
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 TH see 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 diseases like schizophrenia. So the first arm of that is just can people acutely have a psychotic episode to th see your cannabis and answer that is yes. It's not common. I would say in terms of adverse events that happened was people consuming cannabis. It's on the rarer side, but it definitely can happen. So less than 5% of people that are much less than that. I mean it certainly I mean it's if something like this was happening at a regular frequency it would
Very
well-known. What about anxiety attack?
Yeah. Anxiety attack is I'd say more of a standard indication that someone has kind of gone overboard. Like
that's not Gossage 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 and really potentiated the stress of what they were undergoing and had they been given that same dose in a different setting. I'm not sure it would have evoked that kind of response. But there is definitely a dose effect to this in terms of like, you know, the kind of classic low-dose aspects of like of THC or cannabis like that are usually considered more the positive pleasurable response.
Is that are why people use like it reduces anxiety it relaxes blah blah blah that is more of like a low to normal-ish dose. Let's say of what someone consumes to produce those responses if they start going upwards though. It's not like it's graded. It's like a full flip like it's not linear at all. It's almost like it goes in the opposite direction. So, you know, someone can use cannabis to reduce anxiety, but then cannabis can also trigger anxiety in other people and even in the same person if they consume too much and a lot of this at least we
I think has to do with the ability of it to regulate both excitatory neurotransmission and inhibitory. And so for reasons that we don't totally understand. There's like way more cannabinoid receptors on inhibitory neurons and there is an excitatory neurons, but in the early days of creating the genetic lines Giovani Marciano and be at Lutz or over in Europe created like deletion of CB1 only from excitatory neurons or only from inhibitory neurons.
Okay, so to just clarify for people these are Laboratory.
Mice that are genetically modified so that they contain or lack specific receptors on particular neuron 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 ingest the drug or when the mouse is given the drug it affects any site in the brain potentially any side in the brain where the CB1 expresar receptors. It's like a full-body deletion of CB1 and you give a mouse THC doesn't respond to it at all not surprisingly. That's a comforting experiment you want to see that result exactly. So that's how we know CB1 drives all the kind of psychoactive effects of THC. So if you delete CB1 off of inhibitory Gaba neurons, even though that removes like 70% of
The Nur of the CB1 receptors in the brain those animals look just like wild-type. They still get like they still exhibit all the classic signs of intoxication in terms of how they would respond to like pain sensitivity or Locomotion or these other like assays we use in mice to tell if they're high if you delete it the CB1 only off of excitatory neurons the glutamate neurons, then you see what looks like the full knockout. So now the animals don't seem to get high. So even though the majority of CB1 receptors seem to
Beyond these inhibitory Gaba neurons. It's the CB1 on the glutamatergic excitatory neurons that mediate most of the classic signs of what we would consider intoxication from THC or cannabis, but what's interesting is be outworked with the Spanish group 10 12 years ago, then they showed their looking anxiety that if you delete CB1 only off of excitatory neurons, you lose the anti anxiety anxiety lytic effects of THC, but you still have the, you know panicky Aang's eugenic
Backs of high-dose if you delete CB1 off of only the inhibitory Gaba neurons, you still have the low-dose anti-anxiety effect, but now you don't have the high dose Ang's eugenic panicky effect. So what that was suggesting was that for some reason CB W like THC will initially hit CB1 on kind of glutamatergic neurons. And essentially the thought is this will reduce excitatory transmission and probably quiet down circuits, and if we're talking about some of the amazing,
Angela this is probably how it's reducing anxiety. Whereas as dosing starts to increase and you start to saturate the CB1 on the Gaba neurons and turn off inhibition. Then the network effect is more of an amplification and that seems to result in the development of kind of an anxiety genic Pro anxiety response. That's obviously undesirable why there's this differential shift that it's not exactly clear. I mean, it's probably either due to some of the like biology of exactly where the CB1 receptor sit.
Excitatory or inhibitory neurons relative to all the Machinery that regulates transmitter release. I mean be at Lutz has definitely done some stuff looking at the ability of cannabinoid receptors to evoke signaling responses in a cell and on glutamate neurons. They're much more sensitive than they are in Gabon around 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
one consumes too much and they have a negative response. That's probably due to the higher dose starting to saturate on the inhibitory neurons. Now, we obviously can't ever test something like that in humans because we can't know but based on what we've seen in animals, that's my theory of kind of how this is working and why we see these kind of classic biphasic effects. Oh, yeah too much THC not a good thing because then you start maybe disinhibited things like the amygdala and producing these kind of panicky Aang's eugenic like outcomes on that scale though I mean paranoia
That's a hard. I don't know how you study that in a rodent. I mean that's just a strange thing. So but I mean that's kind of the precedent of when you start going into the psychosis because obviously paranoia would be a big component of that. Someone wants to ask me a question about I do, 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? It does like probably on accident because somebody takes cannabis is in the scanner and then
Howard's having a psychotic episode but chances are they're going to try and get out for those that don't know these I don't want to scare people out of doing MRI or fmri, but you know, you're typically told to stay extremely still there. Sometimes even a b bar, you know, like this is a very controlled environment not not an environment that you would want to be in during a psychotic episode. 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 gonna 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 it's happened and someone has actually done something wildly unpredictable because they've had a psychotic response to cannabis. It tends to make headlines. So it's not it's not common. I I could not give you an actual number but it's certainly not a frequent thing because we would hear about this a lot more if we did and there's also the issue of poly pharmacology, which is simply when people take one drug then there's often the tendency to take another drug either because it's available.
Table in those conditions or because their threshold to saying yes is a little bit lower do most people who take cannabis and achieve the high have a tendency to do other drugs. It doesn't seem like a drug that people combined with a lot of other drugs. I wouldn't say parts. 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.
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 mm, you know, someone mixed it with amphetamine or something. You could have a very unpredictable responsible. But I mean, I think the psychotic responses that have been documented that are usually purely due to cannabis like 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 and I think it's an important thing to discuss in the context of science because
You can't establish causality like in my view. It's virtually impossible because there's just no way to control all the variables that play into this what we can say definitively is individuals who have schizophrenia. First of all, they use cannabis at a higher rate than the general population. That's very clear. Yeah. They definitely use cannabis at a higher rate than the general population. There is definitely a relationship between using cannabis and
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 use cannabis as a teenager use high potency is 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 and schizophrenia happens at a higher.
Charade 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, is 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 maybe
Out there in the media of the popular like just in general that people talk about I can't think of any study that I've ever read that explicitly said this was, you know, my 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 episode. So if there's an individual who has schizophrenia we know for certain that cannabis.
This 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 and 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 proportion of people who have schizophrenia to only having that schizophrenia because of the fact that they used cannabis and I think you'd had some discussion about this in the last podcast. I can't remember exactly the way that you described it. Yeah. I was looking toward some of the recent studies and
Lancet Jama Psychiatry believe I we can provide links to these as again and now more recently there's been a lot of let's just call Mainstream media coverage of this potential. Yeah, I think is the right way to refer to a potential linkage between adolescent teen and young adult use of high THC cannabis and Lasting psychosis. But the more I hear you talk about this the more I'm wondering if that ideas.
Being Amplified more than perhaps we ought to let it be Amplified.
I mean, I think this is what happens when you have I mean, obviously you're familiar with this in science. There's different. 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 is
read the literature that this relationship between Cannabis used especially in adolescence in 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 or some biological predisposition, that's there.
I would say in that situation cannabis can trigger an initial onset of the first episode and it can make the prognosis of the disease in the long term a lot worse.
Let's say as I recall and I may have this incorrectly but as I recall from my undergraduate years what you just said is also true for military service for people that have a predisposition to develop schizophrenia that active military duty can exacerbate it.
That's what 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 and I mean some of its 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 some of 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 in 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 his 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 I 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 Dead. Yeah. So now granted we don't
have like really good prevalence data of what schizophrenia was in the era prior. No, I mean even nowadays are prevalent status. Not perfect. But if cannabis is a solitary variable was driving the Genesis of schizophrenia de novo in the absence of any kind of biological predisposition or genetic predisposition. I find it very hard to believe that we wouldn't have seen a shift in the prevalence of the disease as cannabis became more mainstream and more widely used and generally schizophrenia rates have remained largely.
Mole people can make arguments about that better care other things that to challenge that argument sure. So another modern perspective would be. Okay. Well, let's look at Canada and the states. Let's say where we have as I said earlier teenagers in Canada states by grade 12, 35 to 40 percent of teenagers have at least used canvas somewhat sporadically and somewhere around five percent wish are probably using almost daily. So we have concentrated group of what would be the high risk population here that are using at a pretty high rate and then
Compare that to somewhere like let's say Norway or Sweden or any of the Scandinavian countries where cannabis is like not a thing certainly not at a recreational level. I'm not teenagers and I mean the rate use rates. There are probably under 5% globally for teenagers like probably closer to two or three percent. So you have two countries that have pretty similar social structures and other capacities of things. We're both Western countries and yet our schizophrenia rates prevalence wise are relatively comparable and yet in Canada in the state,
Our cannabis use rates in adolescence are wildly Amplified compared to those countries. So again, if this was causing schizophrenia to develop as a disease out of nowhere, how would that not track? Like, how would that not be seen when you just look at individual variances across countries and prevalence
rates. Yeah. I hear your point loud and clear I seem to recall that there is a higher incidence of schizophrenia independent of cannabis use closer to the poles you
no and less so at the equator, I don't know if those statistics still hold up, but I have no idea. Okay interesting for us to look into 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 that you can
certainly 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
I mean, I think it's just part of the culture here. It's just evolved totally differently. I
meaningful dead. No, I'm just I'm not picking on the great but I like the Grateful Dead Rick Rubin convince 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 I've done my duty to listen, is there some great songs, 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 if it's not abnormal for kids were teenagers to drink alcohol is just much more of a cultural thing as
Well, and there are just differences. I mean, it's the same thing you look at like the opioid crisis that we're going through its sure it's there to some degree in Europe and it's nothing like it is in North America. We are just a different Beast for a lot of drug use.
Do you see differences between United States and Canada with respect to either cannabis or opioid use?
I don't think dramatically I think we're pretty comparable for money for cannabis rates. I would say they're almost the same. Like I've not seen sure you might get some Regional differences like we I think Quebec has much lower rates of cannabis use than some other parts of Canada.
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 u.s. Is a lot warmer than Canada and you guys are certainly closer to the Equator than we are. So I mean we know like you do see higher rates of schizophrenia in urban settings than you do in rural settings. And so let me stress are given this
ERM you also have more like this 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 is a lot more Mental Health Services is other variables that can influence that I'm no one's really I think sussed 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 of off the top of my head that I could put the citations down for for sure after this that do look at this from an somewhat. Let's say unbiased perspective, but 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
Otter and there's clearly some genetic architecture that relates to risk for schizophrenia and what these Studies have found kind of across the three of them was quite similar, which was from their analysis the 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
Biological vulnerability to develop schizophrenia and some factor that relates to people using and or liking and or excessively using cannabis.
I've spoken to many psychiatrists in an effort to find someone expert in ADHD. We've done two episodes on ADHD focusing on everything from behavioral to nutritional but also prescription drug treatment for ADHD. And what's interesting is that all of them have relayed the fact that many people not just young people.
People but adults with ADHD will often use not necessarily abuse, but will use stimulants like coffee and other forms of stimulants to a high degree. And then of course you can say well perhaps the stimulants are causing ADHD, but they actually argue for the opposite which is that people are attempting to self-medicate and then it's perhaps no surprise that most not all but most of the medications that are approved for the treatment of ADHD are variants of amphetamine or similar, so it's another
It's 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 I think you so I mean 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, the this idea of self-medication, I mean independent of their
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 there are some studies that suggest this and others that don't support it anecdotally from having done work in the community and talk to individuals who have schizophrenia who use cannabis what their perspective it on it is what I've heard from a few of them is, you know, the medications that they're provided to manage the disease are relatively
Effective at managing. Let's say the positive symptoms like hallucinations delusions that aspect of the disease is somewhat well-managed, but then there's another component which is the negative symptoms which is kind of like things that they do abolitions. I don't like engaging and stuff. There's some anxiety some depression some social withdrawal and a lot of the medications don't manage that component of the disease and they have said that they find Cannabis helps that side of it or it helps them D arouse a little bit even though a lot of them recognize it may
A 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 the saying cannabis causes schizophrenia and therefore if we
Educated it. I think you had alluded to something like that in the last podcast. 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 of made and I'm not personally convinced of that and I say that simply because I look at the data from Scandinavia and I'm like, well there you have a population that barely uses any cannabis and yet their schizophrenia rates are the same. So the only way in my mind if I look at this kind of scientifically from a data perspective that cannabis could be causing schizophrenia de novo in
in a subset of people is that there must be an equal proportion of people for whom for some reason in somehow cannabis is preventing them from developing schizophrenia so that it's a zero sum game at the end of the day and there's no change in rates. Like I can't actually understand any other model that could explain this. Yeah. No, I the way you your explain it now makes perfect sense. I do want to make sure that we distinguish between schizophrenia like psychosis or schizophrenia at self induced by cannabis. Yeah and manic
Polar episode so people who have a predisposition or full-blown manic bipolar sometimes called manic depression, but that's you know, there's still a lot of nuance there. We did an episode about this that people can also find links in the show notes captions. But in any case, is there any evidence for the fact that people who suffer from or have a predisposition to manic bipolar conditions like bipolar depression for instance should avoid high THC cannabis?
So well, first of all, I mean for in like heritability family trees, for example, where you look at something like bipolar schizophrenia the to do kind of track together sure, so it's not I mean, I think it's hard to separate these in some capacity because you know, I remember years ago at Society for Neuroscience Glenn Close was one of the I don't know if you were at that meeting big lanky actress one of yeah, she was one of the public speakers and she had talked about schizophrenia and her family tree and she kind of put up this family tree of like, you know her family.
The the one the previous relatives in our 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 and the way that these track at a her edibility level and so I don't know that area really well enough to be able to comment on and I'm from the Cannabis perspective bipolar is definitely much less study study and focused on than schizophrenia is but I think also to the comment about the high THC thing, I think this is the
the other part of the argument that's emerged out of this and this is the other part where I see a lot of the causality arguments kind of crumble onto themselves to some degree and it's been others who have made these very similar arguments to what I'm making here, which is the push that came out of this out of the UK at least was much more that it's this High potency kind of skunk cannabis. They referred to which first of all was based on a smell which they didn't really hadn't done a lot of analytics on so it was people make the Assumption of it smells stronger. It's more potent cannabis. That's not really true.
Is th she doesn't dictate the odor. That's so say more of a terpene thing. But certainly I'm sure some of the skunk cannabis they referring to his high potency cannabis. And so the analysis on this if you actually go back to those papers and read as they often use like hash or low potency cannabis has their control where they show no association with cannabis. And so that's what's used this argument that it's the high potency cannabis that has driven this. So now the problem with this argument in my view again, I look for what is the
Answer that fits in with the data. Like what's the most parsimonious explanation here that everything can be explained by and so the problem with that argument is if you look at the Cannabis schizophrenia literature, everything goes back to this 1 1987 Lancet paper of Sweden. We're in that paper. They essentially looked at they have really detailed life records and health records in this was Swedish conscripts and they essentially found that if someone had used cannabis the rate the risk of developing schizophrenia had gone up and up and so this was based.
On a cohort of people when it was published in 87 that the data would have been collected through like the 60s 70s early 80s. So we're talking about Sweden and cannabis. It's not a country that is high cannabis use rates and an arrow in cannabis was hovering in a two to five percent THC range. That was the initial finding that provided this association between it and yet the Cannabis in that study that they would have been referring to would have been incredibly low potency compared to what has happened or like what it is today. So if the argument
Is that it's only related to high potency? How would that initial finding have ever been found because it doesn't make any sense. Whereas the alternate explanation that others have put forward which I agree with in is far more sound is that there is some biological reason why individuals were either prone to develop or who have schizophrenia like cannabis and they will tend to seek out the highest potency product. They can get access to so in the 70s in Sweden, that would have been to 25 percent THC.
Of
us 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 there's no question. There's a lot of nicotine consumption. I mean individuals with schizophrenia use they smoke a lot of cigarettes. I mean, that's also that's well as much.
Higher than the general population rate,
which is known as stimulate dopaminergic and 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 individuals 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 there 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 nowadays because of the non-smoking delivery routes that are becoming really popular pouches and things that in fact I
I was chewing a little bit of Nicorette gum to kind of do an experiment. I liked it a lot and then I decided to stop completely recently because it just 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 is a whole other sharing which I have. Yeah, I'll have you back to talk about - I would definitely do not know enough about that to have any kind of informed consent conversation. But so I don't know I would say it to me at the end of the day if I put all the
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 develop schizophrenia also seem to be prone to use cannabis and use it at possibly at excessive levels or possibly 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 were so if you were a psychiatrist in a clinic and you consistently see patients presenting saying I didn't have psychosis I use cannabis now, I have psychosis and it converts into schizophrenia. I can understand why the association would be made regularly that there's kind of a domino effect here and causality becomes attributed, but I think when we take a step back
And look at the larger data in its kind of entirety to me. It's a very tricky argument to make because there's a lot of things that you just can't explain from that perspective. And this is also one of the things that I find absolutely bizarre about cannabis in general is it's a wildly polarizing topic of conversation and people have incredibly deep rooted opinions on both sides of the spectrum. And for some reason if I don't say cannabis is the devil and causes
this disease that means I'm an advocate and then on the other side of the coin if I don't say cannabis cures everything I'm a prohibitionist. So like I'm in this fun position where I get hate mail from both sides and everyone just generally depending on their perspective thinks that I have a bias kind of going in one way or the other and I'm very, you know want it this way. I 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 I can with that and to me that's the perspective I've maintained and I do think that like these aren't trivial questions.
Because when we went through the legalization process in Canada, this was something that came up again and again and again was this association with schizophrenia and in the UK, this is something that comes up again and again and again because whenever there's any discussion about the UK moving forward to legalization these ideas come back and so the public health kind of consequence of this is not intangible. And so for people to be making these very strong causality arguments and having this kind of opinion.
That a lot of people just take up I think can have a lot of influence. And so that's why I like there's literally no reason I should have a dog in this fight. I don't study schizophrenia in any capacity and it's not my area of research. But because I 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 someone uses it because it's going to cause them to become schizophrenic. I'm 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. I'm clearly people are curious about it. And so I just want to say thank you for clarifying. What is
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 predisposition to schizophrenia are seeking out cannabis use and engaging in cannabis use and I think that's a very important principle for our listeners and viewers to just hear and understand any time. We're talking about a substance and a condition. Yeah, and I mean, I think again this is again, no endorsement that that doesn't mean that it's safe and
That'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 will 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 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 as as you know, people are reporting their use we assume honestly, but you always have to assume that there some I guess people could be lying about what strains or misinformed but and then using machine learning to couple their subjective experiences as they report them to Indica versus Sativa strains and then by looking at the chemical composition of those different products because these were products that they had
Trying to tack chemical composition to strain in this case that mainly the Indica sativa discrepancy to subjective experience. And I know that you and presumably others in the field of cannabis research take real issue to that sort of approach and perhaps I have the feeling this is what you're 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 sativas vs. 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 an
you'll 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.
A names at least from everything I've understood from everyone that I talk 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 Nokomis is done like a lot of analysis of like thousands and thousands of different kinds of Candace but cannabis have been submitted for kind of biochemical.
cysts understand THC CBD terpenes minor cannabinoid content and essentially his work as well as from all the people that have done the genetics on this is
the variability that exists within what someone calls an indica or 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 is a chemical profile that relates to the most common indicas or most common sativas. I mean, I think in Nick's analysis there was like a couple of terpenes that may have loaded on a little bit on the things that were.
Divas 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
Ducks 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 purchased something that they think is going to make them calm and it makes them feel calm 20 people tell you that taking this makes you calm you cannot remove your expectation bias from the fact that when you consume it you feel calm like and this has been I think one of the most common things with with cannabis is like this whole area is so ripe with these expectancy biases.
People have about what they assume if you go someone goes into you know, an a budtender tells them. This is a sativa. It's going to energize you. There's no way to remove that expectancy bias from from what you get and I mean like I'm talking to a lot of people that kind of study this more explicitly. They always say the biggest predictor of what someone feels when they consume cannabis is what they're told on the label it's going to do to them. I mean
and a lot of pretty wild the speaks to you know, I did an 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 placebo effect of nicotine on cognition don't see response. If you're told you got a high dose when you actually got a low dose you will exhibit the high dose neurocognitive enhancement effect and by brain Imaging it shows a high dose like enhancement of the relevant brain areas. In other words, the expectancy drives changes in brain activities 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 this is as far as I know. I don't believe this actually ever been a clinical trial that is blinded people and given them sativas and 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're referring to where
It was users who had got the product. They can't remove their own inherent biases from their own experience. It's going to 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 vodka, you know is mellow and white Tequila's feel different than then the other Tequilas and you know for people listening to this thing. Okay? Well that's not science. I agree that's not science. That's just an anecdote. 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 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 or influence. This is called like I think I've said
this before the Entourage effect this idea that THC alone might do one thing but then layering in other terpenes are minor cannabinoids May influence that effect that is a theory that's not a thing that we know definitively in any way. And in fact, there's virtually no research that's ever been done to test this. There's some stuff that's starting to come out. No like Ryan Van re at Hopkins recently published a paper where they kind of in a dose-dependent manner added limonene, which is one of these terpenes. Like I said, I think gives it like a citrusy odor into the THC.
Did find at a really high dose probably a dose that I don't think you could actually find in cannabis. It's a little bit higher than what you would have gotten there. But limonene did seem to be able to curb the ability of high-dose THC to make someone feel anxious and this was done in a blinded manner. So there's I think some validity to the interaction whether that's occurring in cannabis naturally because of the levels of THC to limonene. I don't know but it really was one of the first demonstrations that adding in a terpene could actually influence a component of
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 allene, which is probably probably the second most abundant terpene. I think from Mexico mrs. Work. I think mersin may have been the highest prevalent tripping across all types of cannabis beta carry off Lanes probably the second and limiting I think is probably the third and so I think the I mean and so they're looking at I think ziva's work is in the context of pain, so trying to
Get if a fixed dose of tht if you add in varying levels of beta carry off lien, does this influence this so because again, you do see this in patient communities where they say. Well this strain helps my pain better than that strain and so it's like, okay. Is there actual legitimacy to this or again? Is this just an expectancy bias? Because someone who sold us to told you that this strain is better for pain and the problem is these are all subjective endpoints. I mean, this is like pain sleep anxiety. These are all in so how someone personally experiences that we know from all the clinical trials that study pain sleep.
Leap 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 that interact with THC not just one there is like a lot of work has happened the last few years that has really
To try and look at if these terpenes are minor cannabinoids act at the cannabinoid receptor which none of them seemed to so this isn't like you've got things that modulate how THC is binding to see be one if they're doing something else. It's probably through an interaction with another chemical system. That's influencing what THC is doing. So I'm not against the idea that like different chemo vars or what people call strains of cannabis could do different things subjectively. I just am remiss the believe this incident.
Oh, I see some blind data because I think outside of that we know how powerful and expectancy bias is so it makes it very very challenging to make any kind of firm statements. And so kind of in the context of like how you introduce this. That was again. I think like one of the issues that I took with the other podcast was because as you said, I understand the thought process you went through like you're you know, you had this paper where people were reporting subjective effects. There's some neuroimaging data that's been done with cannabis. So you kind of
I said, okay. This is what that was. And that was what sativa didn't 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 point you to but now what 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 THC. We're really talking about Polly pharmacology. It's not a sub it's not like giving an and abide. Yeah, or it's not
Like, you know adjusting levels of endogenous and an amide, 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 Nolan Williams who's a psychiatrist. He's one of these phenoms triple board certified Psychiatry and neurology colleague of mine from Stanford School of Medicine who mainly Works in ibogaine and transcranial magnetic stimulation, but we talked about cannabis a bit when he was on the podcast and he mentioned a strain of cannabis that is available.
Colorado which is pure CBD. I think it's called Charlotte's Web and the parents of children who have epilepsy will move there or go there just to get this strain because it seems to help their epileptic
seizures. I mean, I would say that's definitely not true nowadays that pre legalization anywhere outside of Colorado. That was true. People were were gravitating there towards
it. Yeah. So the questions are could you tell us a little bit about the biology this
g b d receptor mainly as it relates to see B1 or not, you know to does it bind CB1 as well. If not, how is it working? And you mentioned that people will not report any subjective effect of taking up here CBD compound so lacking THC, but it sounds like it may have some use Wellness 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 and
there's some this 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 teach
e 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 th see by default CBD has been bred out of the plant and it is largely been bred out of the plant for quite some time. And so this I always find it interesting that there's this community that's like, oh well THC is the recreational cannabis and CBD is the medical cannabis and was like, that's bizarre because historically there's always been
Like THC has been what people have bread cannabis for and so kind of any medical benefits that people have reported from Cannabis per se usually are THC and CB1 driven CBD is this other molecule that we can go to the pharmacology in a second. But again, it's just it's I mean, I think in the in the analysis that nature coma state of all these strains and types of cannabis that exists in the United States when they went through their thing of thousands and thousands of kinds of cannabis. It was like three percent of them May.
Maybe had like more than 1% CBD like it's very low like there's almost none and in Canada to get a CBD Rich strain, you have to basically explicitly by it because it has to be bred to make CBD and so this is the kind of chemo of our distinction. I think you did allude to this last time which is the type 1 type 2 type 3. So type one 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 cannabis has that are out. There are type 1 like they're all high.
HC 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 percent. 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 saying we've got a Type 3 its high CBD it's going to be 20 ish percent CBD and very low THC and so no one is ever kind of grown CBD Rich cannabis outside of this recent boom in the
last decade that's happened about people wanting CBD because of the Charlotte's Web which was popularized by I think Sanjay Gupta on CNN and like 2012 or something was a while ago, but that was what got a huge movement going around this idea of CBD and yeah, so the Charlotte's Web was I believe that was what they had named that kind of cannabis that extracted it from and it was this it was a tincture that they were using that was very high CBD content that they were finding was controlling pediatric seizures and kids now,
This is actually been studied pretty effectively. Most of its 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 in the data is incredibly compelling their research is one of the reasons why CBD has been D scheduled or changed in its scheduling down to a what is it five? What is it class like
but EBD. Yeah, like see how the CBD I mean given the
availability of CBD everywhere in gummies and drinks and I mean you can get 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 Dravet 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 were having dozens of seizures a day to essentially not and so and I can understand I'm yeah that's super important Grassroots perspective. I can understand if you were a parent who had a child with a disease like this that was largely intractable and not that well controlled from the medications they're on and then something came.
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 had said like CB D receptor, there is no CB like there's no receptor that CBD by
I was under the impression that CBD also bound to the CB1 receptor.
No, I mean certainly not or
that or that under some conditions. It can modulate the shape of the receptor to adjust th see 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 of THC and Mike. Well, if you're using it in a strain that simply because the strengths of cannabis has less th see how this is possible. So you've read it out. But I mean like a lot of this was based on some work that came out a long time ago from Brazil where they showed that like giving CBD with a relatively high dose of THC could curb some anxiety that came out from
hideauze THC. I thought the explanation for that was that c CB D can modify the CB1 receptor in some way.
That makes th see less able to they're engaged with the TMC
evidence to support that that like we would call these allosteric modulator is there's some evidence to suggest that CBD May interact with a allosteric site on the cannabinoid receptor that makes th see bind less
doesn't sound like you're particularly convinced by that every this I mean like the look at the look on your face with those listening. I'm looking at Matt and he's I think he's he's being generous here. Let me ask it a little differently. It's does anyone know
what CBD binds to know? I know
and so the most convincing thing that I've seen that CBD binds to work CC Hillard has done looking at its ability to essentially block adenosine uptake and so it can inhibit the adenosine transporter. So it
causes should make people feel more alert.
No because you're getting more adenosine. So you get an accumulation of blocks the identity transport mechanism. I see so you get an accumulation of adenosine which is more sedative and that I mean in the pnas paper that Cece's lab had from 2006 they
Show that that also mediated it was the adenosine I think to a receptor that drove the anti-inflammatory effects of CBD. So it was a secondary effect
by totally opposite of caffeine of caffeine. Yeah. I know I have I'm ever doing you're describing this. It sounds like the the anti caffeine
is kind of how I described it people if they ever asked 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 cause that so you could get this identity.
An accumulation at you know, now you're not talking like micromolar levels of CBD, which is what a lot of Studies have done. And so even we're talking about the allosteric modulator esight like yes, there's evidence for it and it is convincing evidence. It's just the dose range the 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 at Hopkins again who is one of the main people who's done a lot of this work has actually blindly given people
Dosing with THC finds the opposite that it actually amplifies some of the effects of THC and this was something we learned from the Pediatric epilepsy world was that when you start giving CBD at relatively high dose is one of the things it does is saturate a lot of liver enzymes. And so some of the efficacy in the Pediatric epilepsy space may be a secondary effect due to an accumulation of some of the anti-epileptics as well because they're not being metabolized the same way and this is now been very well replicated. We know that one
you start taking CBD when they hit doses are at the clinical level, you're going to start having hepatic effect. So it's going to affect the liver and it's going to affect the ability of the liver to chew up other drugs good 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 potentiation of THC by inhibiting its metabolism. If you have high enough CBD on board given the effects on adenosine that you
Sky 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 ice there. You have it everything can't be expecting too much. I have a feeling it's gonna be interesting to see in the comments 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 Polly pharmacology 70 different cannabinoids some way.
HC 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 tht 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.
Opponent Etc. We 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 was CBD, that's interesting unlike THC is you can actually do pretty clean blinded studies because it's really hard to give someone THC in them not know they're On th see this was the big problem with the MDMA trial that happened recently is that people who got the placebo new they got Placebo people.
The drug new they got the drug. It's very hard. You could do a dose-response. But there it's very very challenging to give someone a psychoactive drug and a placebo and them not know which one they have. Whereas because CBD doesn't produce an intoxicating State. It's not really perceptible from the person who's taken it that it's doing anything that actually does make it far more amenable to do blinded trials with and so I mean the interesting thing was 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 glp-1. I and other people have pointed to the fact that certain food products or certain
Xor certain activities can increase glp-1 glucagon-like peptide which is now becoming more commonplace knowledge because of was epic Majora etcetera as very powerful weight loss tools. So there's questions about muscle loss Etc. And then we had dr. Zachary night on who explained that even a four-fold increase in glp-1 brought about through a prescription drug or ingestion of a particular food or drink does not lead to any appreciable weight loss. However, when
Chiefs thousand fold increases in glp-1 through the use of things like those epic majority. You see profound weight loss meaning that you need enormous effects in order to see that the clinically relevant changes in in that case weight loss. So it sounds like a similar thing with with CBD. So if somebody takes a CBD gummy and they feel that they sleep better you would argue that that's entirely expectation bias. I think that's a placebo effect and I say that because the majority of gummies robot like to Meg's five Meg's 20 makes me
never taken a CBD product. I know a few years ago. They were all the rage. I just I was never tempted to do it and I'm aware and we'll talk about this a little bit more that there is evidence according to Matt Walker who did a six-episode series with us on sleep that THC does help certain people fall asleep, but it can dramatically alter the architecture of sleep in ways that are probably not great. Yeah. Yeah. I mean THC and sleep is definitely a whole other thing, but sure a lot of people report this with CBD, but
Again, so most CBD Edibles or things that people take that are sold through commercial markets are in the range of 2 to 25 Meg's 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 Maori and then you're talking about a child who weighs on the order of what 20 kilos maybe you know, like 40 60 pounds somewhere in that range versus so if you start dosing by weight, which is how most
These things are done. We'll say 20 makes per kegger 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 makes per Keg at like 90 odd kilos. I mean you're talking about me taking a liver damaging dose and insane why 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.
If for instance you were to take a high dose of CBD and then maybe have a couple alcohol containing drinks, that could be problematic right? Because now you're talking about the to hit
model. Yeah, I can't speak to that because I actually do not know the metabolism of alcohol well enough, I don't believe so because that's how we call dehydrogenase. So that would probably be a separate enzyme pathway than the sips. This is more
like separate enzyme pathway, but you're 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
that this is a problem for so it's things like Warfarin and like blood thinners in the anti-epileptics funnel into the same metabolic pathway as this th she's 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 two 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 mg and yet in the wild
Then 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 realizes CBD has absolutely horrific bioavailability like so if you take it orally in an oil or in a gummy or whatever you consume it in. Now this might be different with some of these beverages that are out there. I don't know if anyone's actually ever done the pharmacokinetics on them least. I've never seen it but standard Roots we're talking four percent like very very little actually leaves your gut into your bloodstream.
Now we do know from the studies from GW who created the pharmaceutical version of CBD that was used for a lot of the Pediatric epilepsy studies that they did. I don't know if it was random or intentional find that opposite to something like alcohol. If you had just eaten a fatty meal that actually enhance the bioavailability of CBD dramatically. So then it went up to like maybe 20% got into the blood but that's probably because again CBDs a fatty molecule likes 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 can see now it's the steak and CBD. Yeah, where the CBD with omelet protocol 5, I'm just kidding folks. I'm not I'm not suggesting that protocol. But yeah it I mean and so because of this it's like you're taking very low doses of CBD that I'm 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 there's no I wouldn't because I can't say that I think that this has any biological activity because even when we start looking at these potential targets of what CBD could interact with there's a couple receptors people have said, you know, it might interact with serotonin receptor is 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 ask me in 2010 to walk into a room and ask how many people knew it CBD is like maybe one out of 100 like no one knew what CBD was and now it's like 80 to 90% would know what it is.
Cuz everyone you can't walk down a street in any city in North America and Nazi 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 gonna 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
r
eager for things that can help them adjust their anxiety and sleep better, you know, which is a large reason why a lot of this podcast has focused on respiration based tools and another 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 they're much better things that are not of a adjustable type, you know things that one can do that are
Science supported right there are clinical studies meditation breathwork any not so much breathwork. I would argue but certain patterns of breathing meditation cognitive behavioral therapy. There are a whole bunch of different things. That's 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 it is. 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
And
so I find it really challenging to recommend someone to be spending. What can I mean if you're especially we're talking about an actual clinical dose. I mean for someone to take CBD at the level where it could actually be shown to have some benefit in some condition of which currently it really is just pediatric epilepsy. Like this idea was 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 a
End this in any capacity, especially I mean if someone if finances aren't an issue sure go for it. But you know, I understand people are like you say looking for Solutions. So it doesn't sound like CBD is this age? 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 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. We talked about the potential for addiction.
And and the evidence potentially for and against that right. There's also the 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 as 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. Okay, but what are some actual if any what are some actual harms of can
To 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 it.
Cigarette smoke because people are smoking less of it or they're just fewer carcinogens in there. I don't think you could make the argument about fewer carcinogens per se I think probably it relates more to the frequency. I mean Donald tashkin who's in California here. I think he was at UCLA. I'm not 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 with lung cancer the way that you do with cigarette smoking why that's the case. I don't think anyone has like people have theories some suggest because a lot of this in vitro.
Work with really high dosing suggests. It could have antiproliferative effects for tumors whether that's real or not. I don't know but like I think more likely it's because most people who smoke cigarettes at least that were, you know, the relationship with lung cancer where people were smoking regular 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 as if you have any
Bastion product you're going to have damage there. There's no question about that. So again harm reduction perspective would be you know, oral routes of administration bypass lung damage. They come with their own issues with dosing and what not. 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 that the state of it. There is something with cardiovascular function and cannabis that relates to
Higher frequency of Strokes perhaps or cardiac events in some capacity the data is not entirely clear in this in this sense yet. I mean we don't see again. It's not like super clean relationships. Like we're seeing that were there when we they established, you know, cigarette smoking and lung cancer kind of thing. I think that effect was so profound and the population of smokers used to be so high with
can this potential. I want to highlight potential relationship between cannabis use and cardiovascular issues.
Be bypassed. No pun intended by using Edibles not enhance or is it related to THC
itself? I would probably guess and this is a guess that the in 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 on the system. So I imagine we'll make it worse but th see itself has a very
Flex effect on cardiovascular function because it tends to cause typically vasodilation. So you get widening of the blood vessels which is why it relates to a lot of people will experience postural hypotension. So sometimes when what that is is if you stand up 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 when and with Edibles as well. So it's not just from smoking but when they've consumed cannabis in some capacity
I see 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 tachycardia, which is an accelerated heart rate. And so that's a very reliable physiological response for a lot of people who use cannabis and so
it's a bit of a tricky thing because obviously if there is some underlying heart or their cardiac sensitivity or issue the tachycardia itself can be a problem. I mean, so like, you know, if someone has like an underlying heart condition where it rest it may not present itself, but the shifts into that kind of beating faster to compensate for the fact that you've got a drop in blood pressure can do put strain on the heart in a way that could unmask a vulnerability or
Vent and again, this is me, theorizing what I think it could be based on what we understand to some degree about how it affects cardiovascular function. There are occasionally people who have reported having like elevated blood pressure. I mean some of that also could be from a can anxiety state or what not coming around but the typical response and this is usually driven by cannabinoid receptors that are in the vascular beds themselves that it causes a vasodilator response. And so that is usually the first step the second is the uptick in
In the heartrate, so you get these kind of effects over time. There's some work looking at like
You know vascular stiffness that can evolve over time and cannabis users. There's some evidence to suggest that you might get more of that emerging. And so again that could relate to a vulnerability to have strokes or other kind of cardiovascular events in that 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 30s and stuff and people started Living longer you started seeing a lot of these effects of cigarette smoking emerge because yeah, it took awhile for the medical community to adopt the idea that cigarette smoking was bad. I know and I think it's wild decisions with smoke and Clinic
Ashtrays in the doctor's
office. I mean my grandparents grew up in Belfast. They had smoked for years and they even said like when they were younger doctors would say go have a cigarette after a meal it promotes digestion. So it's kind of wild to hear that stuff when you think of how cigarettes are viewed nowadays, but it is I don't think we've kind of been able to track this long enough to be able to say with certainty what we're seeing but I think there's like a people ask me about risks and harms of cannabis. The 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 it being safe because I don't know how to actually explicitly say what I would say the harms associated with it are but I think there is something there. I've seen enough evidence that's like starting to coalesce into a story. That's like 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. We've seen this in Canada bit more now with legalization again because people are going into er's more where it's this somewhat strange phenomenon where it's usually people who are pretty access 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 like one of the things that seems to cure it is a hot shower, which is like I can't even begin to understand this.
I
mean there's Austin they I'm chuckling at the example because it 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 I'm not I'm not enjoying
it because it's deliberate heat exposure, but it just speaks to the fact that we you know, we're talking about, you know, smoking being a regular part of the the medical community behaviors up until you know, a few decades ago and then you know,
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 has specially in the last hundred years plus 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've really struggled to understand because it's certainly I don't think was doctors that figure this out.
Oh, this was people. I think who were experiencing this and then they started telling doctors this and then I think and I can only imagine I'm like, maybe they're going in the shower because they're like vomiting on themselves probably 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 seem to provide benefit. I'm think about activation of the thermal heat thermal thermal regulation because the other thing that seems to have shown some benefit has prepared a wall which again would suggest some kind of sympathetic which is a
It was a beta blocker. So yeah, it's your effect. So there's something with autonomic. It must be messing up some kind of autonomic balance or something with thermoregulation why that results in this kind of bizarre vomiting syndrome. I have no idea. But I remember when I first started hearing the stories of this years ago, and I was just like how because I mean it is again surprisingly counterintuitive because one of the medical uses that people have used cannabis for is as an anti-nausea and especially in the context of chemotherapy and so something that typically has anti-nausea.
Ozzy and quality suddenly triggering a vomiting syndrome is kind of a
paradoxical and yet we started off today's conversation with you explaining beautifully how activation of these CB1 receptors are homeostatic in some sense the thermostat analogy and you know, maybe after you know chronic use there's some you know, the seesawed sort of gets flipped to one side and get stuck. I think that's how most people have tried to kind of conceptualize what's going on is maybe like and it seems to involve the
Sir, cortex at least the anti nausea and effects of cannabinoids are involved through the insular cortex. And so maybe you like a burned-out those receptors from chronic use and so that endogenous mechanism isn't working or it somehow flipped in the other direction on that circuit becomes sensitized but it is it is a very bizarre, but very real thing that seems to happen again. This isn't common like I've I've heard a couple of people I've met describe it but it's not like it's happening to every 10th or 20th person or something. It's
Little it's a little more infrequent, but it's certainly happening enough that we've now captured it at a federal data level that this is a thing that people are showing up in the ER for so interesting it so a hot shower. Yeah. So apparently if it happens hot showers where people claim so yeah. So for me, I would say the 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 from smoking. Those are the main I think genuine Bona
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 of it on the other side was 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 nor do we want to glorify it, but you know the examples that I've
I've heard of medical uses for cannabis include appetite stimulation. We talked about that for glaucoma lowering eye pressure 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 pressure is checked there were drops for this but okay cannabis can reduce eye pressure glaucoma.
Nausea you mentioned and then anxiety. It sounds like if people get the the dose, right and it's right for them that in some cases it can help them with their anxiety. And the reason I raise 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 a way to relax in the same way that they would use a glass or two of wine. What are your thoughts on that? Because I think this is the most common use
Case and 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 that pain is I would say the number one. So pain is certainly the one that is 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 the Cannabis is a profound analgesic. It's that cannabis. It has some analgesic properties, but it's not like super Sledgehammer in that sense, but what it does seem to do is it seems
AAA 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 still there, but now the pains background noise so I can sleep at night and just being able to sleep I think is actually providing a huge amount of the benefit to that Community but it's the day-to-day like they're able to function with the pain because it doesn't they don't become focused on it the same way because they're able to kind of push it to the background that seems to be the main ability of cannabis. I mean, yes, there's
some mild analgesic properties to it to some degree but it really seems to be much more of that component of and I think you alluded to something like that in the previous podcast. You'd said something about how it's changing the emotional state of
pain. So and we know from the biopsychosocial model of paying that emotions and interpretation of the sensation of pain is a huge component of what people refer to as chronic and acute pain.
Yeah. So 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's either with isolated tht I think there's one or two.
Studies have actually looked at smoked cannabis and found small signals of benefit but so anxiety is is an interesting one. So, I mean obviously this is more near and dear to my heart because I study Stress and Anxiety as my primary area and cannabinoids and endocannabinoids in that space. And yeah, you look at questionnaire based studies about why people smoke cannabis and like 85% on 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 endocannabinoids.
Regulation of it because similar to feeding and pain where we know endocannabinoids are involved in regulating 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 biphasic were some, you know, lower doses or angular take higher doses can promote anxiety, but for the majority of people who use cannabis regularly, it's because it helps reduce anxiety now,
That would hold weight in a clinical trial is a different story. There is some old evidence from like I'd say the 70s early 80s where they were using synthetic forms of THC like NAB alone, which is some of you get in Canada or Marinol or dronabinol which I think is what's accessible in the states where they did find some evidence to suggest it was on par with like a benzodiazepine like diazepam or something. I can't remember exactly what the comparator they'd use narrow, 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. It's just basically everyone knows what they're getting. It's not blinded in any way but because of the self-reported data from the veteran population about cannabis helping especially with sleep and the big thing that they reported was that it suppress their nightmares. And so, you know, 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 Dreamscape space that they re consolidate it a little bit more and there's often a high degree of sympathetic activation and arousal that goes on with these nightmares and some of the belief is that this is part of the sensitization process that can happen in PTSD where the disease can worsen over time because the re-experiencing in the reconsolidation and the sensitization of the disease that happens over time in this kind of
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 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 you know, we use cannabis or THC before bed. We find we don't have the nightmares and just the simple trickle-down effect of that is hugely beneficial for them. And so the Canadian military did an open-label trial on this again not blinded. It was small numbers, but they basically found soon as they put people on now.
Abalone this synthetic version of THC it vary in like a large proportion of think like 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 move 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
On a proper crossover design where they got Placebo one point they got an abalone one point. It was switch. They didn't know which one they were on because they're taking it right before bed. Maybe that will remove some of the subjective bias again. You can't totally remove it. But like if someone's taking it with an you know an hour or so of going to sleep they may not feel the high the same way. But even under the double-blind conditions, they found a very effective suppression of the of the nightmares and they're experiencing and then they also at the same time found this increase in kind of quality of life measures, which tracked
the fact that they're probably sleeping better. I don't think they actually reported any change or even looked at maybe the overall PTSD score. They only reported a really focused on the nightmare component of it because that was the primary outcome of the study. But so I thought that was interesting because that's if you look at the anecdotal data in PTSD, that's where a lot of it is focused on is the using it as a kind of I wouldn't maybe call it a sleep aid because it's really more of a modulator of the dream state and I think that
we could presumably because it's reducing the amount of rapid eye movement sleep you're getting which most people will probably
Here in 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 it
depression and PTSD are both tutors to disorders that are characterized by changes in Ram. Like they have earlier onset to ramp so they go into REM faster. They tend to have some altered architecture of the REM component of their sleep. So in those States may be suppressing Ram isn't actually a bad thing at least certainly for PTSD I would imagine
In terms of the context of the nightmares that's providing some benefit whether or not it globally is changing the disease severity or improving the disease. I don't think we really have any evidence to say but again, I can understand the desire for people to kind of self medicate. Let's say by using this as an approach to try and reduce that component of their sleep. So 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 sensitizing the same way, but
Don't think we have any strong data that we can leverage in that capacity to be able to say it. But to me, it's one of the more interesting areas. I think anxiety disorders in general. There's definitely some potential. So as I had mentioned earlier the the FAA inhibitor that elevates an atomized levels. So Johnson & Johnson did do a trial and social anxiety disorder published. I think from a few years ago 21 or something. I can pull the reference that where they did find some benefit. It wasn't huge.
Huge and some of this had to do with the design of the study because they kind of underdose the patient's a bit and so not everyone actually showed the elevation and and amide when they went back and looked but when they actually isolated the group of people that had iron and amide 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 an atomized signaling and the main one of the main things that we've demonstrated that's been
Get it relatively. Well over the years is that stress exposure can actually cause a rapid loss of an and amide signaling and it's that loss of an animated 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 while Ivan and amide, you know, it's that job as its kind of tonic housekeeper at keeping things in that homeostatic range. Let's say we're talking about explicitly and anxiety circuit, you know, this individual variation that exists in humans are
cross 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 and amide signaling spectrum and we've gotten a little bit of support from that from animal work where we've screened animals based on anxiety and looked at endocannabinoid levels in the amygdala and found lower in an
amide this 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 another animals. Also if people take a compound that adjust the sort of homeostatic level of what's considered low moderate and high activation of those circuits that include the amygdala then perhaps they're bringing their anxiety into range. Yeah in a way that perhaps it's 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 nighttime or evening and of course people can wait for their happy hour for a drink as well. But it's far and away different than the way we envision something like alcohol use disorder where somebody discovers the alcohol really helps with their anxiety and then they're drinking, you know, maybe one at lunch maybe a couple of dinner.
And in the evening to fall asleep at night. I'm describing extremes here. But I find your hypothesis 2 square really well with the real-world observations and it's an interesting
one. There is some evidence actually supports. Oh my buddy Sasha 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 endocannabinoids synthesis. So you can create a state of like impaired endocannabinoid function in humans and they did this in rodent. Okay, so this was done in mice and they basically but the
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 endocannabinoids levels and you got the emergence of an anxiety state. So then you could give drugs that would boost the endocannabinoids to normalize this so again, it kind of fit with the idea but then they did one key study where then they gave THC and saw could teach see fill in the Gap and they found that like boosting endocannabinoids giving th see on a background of low endocannabinoids was able to
Reverse that anxiety phenotype and bring it back into more of the normal range. So again, maybe for some people this is if this 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 similar to what you're saying, which is maybe some people are trying to fill in a gap of something that's deficient in them. And therefore that can help them feel less anxious and that again may be very different than someone who is like, you know, very
Anxious for different reasons or has normal under cannabinoid function or something else might be a play there. So
very interested. I
think it could explain some of the heterogeneity that exists out there for sure. Yeah, so
perhaps genetic differences in sore Baseline levels of anxiety, perhaps map to endogenous levels of Ananda. My dad might predict propensity for THC use. Yeah.
I mean, we have definitely found in human populations through work. I've done with a lot of clinical collaborators and others like, you know, we look at endocannabinoids in the blood and it's not in the brain, but they are lipids.
Can move pretty easily back and forth and we have found relationships between peripheral endocannabinoid levels and mood States both anxiety and kind of depression of measures which does you know, somewhat relate to the 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 working depression populations that have found some relationships.
That are pretty similar so it's certainly a possibility. But again, this is all like our Theory at this point. So we'll see as things kind of move forward if they pan out but yeah fantastic and I really appreciate that you're able to share some of what your laboratory is working directly on now and looking into the future and I want to thank you for what has been an incredibly clear precise and in many cases actionable whether or not it leads to a yes or a no action.
Information here because cannabis and CBD as you pointed out our kind of everywhere around us. Yeah, 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 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 and also pointing to the fact that this is a complex system complex biology, you know, there are a lot of things about psychosis about negative effects about potential positive uses of
An abyss 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.
At 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 was that I had had issue with your previous podcast and I think the discussions that came out of that were for the better. So that's all the best and hopefully if there's other contentious issues that happen down the road similar things move forward and you chat with people I always yeah if somebody who
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 Etc 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 presented data and we disagreed what we would probably do would be to head. Well traditionally would be to the bar but we 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. So and I think it's really good for people in the public to know this is house.
Science progress. This is this is you know, someone says something someone disagrees with it you get an opportunity to clarify things and I think that that's really good just to move things forward. So I think that was a good process that we've gone
through. Yeah likewise and it certainly within the spirit of the podcast in no way shape or form do I report 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 involves, and we can learn more about these topics and more. So, thank you so much Matt. Appreciate you great. Thank you for joining me for today's discussion about cannabis with dr. Matthew Hill. I hope you found the discussion to be as informative as I did. If you're learning from and or enjoying this podcast, please subscribe to our YouTube Channel, please also subscribe to the podcast on both Spotify and apple that's a terrific zero cost way to support us and on both Spotify and apple you can leave us up to a five star review, please also,
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