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

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology 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 hubman Lab podcast about cannabis the biology of cannabis some of its medical applications and uses as well as some of its potential harms that episode came out several years ago now and remains a very popular episode it's had millions of views and millions of listens several months ago we posted a clip of that episode to X formerly known as Twitter and Dr Matthew Hill responded to that clip on X with criticism about the specific points made within that clip most notably my discussion of the data that cannabis use can in some individuals cause psychosis he also took issue with some of the specific points I Made In that clip related to potential differences in the biology of the effects of different strains of cannabis most notably indicia versus Sativa strains and a few other points as well now now as somebody who's been in the field of science for several decades now I'm very familiar with the fact that every field every single field within science has debates within it controversies and sometimes outright battles and to me that's part of what makes science interesting it's an evolving process it's something for which we should all be very curious to try and understand what we know what we don't know and try and get to the real answers so right off the bat on X I invited Dr Hill onto the podcast and he accepted the invitation so today's episode is really a unique one in that first of all we cover an enormous amount of biology and clinical data as it relates to cannabis meaning today's discussion is not a debate it is really an up-to-date discussion about how cannabis works so we talk about THC versus CBD we address the question of whether or not indas versus sativas have different biological and subjective effects or not we of course talk about the potential correlation maybe even causation between cannabis use and Psych is I think you'll find that discussion very interesting and we talk about how cannabis relates to hunger to memory to anxiety and to the treatment of anxiety I'm certain that given the widespread use of cannabis nowadays that you'll find the discussion to be both an informative and potentially useful one that could help guide decisions as to whether or not you or 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 neuros science 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 eight sleep makes Smart mattress covers with cooling Heating and sleep tracking capacity I've spoken many times before on this podcast about the critical need to get sleep both enough sleep and enough quality sleep now one of the key things to getting a great night's sleep is that your body temperature actually has to drop by about 1 to 3° in order for you to fall and stay deeply asleep and to wake up feeling refreshed your body temperature actually has to increase by about 1 to 3 degrees one of the best ways to ensure all of 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for having me delighted to have you here because you're an expert in the biology of cannabis a topic that many many people are curious about for for a variety of reasons so just to kick things off maybe we can get people up to speed on what cannabis is a little bit about how it works in the brain and body to produce the various effects that it produces and how some of that comes to be and then we can dig into some of the Nuance I have a lot of questions about different types if you will of cannabis um the relationship to mental health potentially to mental illness we're going to drill into all of that so just to kick things off what is cannabis I mean cannabis is a plant that has been around for some time it's kind of got like a very rich history of use around the world for different cultures um for both kind of medicinal and spiritual and recreational purposes over several centuries um the plant has kind of become I mean in the west it really wasn't a thing mainstream wise until about the 60s uh 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 and I think that was a lot of the time that cannabis got popularized um and then I'd say more recently cannabis has you 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 uh 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 uh we call these cannabinoids and they come in a lot of different flavors but the main one that's the most important one when we talk about cannabis and what drives the kind of intoxicating and what I would refer to as psychoactive effects of cannabis is uh Delta 9 tetrah hydroc canaban or what we call THC um 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 uh there are probably 70 to 10 and some odd other cannabinoids that are within cannabis most of them are pretty Trace levels like and they vary from different types to cannabis from one another uh but the other one that's had a lot of attention is cannabid or what we call CBD uh CBD is structurally looks pretty similar to THC but doesn't behave anything like THC it's not intoxicating at all um I'm not sure I would probably say it's not psychoactive in the sense that people can't tell if they're on it or not but I would some people still say it's psychoactive because people claim you know it can affect anxiety state or mood state or other things so in that context maybe psychoactive is still somewhat appropriate of a word to use um and then there's a whole bunch of other things like cannabinol canaberal and these other minor cannaboids most of which we really don't understand any of the biology of we don't know what they're doing um they may influence some of the effects of THC they may not um but they're there and they vary in their composition from you know different flavor of different cannabis to different flavor uh and then there's those other things called tpin which are kind of Highly volatile compounds but they're not specific to cannabis they're 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 lemoning which U you know gives some cannabis kind of a citrusy odor or flavor to it um pinene which gives things more of like a earthy tree kind of smell uh beta caropine merine and these Turpin are also some of which do have gnome biologic IAL activity some don't and they vary quite heavily across different kinds of cannabis as well and again there's some thought that they may be influencing some of the psychoactive or intoxicating properties of cannabis but the reality is we really don't know a lot about them at this point there's kind of some emerging work that's starting to come out now that kind of plays with you know giving someone THC and adding in one other tpine or one other minor canabo and seeing how it influences things and so you can imagine with the plethora of molecules that exist in cannabis doing this in a piecewise manner could take decades to kind of really get to a point where we understand all the interactive um 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 um and so there are some like distillate pens and things that exist out there now in the product Market which are basically isolated THC with Trace levels of anything of other stuff would be very different than if you had THC in combination with some of these other molecules and how they might influence how THC itself is working or not so fascinating plant you mentioned the psychoactive effects um some people listening to this and watching this presumably have experienced those psychoactive effects others perhaps have not how could we describe for both groups um what the quote unquote psychoactive effects are you mentioned um the higher the concentration of THC the quote unquote higher someone will get right the greater the intensity of the High um what is the high um and I know people are probably chuckling saying you know does huberman not know because he's never done it I mean that's my own business I I just want people to understand what you mean by psychoactive effects so I mean the way that people would usually describe the the intoxicating effects of cannabis is uh they would I mean people often refer to it as there being some Euphoria or some positive mood not on the same order as what people would describe with say cocaine or some other stimulants but there certainly is some kind of positive aspect I mean if there wasn't people wouldn't be using it if they didn't feel positive about it afterwards uh there can be you know other aspects uh in terms of changes in feeding Behavior people might find things funnier than they found things it might change the way they perceive various environmental stimuli um but it can also for some people create a bit of a dissociative state to some some degree where people might feel a little bit out of body so it's kind of a a complicated intoxicating state to describe I would say because usually if someone's referring to something like a stimulant they're just like oh people feel like they're God they're like you know possibility everywhere yeah exactly like they're very happy and they're kind of jacked up and I think with cannabis the way people would describe it would be very different it's like kind of an introspective State you might be more aware of your bodily feelings and um states that are going on inside you you're kind of internal state but you also have like a different perspective on external stimuli you might process information a bit differently focus on things a bit differently so it's kind of a a complicated state to describe I would say usually when people are assessing if someone's intoxicated like um the kind of lab work where people get some on high they just kind of use a what we call a visual analog scale which is like a one to 100 or something or zero to 100 and say do you feel high do you enjoy this would you say you feel euphoric is your mood elevated so they're kind of scaling things like that so I think that's more typically in a lab setting how you would Define if someone's high or not from it and this is why when people do studies with something like a placebo cannabis or a very low THC cannabis you'll see kind of a scaling so um even if you give someone a placebo cannabis if they think that they're getting cannabis a lot of people still respond by saying they feel a bit High that's interesting is that true even if they've never used cannabis before I'm not actually certain if you are allowed to have someone in a drug study if they've never done something before I think they have to have had some previous experience with a drug be ened now smokers everywhere running to look at subject but I think yeah I don't think you can use drug naive people I mean I don't run human clinical lab studies so I can't explicitly say it but that's my understanding is that someone has to have had even limited like you know not much but at least once or twice they have to have experienced the drug before so I don't know if you would take someone who was completely blind cuz I don't know how they would replicate that state if they're not expecting it what about the effects of cannabis on time perception you know there's this um reputation that cannabis has uh 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 um 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 d like you're saying where people think things have you know someone will be high and someone will ask them how long do you think time has passed they would report usually longer periods of time have passed than I 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 uh but it might be in rodents it's looking at like temporal ordering and they give animals cannaboids 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 you can really train animals to have this ordinal timing where they kind of know distinct periods of time and if they give them canabo they respond differently so it in that context it does still seem to produce some state where there's a an altered perception of time passing and so I think if we were going to really understand the mechanism of it that would probably be the way to go but I'm not super familiar with the work because no one's I mean anything I can think of is pretty old I can't think of anything modern where people have actually looked at this interesting uh 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 um is the mechanism by which cannabis can stimulate appetite known and if so um what is the general trend of of effect makes people hungrier obviously but we hear again in um kind of uh recreational ter terms of people getting the munchies you know becoming exceedingly hungry is that related to some cannabis induced effect on say blood sugar like insulin or glucose regulation or is it happening at at a different level yeah I think we almost need to take a step back actually to talk about how cannabis works in the Brain before we kind of go into that so THC as a molecule exerts almost all its effects they're acting at this one receptor for the most part that's widely expressed through the brain called the cannabinoid type 1 receptor um CB1 yeah CB1 is the shorthand for it and and I think um you know as people tend to create analogies to describe what receptors are for those you who don't know it's most people use like a lock and key analogy that like a receptor would be a protein that sits on a cell and a molecule that binds to it like THC is the key that fits in that lock when it activates it it triggers some biological process in the cell in this case a neuron that changes its activity in some capacity um and so THC acts on these CB1 receptors which um are very widely expressed in fact outside of like kind of ION channel that are expressed in the brain the CB1 is I think one of the most if not the most widely expressed receptor in the brain it's everywhere so it's really important um and I think as as kind of you had alluded to previously uh it didn't it doesn't exist in the you know this didn't evolve in humans in the hopes that one day humans would find Cannabis this is just although cannabis users everywhere use that argument um I know people love to leverage U 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 um but but I mean really this is just biological redundancy I mean you know nature only has so many ways to create something and so there's going to be things that end up overlapping in the way that they function and so the receptor that's in the brain and throughout the body the CB1 and there is also a CB2 receptor it's not really expressed in the brain it's in some of the immune cells in the brain and maybe maybe some limited distribution in um actual brain cell neurons where where in the body is it it's mostly immune cells so you'll see CB2 is mostly on like macroasia 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 um so that's kind of a separate role that can certainly impact the brain in different ways but uh when we talk about the effects on the central nervous system and the brain and behavior we're talking almost entirely about CB1 and so both the CB1 and CB2 receptors like I said don't exist because nature was like humans are going to find Cannabis they'll this will all work together now so there are molecules our body producers which we call endoc canabo um and they are kind of funny little molecules because they don't really behave like certainly in the brain they don't behave like a normal neurotransmitter so I mean I assume most people who listen to your podcast are relatively Adept with the basic idea of how neurons work so you have Neuron a let's call it the Press synaptic neuron because you have that gap between the two cells where they communicate called the synapse so Neuron a releases a transmitter and it can be something that excites the neighboring cell neuron b or it can inhibit it um and so the way that we always kind of talk about neurotransmission in the brain is Neuron a releases a chemical that crosses the synapse acts on neuron B and it can either you know Jack that neuron's activity up or it can scale it down and that affects you know brainwide patterns of activity uh and we call that anterograde because it moves from neuron a to neuron B which is kind of the general flow of things um and how we usually think about it so endoc canabo are kind of this you know little bit of an oddity in the sense that they could do the reverse and so endoc canab are actually made in neuron B on the post synaptic side and then they go backwards and act on Neuron a to regulate how much transmitter is released and so in many ways this is like I kind of liken it to a thermostat model for the most part certainly if we're talking about something like excitability so if Neuron a is dumping out something that excites neuron B like glutamate which is an excitatory neurotransmitter as neuron b gets too excited it's going to start releasing endoc canabo to go back and Neuron a to stop driving it so so sort of a homeostatic scale and trying to maintain a middle range yeah I mean at the end of the day no matter how you discuss it and what system you discuss it I think the majority of people in the canabo field would agree that the primary physiological role of endoc canabo 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 um that is raise or reduce the amount of electrical activity in the let's say nearby neuron cuz you talking about retrograde signaling but um ultimately you don't want runaway excitation that looks like epilepsy exactly and you don't want runaway inhibition because that looks like um suppression of ability to think move Etc exactly so you want to keep things in the in where they should be and so you want neurons to get excited but you want them you don't want them to get ere excited so endoc canabo in kind of a very prototypical sense act as this circuit breaker essentially where they go back and gate how much is coming in and they do this by through various mechanisms essentially turning off the electrical activity of that prestic neurons so that it stops releasing neurotransmitter um they can also regulate though inhibitory neurotransmitter release as well and this is usually done through a little bit more of a complex process where it's driven by excitation but then it regulates the inhibitory pathway so inhibiting the inhibitor leads to more excitation exactly I usually liken it to basically taking the brakes off of a car while you're going down kind of thing like you're you know you use your braking system to keep things in check but if you want to go faster you take the foot off the brakes and you let things accelerate and so this can be really important for things like forms of synaptic plasticity or or neuroplasticity let's say where you want synaptic strengthening to happen so like under a learning event or something you want that synapse to really hardwire better and so having endoc canabo 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 endoc canabo can weaken that synapse at the same time by acting right at the excitatory terminal itself and so their ability to kind of play with the relative activity of a circuit is really dependent on which neuron they're acting on and so they can regulate excitation or inhibition differentially and I mean CB1 receptors are found on virtually every single kind of neuron in the brain um except one and I think you'll find this interesting because it's dopamine uh and and doine neurons are basically the only neurons in the brain that don't really at least as far as we've been able to characterize to date Express cannaboid receptors interesting uh if I may um earlier you mentioned one of the potential psychoactive effects of uh Canabis 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 yeah I wouldn't say that cannaboids don't affect dopamine because um what we understand in the ventral tegmental area which is kind of the hot spot of dopamine neurons or at least the ones that are involved in motivation and stuff um those neurons are are regulated by a lot of inhibitory neurons that dump out inhibitory transmitter and keep those neurons kind of quiet or so there's an opportunity for indirect reg exctly so what you have is those neurons that regulate the dopamine neurons are very rich in cannaboid receptors this is actually kind of similar to how mu opioid receptors work for things like morphine or heroin um and essentially what the cannaboid receptors will do is when they're activated they'll turn off that inhibitory control and that allows dopamine neurons to kind of uh move into a state where they're more prone to go into burst firing and have big dumps of dopamine whether or not that relates to you know the positive affect or the Euphoria I don't think anyone has cleanly demonstrated that I mean obviously dop mean's very complicated in terms of its relation to end points and whether it's reward or motivation um but canabo 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 canabo signaling is why the brain would have evolved in a way to allow every other neurotransmitter system to be actively and directly regulated by endoc canabo but doemer is kind of spared from this so I don't know no one I mean obviously you can always just theoretically guess as to why someone do that I don't know what the reason for it would be but it is something that has kind of uh intrigued a lot of people because every other system in the brain is so tightly controlled to some degree by cannaboids and then this one circuit is kind of free of it so um but yeah so the main role of endoc canabo is really to to regulate plasticity of homeostasis allow flexibility of circuits to either Goose up their activity or 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 endoc canabo play in that domain but even within the endoc canabo um I mean there's there's two primary endoc canabo and again this is one of the weird things about how endoc canabo 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 uh dopamine has at least five uh and so the different actions that serotonin or dopamine will have is all driven by the diversification of The receptors it's one molecule whereas cannabinoids are the reverse not only do they work backwards across the synapse and work in this retrograde fashion but really you have one receptor that is regulated by two molecules so the diversification happens more at the level of the molecule than at the receptor which is again very unique and the two molecules that we know are kind of the Bonafide endocannabinoids there could be more um they're called anandamide which um is actually kind of a funny name because it comes from the Sanskrit word Anand for Bliss and so Rafi mulam who was in Israel when he discovered the molecule you know 30 odd years ago um wanted it to reflect inner Bliss and so he named it anandamide so it's like inner Bliss with an amide bond is kind of the joke he had for it and so he discovered um an emide and decided to call it Bliss because he had familiarity with cannabis or because he he took an emide as a as a direct experience and because it takes a lot for a scientist to discover a molecule but then for a scientist to discover a molecule and then name it Bliss for a particular reason you have to speculate that they they had some familiarity with with the m was also the guy who who isolated and discovered THC so I mean he has a very he's kind of the grandfather of whole cannaboid field so he has a landmark paper from 1964 which ironically um and this is one of these weird pop culture things I don't know if this is true that paper was published on April 20th 1964 and so the joke is is this where 420 came from because the original like birth date of the first THC paper was 420 1964 well now that that now that um potential myth is definitely going to propagate um but yeah so he he he'd been in the field for a while and so he had studied cannabis on that side and then in 1990 his lab isolated an andite has being the first molecule that activated the receptor endogenously and so um it was kind of uh yeah I think it was a little tongue and cheek that he named it the way he did a few years later the second molecule which is just called tonal glycerol or what we call 2ag that was discovered kind of in tandom both Again by Mulan but also by a Japanese group um and so we understand these two molec don't do the same thing like they are a bit different so the way anandamide binds the receptor is it's what we would call a high Affinity but low efficacy um Agonist or molecule at least and what I mean by that is very low levels of anandamide are required to actually bind to the receptor but once it binds its ability to stimulate a biological response in that neuron is kind of caps out pretty fast so it doesn't have like a sledgehammer effect whereas 2 a seems to require a bit more more concentration in the synapse to be able to bind to the receptor so it has a lower affinity for the receptor but once it binds to the receptor it's like pretty heavy duty so it evokes a very robust um intracellular signaling response and so why we have two endoc canabo we're not totally sure some of us have theories I'm of the camp that I think they may play somewhat differential roles either based on the synapse or the circuit that they're working in or this idea that maybe anandamide might be more of aonic molecule and what I mean by that is we'll say it's like a stage Setter so like an emide might just be kind of made by neurons on an ongoing basis and just released and its job may be to kind of keep the steady state of a brain circuit in a desired range so that under resting conditions it's not too active or too quiet your thermostat analogy is perfectly so in that context it kind of is like just the thermostat of the house whereas 2ag is like let's say the pinch hitter who gets brought in to do the heavy lifting and so 2 AG during a situation like let's say something like even like a seizure as an extreme example where you 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 2ag and that acts as the okay we really need to turn off this circuit very quickly in this situation and in most of these forms of like synaptic plasticity like I was saying earlier where you need to either strengthen or weaken a synapse in response to a change in the environment or in response to an experience or something that's going on most of that is driven by 2ag signaling and so um you know all these forms of like turning things up or down in an in a kind of rapid and ond demand manner that's mostly 2 AG so most people who study like neurophysiology and like record activity in neurons and look at endoc canabo they're almost entirely talking about 2ag when they play with stuff um so yeah that's kind of one of the ways we do it we say that anandamide may be more tonic and 2ag might be more phasic and like brought online when needed but doesn't do a lot there is some evidence that 2ag may also have a role to regulate some circuits under kind of resting conditions as well and there certainly are some situations where anandamide might get brought into play um 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 the end of the day do the same thing they're regulating neurotransmitter release um through retrograde signal but what stimulation brings them online or what drives their activity May differentiate and we don't really understand all the details behind that outside of the fact that we very clearly know 2ag is activity dependent so as that neuron becomes more active it's going to make 2ag to regulate its inputs um so yeah you have this very complex system and it's really widely distributed in you know it's everywhere cannaboid receptors and the endoc cannaboid molecules are in the cortex they're in the hypothalamus they're in the strum the hippocampus the cerebellum all over the except the one area where it's really interesting actually um where you don't really see much receptor is in brain stem populations that regulate um 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 cannaboid receptors are quite similar but um as it's been well established people can overdose and fatally and die from opiates relatively easily and the way that that tends to happen is uh when you activate the receptors in the kind of cardiorespiratory parts of the brain stem it depresses neural activity so as the person loses Consciousness um they also unconsciously will stop 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 um and breathing function and so that's I mean you know there's always the saying like there's never been an account of someone actually dying from a cannabis overdose or a THC overdose I mean certainly people can do stupid things while they're intoxicated that result in their death but in the same manner that someone can die from consuming too much opiates that doesn't seem to be physically possible with cannabinoids as far as we've seen so far um and a lot of that is just because of the localization like for some reason it's just not the receptors in that part of the brain so very interesting um a lot of uh kind of afficianado questions about the receptor biology I'll just um spare everyone the details by just um highlighting something that you already said far more eloquently than I will which is I think it is fascinating that this whole system has both a tonic like a steady release capability and uh a phasic you know so the ability to spike forgive the p p the neuroscientists will know what I'm talking about to spike more activity of the system superimposed on that tonic activity because this is something that you see in the dopamine system this is something that you see in essentially every neuromodulator neurotransmitter system um but it seems that the endocannabinoid system has accomplished this quite a bit differently so very interesting um uh unique system in in a number of ways that raise a number of key questions so yeah if you go back to the munchies question you had um so if we tie into that one of the so there's a few ways I mean cannaboids and feeding are a really interesting thing because Proto like if you ask people like kind of the prototypical responses to consuming cannabis most people would usually say Munchies is one of the things that pops up pretty regularly and so you know the cannabinoid receptors are very um they are expressed in these feeding circuits in the hypothalamus um and you know there's a lot of complex circuitry there that can regulate food seeking behavior and yeah we just had an episode with Zack knight from hhmi and UCSF where he talked about like the agrp neurons different neurons of the hypothalamus we can link to that in the show note captions um uh nowadays a rich understanding of the neurons that stimulate food seeking craving and and and so we know that like cannaboids they regulate again those inhibitory inputs around agrp neurons for example and so one thing they can do is disinhibit those agrp neurons so they become more active and that can drive food-seeking Behavior so that's certainly one mechanism of it but there's also a huge reward component to this um in terms of the munchies and so we know that like you can also just dump an anide for example this is you know Steve mer and Kent be did this work years ago where they just put an anide into the nucleus of incumbents and that can also stimulate palatable food intake so you also have this ability to integrate with the reward circuitry um and then there was also this fascinating paper from a Japanese group in PN I think about 12 years ago and what they found was they would um give a rodent a canabo 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 canabo if you stimulated sweet taste buds you got an enhanced response in the gustatory cortex but not if you did salty bitter or sour or I don't know if they did do mommy in that one but it was very explicit to sweet tasting and so you have this kind of ability to like jack up the way the brain is processing sweet tasting Foods you have this engagement of the reward circuitry and then you also have this ability to regulate agrp neurons as well as the Palm C neurons there's kind of both sides to that in the in the aru nucleus um 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 a component of my lab that studies feeding behavior and one of my posts has been doing these projects for years now trying to understand almost like at a behavioral mechanism level what the munchies are and what she's been looking at is we kind of started thinking about the idea that you know what is it that because it's not just food seeking and it's not just you know like just want to consume something there's there's a maintenance of eating and so we know from humans and animals you can satiate them you can make someone full and then get them high on cannabis and they'll reinitiate eating so that's an interesting thing in of itself because that means you're disrupting either the ability of the brain to detect satiety or you're messing with a process we call reward devaluation and so reward evaluation is like you know if you haven't eaten for a day and you see like a picture of a pizza someone brings a pizza in front of you it just looks delicious that First Slice tastes amazing it's salty it's fatty it's delicious you eat five of those slices it feels greasy and nasty and so that process of how you perceive the food and its reward salience degrades as you eat and as your brain basically shifts into a thing of we don't need to consume calories and food anymore we're okay we're full now um and so we've done a series of experiments in the lab where You' 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 um and you get them high on like a cannabis extract we have these Vape chambers that are like um I don't know how else to describe it outside of like a little hot box it's probably the best way to this CU it's essentially a kind of a a locked airtight box that the rack goes in and it gets like Vapor Puffs and it fills up and then they inhale this and then it clears out and they get another puff and then it fills up and we do this for like 15 minutes and we've tit traded all this to get exactly blood levels of THC that you would achieve in someone who's you know consuming cannabis through smoking um and so we get them to that point and then give them access to food and they will yeah go Gang Busters they eat food doesn't matter what you give them you give them plain Chow they go to town you give them fatty you give them sweet they love it all but you pre satiate them and they get them stoned they will reinitiate eating again and you make them work for it where they have to like lever press um and you get them stoned and they will go to town on that and they will work and proof that even under the influence of cannabis um animals will work hard yeah they for food I don't know about other stuff but for food they certainly will I mean and at least weird it's in C Mo have done this at Hopkins as well they've shown similarly using what we call Progressive ratio which is a essentially a thing where it's like the first time you press a you immediately get a sugar next time you got to hit it twice to get a pellet then you have to hit it four times to get one yeah then you got to hit it 16 and then and it kind of scales exponentially up um I mean we've had this one female we kind of joke about in the lab this one female rat and you get her high and she'll do like 300 lever presses to get one sugar Pelt like she really wants it um so you can really kind of goose up their motivation to eat and so there's clearly a rewarding aspect of this because they're motivated to engage enough in working to get access to the food but you can also um do another way of testing this question which is you comp paare a food with um something that will make the animal feel nauseous like lithium chloride this is kind of the way that you would test uh condition taste diversion so you give them access to a food and then you give them something that makes them feel nauseous and the animals will avoid that food and so um that's another way to kind of devalue a food is by pairing it with a nauseant so the animal no longer likes it so again same situation you can get the animal stoned and it will re-engage in eating that food that it had devalued through being paired with a nause and so through either satiety or making it um kind of a a negative Associated flavor because the animal got nauseous before you can kind of override these Effects by giving THC and so that could be a complex process that either involves changes in the reward circuitry this could be something that's like from the orbital frontal cortex which is a very important part of the brain that scales reward and kind of assesses how much someone wants to work or an organism wants to work to achieve a reward at the end so we haven't figured out the circuitry of this and where exactly it's acting but I would say a lot of the stuff that you know we and others have done kind of supports this idea that a lot of what the munchies is is this ability to kind of almost lock in the reward value of food so that it doesn't Decay despite satiety despite eating over time it just keeps it highly Salient so that they want to work for it still um and then similarly we've also we and others have also done work to show it can block satiety signals so we know endoc canabo at least um are capable of overriding leptin so leptin is an anorectic molecule comes out from the fat and usually we release it when we've eaten a lot and it's one of these things that tells our brain stop eating you know it works through again uh populations in the arcu nucleus and changes the way those neurons function to drive food seeking behavior um and we and others have shown previously that that you know if you elevate endocannabinoid you can override that and actually one of the mechanisms by which leptin seems to suppress feeding is actually by turning on the the metabolism of endoc canabo so that their levels Decline and so as you lose that endoc canabo function the animal is less interested in eating and so you can prevent these anorectic effects of leptin by like goosing up endoc canabo activity as many of you know I've been taking ag1 for more than 10 years now so I'm delighted that they're sponsoring this podcast to be clear I don't take ag1 because they're a sponsor rather they are a sponsor because I take ag1 in fact I take ag1 once and often twice every single day and I've done that since starting way back in 2012 there is so much conflicting information out there nowadays about what proper nutrition is but here's what there seems to be a general consensus on whether you're an omnivore a carnivore a vegetarian or a vegan I think it's generally agreed that you should get most of your food from unprocessed or minimally processed sources which allows you to eat enough but not overeat get plenty of vitamins and minerals probiotics and micronutrients that we all need for physical and mental health now I personally am an omnivore and I strive to get most of my food from unprocessed or minimally processed sources but the reason I still take ag1 once and often twice every day is that it ensures I get all of those vitamins minerals probiotics Etc but it also has adaptogens to help me cope with stress it's basically a nutritional insurance policy meant to augment not replace quality food so by drinking a serving of ag1 in the morning and again in the afternoon or evening I cover all of my foundational nutritional needs and I like so many other people that take ag1 report feeling much better in a number of important ways such as energy levels digestion sleep and more so while many supplements out there are really directed towards obtaining one specific outcome ag1 is foundational nutrition designed to support all aspects of well-being related to mental health and physical health if you'd like to try ag1 you can go to drink ag1 / huberman to claim a special offer they'll give you five free travel packs with your order plus a year supply of vitamin D3 K2 again that's drink a1.com huberman you you're talking about increasing endoc canabo activity um 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 um 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 um but just to make it very clear um is there a way to increase the activity of endoc canabo with without ingesting THC yes I mean they dynamically change all the time so but you're I'm talking about um you're talking about experimentally or recreationally adjusting their levels but how does one do that um without using THC so okay few things there we'll take a step back so THC itself isn't going to um it does its thing by acting directly on the cannaboid receptor not so it sort of mimics the anandamide and and 2 AG yeah so THC going back to kind of the pharmacology of this so THC if you look at how it interacts with the receptor um 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 th use a sledgehammer and it overrides endoc canabo by the way um Matt's referring to the fact that I said that in a previous solo episode about this um and there I was nesting it in the concentrations of THC that can be found in high THC cannabis yeah um so essentially what I was saying is that at very high THC concentrations the amount maybe not The Binding Affinity but the amount of THC that is available to the CB1 receptors is going to exceed what's normally found in terms of the amount of anandamide that can bind to CB1 receptors because what you're talking about is a superphysiological condition it's I mean you don't really actually need much THC in the brain to produce psychoactivity like it's it's a little bit of a mystery to be honest exactly how it works I mean I think the main way that most people in the cannaboid theory field would look at this is that THC is not like a very strong Agonist I mean even if you look at its ability to trigger an intracellular response it's much lower than 2 AG it's actually more like an anide so you said an anide is high Affinity low efficacy so THC is the same THD is actually only a partial Agonist it's not even a full Agonist at CB1 but it is high Affinity it's high Affinity so it has the ability so but the tricky thing with that is it can out compete 2 a but because it's a lower efficacy Agonist than 2 AG in that sense it's almost blocking the effects not um amplifying them blocking the effects of 2ag but does it block the effects of anandamide um it you know to THD and anandamide I would kind of the way I would visualize it is because they seem to have relatively similar affinities and efficacies of the receptor they might let's say dance around so it would be somewhat interchangeable the difference there is and this I think is the big point about what THC does versus endoc canabo because we know now through the pharmaceutical development of drugs that can boost anandamide levels which exist we have Inhibitors that prevent their metabolism we can Elevate them there's no intoxication and no psychoactivity associated with elevating anandamide that's a very interesting point that we should highlight so there are drugs that now exist that can block the breakdown of anandamide make more available presumably by disrupting some enzymatic breakdown exactly and therefore lead to more binding of the now elevated levels of an anandamide that are available to CB1 and you see no psychoactive effect no psychoactive people are not aware that they yeah you can do no one can guess yeah no one can guess what is it used for um well I mean it was developed the first molecule really was developed by fizer to look at if it could work on pain um the first trial that was done did not work it was like um kind of strange osteoarthritic knee pain trial that was like even in that trial the positive control of nioxin barely worked but because the fa inhibitor which is uh take a step back FS the enzyme that chews up anandamide so the drug that is developed inhibits that enzyme so you prevent the enzymatic breakdown of anandamide so we just call them fa Inhibitors um so this drug will boost anandamide levels quite high and in animal research showed some efficacy in modulating pain and so they put it a trial and it didn't work against the positive control of nxen which is like an ends say just like Advil basically a leave yeah essentially yeah so um and that drug didn't work that great to begin with so it was maybe some issues with the trial but it essentially killed the development of the drug from that point on because everyone's like oh it's not going to work so it kind of sheld for a while um a colleague of mine Marcus hilig and leam Mayo uh Leah's now a colleague of mine in Calgary but at the time she was a postto with Marcus in Sweden and they were able to get access to this molecule right before covid essentially um and they did a a trial in just healthy controls with it which again this is kind of jumping the gun and so of other stuff I'll talk about so I'll tether back to that but what we did what they did was they dosed people for 10 days on this drug and then we looked at stress and fear because this is something that I study this is something that they were interested in um and we did find that boosting an anomid with this drug over 10 days uh was sufficiently cap capable of dampening stressinduced autonomic responses so like looking at heart rate or skin conductance I think skin conductance was the measure we did there but it's a proxy for like adrenaline release um so it blunted that and it blunted subjective feelings of stress as well so people had lower levels of saying they actually felt stressed um and it kind of helped remove this like conditioned fear memory that we had they had trained people to do and so I worked with them on kind of doing the biochemistry of this to make sure the drug was working properly um but it was very interesting because we did see in that situation where elevating anandamide produced kind of like a reduction in stress perception a reduction in stress physiology responses and kind of um help kind of reduce fear and so that is kind of an interesting outcome because it 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 um so that's kind of one of the things the drug has not really been used that widely yet it's still it's one of the frustrations I have is um a scientist who does a lot of translational work and with clinical Partners like Leah uh 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 mid them trying to do that um we did just complete a trial that LE and Marcus ran that I worked with them on as well that was on PTSD um and so there are various potential indications for this I mean Johnson and Johnson developed one as well and they looked at it in social anxiety disorder they had some moderate efficacy in their trial so I'd say the jury's still out on exactly what we're going to do with these but um they have some potential I think in certain clinical settings we just have to figure that out exactly but I think going back to where we started this from they're not psychoactive and so I mean when fizer 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 end cannaboids 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 um fiser then actually had to do they did a sleep study to show that it did have some effects on sleep cycle um the same way THC does and then they also did like a an invivo pet binding study to show that they could displace um 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 Anand by blocking this entic breakdown of an endide leads to at least from what I'm understanding vastly different subjective experience than ingesting or smoking THC which brings us back to THC so what's it doing and cannabis like you know um so I think it seems that this this thing that we call cannabis and THC are overlapping with the endogenous effects of anandamide but here you're not talking about endogenous normal levels you're talking about pH logically greatly increasing anandamide no psychoactive effect no Euphoria no Munchies you know Etc then people smoke or take an edible of THC or cannabis and you get a vastly different set of effects so maybe we could talk about uh THC and the CB1 receptor and since we're here we might as well um talk about CBD and and the I think you're going to tell us the lack of interaction with CB1 receptor right um and what is cannabis doing at the level of these receptors because um 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 uh active molecules in there tpin 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 cannaboid system yeah I mean I think I would say the main way that we think about this is the difference between endoc canabo and THC is endoc can abono are going to be released in a very specific spatial and temporal manner so they evolve to do that yeah so there's going to be and I think like it's very clear that like anandamide for example is not active at every synapse that has CB1 and so when we boost anandamide signaling by inhibiting its metabolism all we're doing is amplifying anandamide signaling at the synapses it already exists whereas THC when you consume it orally or inhalation wise and it gets into your blood and into your brain um it's just blanket activation you're just carpet bombing the whole system indiscriminately and so you're introducing the Lian the thing that binds the receptor this is Far and Away different than say like the actions of amphetamines which are disrupting the normal biology in a way that's giving you an amplification of an endogenous mechanism yes right um if that was all just nerd speak for those listening it's one in the context of amphetamines what you're doing is you're taking an endogenous system a naturally occurring system and you're greatly amplifying the amount of dopamine the amount of norepinephrine that's available with what we're discussing today the endoc canabo system seems to be producing a set of effects that might overlap with the THC effects but THC is doing a bunch of other things it's and that's because THC and we'll talk about CBD but at least THC is acting as the Lian it's in some sense we don't want to say replacing but it's masking the effects of an andmine I think the problem is when you just blanket activate all the CB1 receptors in the brain indiscriminately like you do when you consume cannabis with THC the resulting effect is the intoxicating State and it's probably because there's a lot of CB1 receptors in the cortex and those are going to be differentially regulated at different times by endoc canabo whereas when THC hits them all of them are going to get affected at once and if you think of the way that I had described how cannaboid receptors work by essentially I mean in its simplest form what cannaboid receptors do is they change the way that two neurons talk to each other um and so so you're changing all the networks simultaneously yeah so if you hit a whole bunch of networks simultaneously you're just going to change the way that information processing and perception occurs 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 endoc canabo or that it's boosting endoc canabidol as opposed to a system that's very finely tuned to do very specific things at very specific times that's very helpful so the analogy that I was considering using coming in here like the difference between endogenous testosterone or estrogen versus pharmacologic uh testosterone or estrogen given as a therapy doesn't app is very different because that's that's an 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 uh it's been established at this point that for example if an organism doesn't eat for like a day so you f Ed um at that point in those feeding circuits in your brain like the aru area where these arrp neurons and stuff are you'll start seeing elevations in endoc canabo so endoc canabo levels start kind of going up and up um 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 Reser reserves we should probably eat more and so there are obviously a few mechanisms that do this npy is another one and uh gin and things like that so there's a lot of redundancy in these systems but endoc can aboid are just one of the molecules that seem to fine-tune like the feeding circuitry and so in states of fasting endoc cannaboids go up explicitly in that circuit and there's some evidence they also go up in like the nucleus accumbens and affect some of the reward circuitry so they're probably driving food seeking behavior and enhancing the rewarding aspects of food at the same time and so that's like a natural IND ogous mechanism to regulate feeding B based on nutritional State THC on the other hand you know it hits the brain yes some of it's going to be the intoxication but in tandem you're going to hit the CB1 receptors that are in those feeding circuits as well and the consequence of that is going to be I mean the way I kind of analogize it to people is I say it's almost like tricking the brain into thinking that you've been fasting because you're now activating receptors that are normally activated following kind of a fasting State and as a consequence of that it pushes someone or an organism or human or whatever into a state of food seeking Behavior because now food also has high reward value and they're kind of the way their food circuitry is responding in the brain at least seems to be similar to what would happen if they' been fasted and the thought is that's why when people you know when someone gets Stone they're not like going eat lettuce they want high calorie food they tend to like things that are high carb high fat that that combo seems to be what people like when they're intoxicated with cannabis and that comes with a lot of calories and the point of that would be trying to replenish lost energy stores and so this at least is the kind of the theory that I have about what it is that it's doing is you know and I think you can make this analogy for multiple different things you know if we talk about pain or stress we can say similar kinds of things are going on is that endoc canabo normally do one thing but when THC hits the brain it's still activating these circuits in addition to everything else it hits so you still drive that response that the endoc canabo 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 um what are some other known mechanisms by which um cannabis can change people's psychology um let me focus in on one particular uh aspect of subjective experience which is Focus do you think that some people use cannabis because it allows them to focus better um and I rais this specifically because I think that in the past uh cannabis has had a bit of a reputation for making people Spacey you use the word stoned I'm 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 um either way or I just don't I mean as far as I'm aware it hasn't been studied in a lot of depth I mean there's some things you know a lot of the stuff that's been done is usually more like kind of acute memory tasks like a working memory or recall or something like this as opposed to explicitly studying Focus anecdotally there is certainly a lot of people that report that so my understanding is that people who use cannabis have poorer certain forms of memory but not necessarily poorer 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 can say confidently that I would be comfortable saying is that acutely while someone's intoxicated on cannabis there is definitely shortterm effects on memory processing so people tend to negative effects or enhancements or decrements I would say most of it has to do with recall or consolidation so there does seem to be some I mean certainly the animal evidence is very compelling there but again we can talk to what some of the limitations of that are um but in humans I would say most of the work that's been done would suggest there is some short-term memory deficits that are present during the intoxicated State I have not seen very much compelling evidence of long-term effects that emerge like when someone's not intoxicated but they use cannabis somewhat regularly I don't think there's anything compelling for that um 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 is usually not super robust um it's still there I mean I think the effects that are more often seen in kind of um let's say smaller laboratory studies where they're using people who've used cannabis but aren't regular users might be a little bit more profound because they may not be you know used to that state let's say I mean there's certainly something we call State dependent learning which I'm sure you're familiar with um and this is something people I mean I remember learning about this in undergrad through alcohol so like you know someone first time they get drunk tries doing something they're very bad at the task but if every time they're drunk they do that task they become better at doing it under the influence and so then all of a sudden you know they regularly do this task while they're drunk and someone tests them and they don't look like they're impaired at all because they've done it so much and so I should just say this point has often been confused by undergraduates and others to assume that just because one can gain proficiency at a task while under the influence of a substance does not mean that you have higher proficiency at that particular task while under the influence in fact the way it was presented to me when I was an undergraduate um uh was incorrect the I remember the lecturer said and later corrected himself um I won't call him out here because that's unfair he's not here to defend himself but it happens in lectures um that people who studied Dr drunk would be better off coming to the exam drunk that is not true from what I understand I don't think better off no but they would probably score better than someone who had never studied drunk and came to the test drunk correct just because they had had some State dependent learning uh and so I think when we're talking about if you're talking about someone who's a chronic cannabis user they're going to have done a lot of cognitive tasks while they're under the influence and so if you acutely test them the impairment you might see in them is probably less than you would see in someone who's relatively naive or much less experienced user that being said I think it's relatively well established most people would agree that uh acutely intoxication with cannabis doesn't paare memory processes in some capacity what explicit form of memory I don't think I could speak too comfortably just because I'm not a memory researcher and I know there's very specific things of like episodic and declarative and whatnot so um I can't say that but I'd say it's kind of generally and I mean again you can replicate this in animals where if you train them on a task while they're under the influence they don't seem to have consolidated information as well um 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 or stable in anyway so yeah thanks for clarifying that and also thank you for clarifying the um discrepancy between endogenous cannabinoid binding and affinity for CB1 versus THC I really appreciate that because that's something that you and I discuss in light of the solo episode I did about cannabis and uh now you've made it clear uh 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 binding more uh with higher Affinity at particular receptors yeah I mean I don't actually even think it matters if it's high THC in the Cannabis I think like some people can get very intoxicated off of very very low doses of cannabis is that right I mean you look at Edibles for example I mean this may be an interesting segue into root of administration stuff because I think it's an important point that a lot of people don't recognize is the difference between someone inhaling cannabis versus someone orally consuming cannabis is like a different game yeah let's talk about this because I know that um you and I um arrived at different understanding of the fastest typical and slowest um routes of Entry um for uh THC into the system um into to get to arrive at the brain right um the numbers I gave in the previous discussion about this were related to how quickly inhaled smoke moves from the lungs to the bloodstream and crosses the bloodb brain barrier which is very fast right which is very fast um 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 I it's very fast okay so so there may be um it may be that it is the same as nicotine it may be that it's faster but um importantly it it can be fast but but typically how fast is the onset set of the subjective experience of okay um you know somebody takes a hit off a joint or a bong hit and they start to experience the subjective effects of euphoria Etc how quickly after two to five minutes I would say 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 um it's pretty quick and people titrate cannabis pretty well like at least people who've used it a couple times and understand this I've seen some people not tit tra it very well depending again on how you so again this can vary so like you know cannabis from the 70s was like I don't know 5% THC let's say it was pretty low uh 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 um yeah I mean that's a that's not just a fair amount that's I mean if we if we were talking about alol concent Spirit of vodka yeah basically you're talking about a beer or a wine to a spirit and there are aquavit varieties so to speak um by the way I think when people um hear me talk about any kind of uh drug that can be used recreationally or alcohol I think some people assume that you know I'm um ult Ultra anti all these things I'm actually not right I'm not an alcoholic so I can um drink a little bit and I have I just don't tend to and um we could discuss cannabis in a different venue um but the uh the point here is we're not trying to frame this as what people should or shouldn't do we're just trying to inform people I want to be very very clear about that so um but when I hear about you know um 20 to 30% concentration as opposed to you know 5% concentration that's significant so I would say this is what's super interesting and this was something that came out of the way that cannabis research is done certainly in the states and Canada's been quite behind on this even with legalization we haven't caught up um but they have been doing lab-based studies of cannabis you know mag Haney Harriet dwit there's cluster of researchers around the country Zea Cooper at UCLA here have all done this where you know you have people come into the lab you give them cannabis you measure subjective outcomes or neuroimaging outcomes or whatnot so to do this you can't use commercial cannabis and pre even like the state-by-state legalizations hasn't Chang this so if you are doing cannabis research in humans and you're funded by like naida which is National Institute of drug abuse um you get all your cannabis sourced I mean this may be changing I think there are some shifts that are happening but historically in all the literature that we would talk about that's kind of pre the last couple years all that cannabis came from one source which was I believe a farm in like Mississippi that was essentially funded by naida to produce cannabis lucky farm and well the Cannabis that came out of it though and this is one of the reasons a lot of the clinical stuff people have kind of been like oh I don't know how representative this is cuz it reflects cannabis that I would say is more from like the 70s or ' 80s so it would be like 5 to 9% kind of THC cannabis now when you put someone in a lab setting and you get them to smoke to level of intoxication people would take you know whatever eight toes let's say something like that um and that's where they would stop and so you know a lot of the labs that use this have always been like our people who are regular canabus users are getting high off of it it's not as potent as the stuff that's on the street but they're clearly getting intoxicated from it and it's giving us reliable data um so when they started looking at the blood levels of THC that you achieve it was around 100 nanograms per male of THC give or take that seemed 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 wouldn't you study what we're using but because of the legal aspects of this you could bring those products into the lab they'd never been standardized no one knew exactly what was in them pesticides all this other stuff that could influence it so from a safety perspective it was always like no you use the the Cannabis that sourced from naida um so there's a group in Colorado Kent Hutchinson and Angela Bryan and cinnamon Bidwell have kind of I would say became very creative actually to figure out how to study cannabis that's being used I call it in the wild like in kind of an ecological sense setting let's say and so they created what was called the canavan and the canavan was a way to study people using products on the street but not have them come into a laboratory setting where it was complicated and so what they would do is they would drive the canavan to someone's house but they'd be parked on the street and someone would use the product whatever it was on in their own property and their own time and then come into the canavan to have blood taken to look at what their THD levels are and to undergo testing so it was actually like I think this was a 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 naida with what is being used on the street I love this I mean as somebody whose lab has done a in laboratory vr-based experiment on human anxiety and fear and then compared that to a you know a clinical study that we did sort of in Mass where people were at home doing specific respiration practices you have many more subjects but of course they're reporting back their effects um well you can monitor them by device you know look at HRV look at heart rate Etc um I think having the ability to compare and contrast in laboratory and X laboratory data is extremely valuable and I mean my view is you need both because you need the in laboratory for the control because we all need control over various things but you also need the ecological validity to see how it shakes out and make sure it looks the same yeah for people that have never been to a laboratory or tried to find a parking spot at a university that's an anxiety inducing experience of itself a novel experience while someone's intoxicated with cannabis can also create a very different altered state I wouldn't want to be stoned in a laboratory I'll tell you that much I feel like there's pluses and minuses to both sides but I think the data together is very compelling and that's where we get a lot of advance in the field so what uh Kent Angela and cinnamon did with the canavan was kind of create this situation that allowed this research to occur and what we found fascinating I remember talking to me Haney about this because all the people in her lab setes tended to always hit around 100 nanograms per male 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% their blood levels are the same so they're still coming in around 100 nanograms per male because people are really good at self titrating now where Things Fall Apart is with the concentrates so then you go into things like dabs or these like high potency products that are now like cuz 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% THC just by sheer biology so it Taps out there that's about as high as it's going to go concentrates can go up to like 90 98% so you can get really really is there tinctures distillates like yeah various just in oilbased forms that are very very high potency products those are incredibly challenging to tight trade like they cannot be tight traded 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 Mill so with cannabis planned there does seem to be this ability for people to relatively self- titrate and then my buddy Ryan mcglaughlin 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 uh 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 well other reinforcing drugs so it was a really important finding that you could do this um and what Ryan found was he actually did one study where he gave them access to a low potency product a we'll call it me medium and then a high and what you ended up if you look at the data is the one the rats like the best was the medium potency product interesting and if you gave them the high potency product they would actually take less Vape hits off that than they would off the lower ones and again all their blood levels tended to Cluster in the same range because they titrated like even at the at the rodent level they're able to titrate because of the lag between inhalation and feeling the effects is only on the order of a couple of minutes people can titrate better I mean not just people it seems like the rodents can as well so the higher potency cannabis where it becomes a problem is if someone's highly inexperienced and they consume a whole bunch of it without allowing that time lag to occur um and then they can probably exceed the levels they intended to and consume too much and then have a probably an adverse response so does that mean that cannabis use rarely leads to tolerance of cannabis use I wouldn't say that there's definitely some degree of Tolerance the Toler 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 yeah sounds like those are are precarious that somebody who thinks they have a lot of experience or God forbid no experience takes a concentrate and is what no longer um getting the euphoric experience that they anticipated but instead are getting what a a paranoid anxiety I think I think you're you're far more likely to go overboard and have an adverse response but also I think the problem is if you're using a product of that potency and that much THC floods your system on a regular basis the biological changes from that are going to be very different then what you get if again you're titrating your your THC from um inhaling plant at roughly the same level whether that's a 10% 5% or 25% people generally tend to scale this is a very important point and I'm going to highlight it because I think it's um 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 um present in the 70s and 80s and presumably 90s as well yeah I'm a uh I was a teen in the 90s so maybe I'm alluding to to something there um 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 um people are overwhelming their system with THC basically um this could be stated in real world terms as people are taking fewer tokes um of the higher concentration stuff that allow them to match blood levels that were present in the person taking many more toes in the 70s so the joke I always make to people is they say go watch a chich and Chong movie from the late '70s look at the size of the joints that they smoke in movies like that relative to what you would see someone on the street consuming nowadays 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 overc consume let's say because there was a much lower concentration of THC in the plant so they're able to consume assume 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 overc consume higher potency cannabis even independent of concentrates if they're not allowing that titration to occur also if you have someone who is just exquisitely sensitive to THC for various reasons um even one or two toes 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 um anecdotally you talk to people about cannabis and a lot of people who don't like cannabis have say oh you know I've tried the new stuff's too strong and if there's someone who's kind of more in our age range who grew up in an earlier decade where things were a bit different they may be referencing their own experience from when they were younger and what they were able to consume and now they try doing the same and it hits them like a sledgehammer so it's a little different in that sense but you know and I don't think it's to say it's like not concerning that cannabis is as high as THC as it is I just think if I'm going to put my efforts into kind of like you know Public Health perspectives of this I would be digging my feet in much more about the access to concentrates and the issues and the potential harms that are going to come with them than I would about the Cannabis flower myself that's just my opinion based on what I see with the concerns and what we've seen from the data in humans and I think the the real world e ecological studies that the Colorado group have done have been very informative in this sense because yeah if the if the blood levels of THD you achieve from concentrates are double to Triple of what you get even from higher potency flour that's a concern like I think that's where problems start arising because then you're going to start seeing a lot higher degree of Tolerance I mean there used to be more of a debate in the field as to whether people develop tolerance because one of the things with cannabis that I do find very interesting is with a lot of chronic users they don't escalate the way you would see with cocaine or alcohol where there's very profound tolerance that develops and so I mean people definitely see this in cocaine where people can become um tolerant almost immediately and so dosing starts scaling up very fast yeah usually it's the life destruction that that thwarts their Progressive increase seriously or the cost I mean the sheer cost another form of life life life life deterioration yeah that is required to be able to maintain that but with cannabis um 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 me 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 um don't although people get their pets high and we don't know what those uh pets think about that not good don't get dogs if also High one can assume a lot of things about what your pet is thinking while also High um sort of half joke there um but yes positron emission tomography is one way to assess their binding of um drugs within the brain as well as activity of endogenous uh neurotransmitters neuromodulators such as um anandamide uh dopamine Etc yeah so so a typical pet study in a human looking at this they'd give a molecule that's radi labeled that will bind a CB1 receptor you can scan them uh 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 um 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 downregulating 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 uh 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 Sheely I think as a response to the biology of hitting the system that heavily with that much you know THD as it comes in because they can't titrate it the same way it makes sense yeah these concentrates sound like something to at least pay attention to as a potential problem I'd like to take a quick break and acknowledge our sponsor insid tracker insid tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals now I've long been a believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long-term Health can only be analyzed from a quality blood test now major problem with a lot of blood tests out there is that you get information back about metabolic factors and hormones and lipids and so forth but you don't know what to do with that information with inside tracker they make it very easy to know what to do with those numbers because 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this is not an experiment U but in my experience more irritable when they don't have access to what they call their quote unquote medicine yeah so um you know that speaks to a dependence or something um 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 um have defined it as a you know Progressive narrowing of the things that bring you pleasure such that you know it causes um disruption to other areas of life your life becomes maladaptive yeah I mean I'm not going to play with the definition of addiction I feel like I have enough friends in the addiction space and it's a very contentious field so I mean I will try and not use that word although I understand talking to the general public that's kind of you know if you say someone has a use disorder versus an addiction that may not make sense to them right but that's the nomenclature now that people are using alcohol use disorder cannabis use disorder this is what you start to see now instead of saying being addicted to pot or being addicted to alcohol and so I mean an addiction is obviously a very complex thing that again I don't want to touch it simply because it's not my space um but that being said there's no question that people can develop cannabis us disorder I mean it's it's definitely a thing so if we say is cannabis addictive in kind of a you know normal lay speak I would say yes it is addictive what does that look like how does that relate to other substances of abuse I mean certainly um 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 uh fatality potential there's a whole bunch of other health consequences but if we look at how we would Define a disorder the criteria for someone hitting cannabis use disorder is really no different than how someone would hit alcohol use disorder or opiate use disorder in the sense that it can consume their life it can shift the way that they behave they can put themselves in Risky positions to get access to a drug it can consume their time and their energy to have it like you said if they don't have access to it it can trigger you know an assembly of behaviors that looks like irritability anger frustration things like that so I mean the numbers in terms of the conversion rate of use to developing use disorder I would say are not entirely clear the kind of old numbers that used to get tossed around where like 9 to 11% of people that would start initiating cannabis use would probably transition to develop use disorder the more modern numbers I would say you know if we're looking at people who are already using weekly we're talking probably closer to 30% like so it's a much higher I mean when you're using that frequently then the rates of people who would qualify as having cannabis use disorder probably go higher so 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% i' say in in that neighborhood they would probably qualify as meeting criteria for a cannabis use disorder because weekly doesn't seem like that often no I mean it'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 life with cannabis the way they would view it is very differently cuz 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 uncom I don't think they would uh similarly if someone had a Brandy at the end of the night or like you know a night cap to go to bed and they did that on a nightly basis I don't think anyone would say that they have a use disorder and I think with cannabis there are a lot of people that kind of fall into that bracket that would use it you know even daily but relatively infrequently and kind of as an end of the day thing I think some of them certainly would fall under the criteria of cannabis use disorders because if you start looking and say well you know if you travel to like Egypt are you going to go put yourself at risk of going to jail to get access to cannabis because you can't function without it if you do then yeah you know you've got cannabis use disorder you know are you going to burn relationships are you going to start failing at meeting responsibilities or getting things done in time because you're preoccupied with cannabis yes you're GNA hit the criteria for cannabis use disorder if it's someone who's kind of just intermittently using it the same way that a lot of people casually use alcohol I would say a lot of them probably wouldn't hit criteria but I think to someone who has never had cannabis in their Inner Circle or in their life they look at it like a drug like cocaine whereas they're like wow if you were using cocaine on a daily basis we'd be super concerned about you and so I think that's this like it's just as you go I mean cannabis is in this really weird transitionary period I would say of going from elicit to not just because of the changes in the legal regulatory framework I mean in Canada now we're like five and a half years into legalization so in many ways I would say the transition has happened where a lot of people view cannabis very similarly to alcohol whereas you go to some states and the perspective is still very different and certainly if you're still in one of the states where there's no legal access people still look at cannabis the same way they look at a lot of other um illicit drugs like cocaine or amphetamines or things it's interesting I I was under the impression this has really changed over the last you know 5 10 years you know growing up it was I mean I think there are still people in jail now because of uh possession and sale of of cannabis and then of course there are stores not far from here where people are selling can ironic yeah sadly it's a very I mean obviously a big push for legalization is not um endorsement of the safety of cannabis it's more the the harms associated with prohibition outweigh the harms associated with legalization I think that's generally the public health perspective that's certainly what motivated it in Canada um and there was a you know some attempts let's say at restorative justice in terms of removing criminal records and things may not have been entirely as successful as people had hoped it would be but it certainly has changed things I mean we can look at our federal data and see that arrest rates related to cannabis are obviously very low compared to what they were um that obviously becomes very important because there are clearly minoritized 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 um just potentiates all that so I can understand the legal framework behind why there would be a move to a legalization state over a Prohibition state which again a lot of people confuse legality with safety which is a weird I mean alcohol is the perfect example of this I mean you look at the scale of harms on a public health level I mean alcohol Stacks at the top it across the board in terms of harms to the individual harms to society it's it's a lot cannabis has harms there's no question on that um it just would fall lower than alcohol um but the way that people view it a lot of people are like alcohol is legal therefore it's safe and it's not something to judge people on cannabis at least historically was illegal and in some states still is so people view it very differently and I think it's an interesting thing um 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 um Andor um incidents of people going into the emergency room uh 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' would say there's like demographic differences uh proportionately when we look at the biggest change in use it's actually elderly communities it's like 55 plus um especially women over 55 tend to be more cannabis use more cannabis use now granted their Baseline was quite low pre- legalization so if you look at a fold change it looks like a very dramatic increase raw numbers it's probably not that that high but I mean it was like 1 to 2% or something before and now it's gone up to like 8% or something so it's a 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 20 24 that group has definitely seen um increase use as well does it split male female historically cannabis tended to be more male biased i' would say the the gender separation there has kind of narrowed quite a bit um where you do see a lot more like more females used and historically had um there is a little bit of difference females tend to prefer Edibles over males so um males tend to like inhalation over females so like roots of administration vary a little bit based on um who someone is but um yeah interestingly we don't have a lot of actual indication that teenagers have used more um so like you know you look at 14 to 18 year olds that has been now granted our Baseline going in was pretty high as is down here in the states I mean Canada and the states both hover you look at like grade 12ers and you know it's somewhere between 35 and 40% of them have used cannabis now I mean you even have some that are like probably around 5% are probably almost daily users so like you do have a pretty high Baseline to begin with in that group but that has remained relatively unchanged uh if anything some of the states when they legalize saw slight dips in in teenage use of cannabis so I think like that's obviously an important demographic to have ra this was one of the concerns with legalization was you'd Pro 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 um 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 um 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 um 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 I want to make mention of something along those lines um I actually know somebody whose child um accidentally a at THC containing gummies um fortunately the child was fine um but they're actually pretty serious ramifications for this um the parents actually are quite susceptible to uh legal action if this happens right so this is something to like really keep in mind I mean there are a million other um Health rated reasons why this is probably I don't know if that's true in Canada the same way but I in the states yeah like if if if your kid gets into a of THC containing gummies and ends up in the emergency room there will also be uh most likely there'll be a police visit to that emergency room also and it doesn't bode well for the parents so it's it's a very serious issue and again this was highlighted to me by someone that I know who um 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 one of 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 in legalization and the change in policy and so you know if your kid ends up drunk underage it's not the same ramifications as if your kid used an illegal substance underage and so people are when some once cannabis was legal people were more likely to actually go into the ER because the consequences were different I see and so sure some of this is availability and some of it is just like okay I'm not as concerned now about something happening because I've taken my kid in like I'm not going to have my kid taken away from me or whatnot so so there is I mean both those factors I think have contributed to it but we definitely see the majority at least of kids ending up in the ER is almost all based on Edibles that's I 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 cuz kids find them so as long as we're talking about Edibles is there any fundamental difference between um the dose regulation that you talked about earlier of inhalants versus uh excuse me versus Edibles um meaning earlier you said that even if it's high THC containing uh 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 um you can end up in a vastly different place than you expected so Edibles so this throw is a wrench in the whole system and I'll say this in the context of blood levels and then what that means for my regulatory capacity as well because of the impact this has so Edibles are very low doses for the most part um I mean in Canada at least you cannot buy a pack of Edibles and I think this law might be changing at least when they first brought it in no pack could have more than 10 milligrams of THC in it so that either meant one 10 Mig gummy or two five Mig gummies or four 2.5 Mig gummies you get it um so you couldn't in one package have more than 10 milligrams of THC now for people who are I would say relatively naive to cannabis or THC even people who might use it intermittently most people will feel five milligrams like they'll feel some form of intoxication you know some will even feel it at 2.5 migs most people will feel it at five virtually everyone will feel it at 10 now if you look at the blood levels these produce we're now talking blood levels of 2 to 5 nanograms per Mill so folds lower than what you get from inhalation before you said 100 yeah so this is dramatically lower and so also the time course of this is fundamentally different so an uh oral consumption you know you're looking at a minimum of 30 to 45 minutes for onset of intoxication for some people up to 90 minutes after they've eaten now this is also the reason why the majority of Adverse Events that happen with cannabis happen with Edibles because people don't understand this and so they eat a cookie or a gummy they wait half an hour like I'm not feeling anything I clearly didn't take enough and then they'll double their dose and then like 15 minutes later it starts hitting them and then like once it fully kicks in it's just like a steamroller like I've heard of this happening yeah I mean there was that New York I think it was Moren Dow or someone went down to Colorado and she ate like an insane amount of THC in a chocolate bar or something like 50 or 100 milligrams and spent like the weekend on the floor of a hotel room being like this was the most aversive experience why would anyone do this um and again I think people just don't understand the dosing around this and so this is one of the things we're trying to do in Canada and I was create this idea of standardized dosing units so that people have an like we with alcohol we always say one beer is the equivalent to one glass of wine versus you know like a shot of tequila or something so that there's some uh comparator that people understand how many drinks are you know you know say two drinks you do you're going to hit legal limit kind of thing it seems very important yeah and so this is very difficult to do with cannabis because the dosing with oral consumption is just a different ball game it is with inhalation but what happens with oral consumption is like it kind of very slowly leaks out of the GI tra and it also goes through first P 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 its efficacy at least at driving a response through CB1 receptors seems to be higher than what you would get uh with just the parent molecule of THC itself self um and so and it it seems to accumulate a lot more as well so at any given time you know you've got THC kind of leaking out of the gut going through the liver making 11 hydroxy and it progressively accumulates in the brain and that's one of the reasons why it takes you know 45 to 90 minutes to kick in but then the high itself also lasts like six hours four to six sometimes eight depending on the person what they've eaten versus inhalation is just this like Spike so you get this very rapid because it goes right through the lungs into the blood goes into the brain but it also clears out and so yeah people will start feeling intoxicated two to 5 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 3 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 um you know based on what I was able to find um 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 um previously was there are a number of people who have used cannabis are going to take a drug test and want to know how fast it can clear from their system um but based on conversations we had offline um sounds like that 80 Days might be a bit too long I mean you could still fail a drug test at 8s I would say I feel like I think I think the way it was worded more it was like that you made it sound like that was the standard I wouldn't say that was the standard at all I would say for the majority of people 30 days probably after that they would not pass or they would be able to pass a drug test but that so abstinence for 30 days yeah after abstaining for 30 days and it's going to be highly variable depending on how much you consume I mean if you're talking about someone who's used it once I I don't imagine it would be in your system that long that'd be surprising the thing is THC is a lipophilic mod fat so it's fat soble it likes the stor it doesn't like the blood the blood is aquous and watery it likes fat so it goes into the brain it goes into the fat and it kind of resides there and it can essentially kind of slowly leak back as it as you know THC concentrations in the blood would reduce THC that's in the fat will start kind of leaking back into the blood still so detectably you will still have THC for quite some time I mean some of this again it's going to be dependent on how much cannabis someone's used how much THC they've consumed how long it's been in their system for I would have thought this was going to be somewhat reflective of people's body fat content although talking to colleagues who do this they say not always um but we do know you know certain things like exercise for example anything that's going to trigger adrenaline because adrenaline is lipolytic so adrenaline causes fat to metabolize and release stuff that's inside it so there are plenty of cases I've heard from people where they were testing themselves and were negative and then went for a run or went to the gym and then tested positive or lost weight yeah or they've lost weight and anything that's going to cause the the lipolysis to occur so that it releases that THC um you can certainly all of a sudden test positive again when someone had tested negative previously just because of the fact that there still is some in the fat and so this is where something like and this is what I mean by standardization of regulatory issues become very complicated was remember right when legalization happened in Canada all these kind of chemists were like talking to me about they're going to create like a breathalyzer for cannabis because this way they'll be able to do roadside detection the same way they could do with alcohol and I kept trying to say to them I'm like the rate limiting step here is not the science of detection thresholds it's the biology of how the body processes cannabis and you're never going to get a test that works because you can take someone who has eaten an edible and is profoundly intoxicated at and they will have possibly under 5 nanog per Mill of THC in their blood but you were talking about this metabolite that can come from the uh Edibles that doesn't come from inhalants that can have a much more get B from inhalent but not nearly as much as you get from Edibles um so it's a different it's sort of a different situation altogether it is but it's also the timeline because of the fact that with inhalation it's like a a a bolus that hits you at once so you get a high blood level um with Edibles it's like the time course so I mean it's going to be like 5 nanog per Mill let's say but it would be like that for a long time whereas the 100 nanogram per Mill from smoking is like for 20 minutes and then it starts dropping so but the problem is with the way that um 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 basil 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 it would leak back into the blood and so you have this issue where you let's say your cut off was 5 nanograms per Mill which is for some of the stuff detection thresholds would hover around that area so you could have someone who's dead sober that tests positive and someone who's profoundly intoxicated who test negative so it's like what's the value in this it's it's not telling us anything well I guess it sounds like the drug tests either have to be revised or discarded and it also sounds like if somebody is going to take a drug test for cannabis and they have used cannabis in any form in uh the previous 90 days let's say uh going for a run right before your test is going to liberate uh whatever um THC resides in the fat stores potentially yeah so I mean it it is it is a lot of people are writing this down along the lines of what's known and not known I'm curious uh what is known and not known about the effects of cannabis THC in particular on hormones um I've seen studies that site increases in testosterone from cannabis use I've seen studies that site increases in estrogen from cannabis use and they argue for increased aromatization of testosterone into estrogen as the mechanism I've also seen studies that say the exact opposite yeah so um 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 see I would say it's you it's there's nothing that's super clean cut um I mean I know in the previous podcast you talked about a prolactin thing right well there there's um and this is where I think it's important that people understand um 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 um and one of the experiences that is talked about a lot in certain um let's just say online communities is the experience of people who had no pre-existing gynocomastia male breast development yeah will smoke does do we call it marijuana these days I got we'll go with cannabis I actually got I got um someone I got a lot of comments that said marijuana is an inappropriate term okay smoke well go back to that I I that was new to me I didn't know so forgive me if I I mean I understand it but yeah a lot of people don't know that so um will'll smoke cannabis and experience gynecomastia or in females so males and females both have breast tissue but in males it's typically um uh it's not hypertrophied um but they'll smoke cannabis and get a um gomia growth of the male breast tissue um 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 um 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 it's super mixed so I mean you talk about something like prolactin for example that is another one that's obviously involved in in this whole Cascade stuff generally I would say the the bulk of the literature actually says that cannabis would suppress prolactin not increase it that's the majority of the liter because dopamine is one of the main ways that prolactin is suppressed they're kind of in a seesaw they work in somewhat seesaw fashion um and it probably I mean the rodent work would suggest it's through dopamine that's turning off prolactin because you can reverse some of these Effects by playing with so I don't doubt that's the mechanism but so typically I would say more often I mean there's studies with inhalation and IV that have generally found reduced uh 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 Yale interes um 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 any reason to think that would be the case I don't know I yeah I mean that being said a lot of the stuff now granted this was mostly done in the 70s um and like this is from my previous life because my undergrad and graduate supervisor he was a neur endocrinologist focused much more on sex hormones and reproductive hormones so we've written a few reviews so I've done like reviews on this area and I know the literature somewhat um it's mixed but generally from the70s studies what they would often see is that if they um would look serially look at testosterone after someone consumed they would have little dips like that wasn't uncommon for them to find it not every study found it um that being said the 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 hypogonadal or would lead to something like gyom at least from a testosterone deficiency side in terms of the balance between testosterone and estr um 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 gyne kamasa stuff is I mean certainly people online might be talking about it and there might be some other components to this I've also heard and again this isn't like science this is just the same kind of stuff you see on random internet communities people talking about oh well you know it has plant estrogen so maybe they're subbing in and having estrogenic effects I don't know how valid any of this is yeah it seems a bit I mean they're f estrogens and tons of different plants the sort of attacks on soy and the attacks on uh this I think grew out of the um kind of the soy versus meat communities and plant-based versus carnivore this podcast has always been agnostic with respect to nutrition and is really um if we encourage anything it's that people consume um unprocessed and minimally processed foods um as the bulk of their food intake there seems to be enough dat on that but whether or not people choose to be vegan and eat a lot of plants or carnivore and eat just meat you know we've essentially stepped out of that debate because um let's just say it's as futile as um about any other debate you're just never going to it's it's completely circular you end up right back in Twitter yeah and I think that um I mean when it comes to something like this I don't I I've not seen any compelling evidence for it so I can't I certainly wouldn't say that it's a a typical side effect that men would experience is like developing breast tissue in response to Canabis I feel like if that was the case it would be very known in the scientific Community as something that comes out so this seems to be something that um Ur purportedly occurs on a backdrop of elevated androgens meaning in puberty or a backdrop of some other um form of Androgen incre like someone who's on steroid yeah that's not the community I'm referring to it seems that um because transient um gomasa during puberty is actually fairly common um because of there's just so much Androgen being produced in puberty that some gets aromatized and that um the the idea I'm not saying stating this as fact is that it may exacerbate that in any case it sounds like the takeaway from this is that there aren't a lot of conclusive studies about the effects of cannabis on testosterone or estrogen or aromatization in any direction I I don't I mean I'd say like yeah this enough studies that suggest that you might see transient drops in testosterone from Cannabis and it seems to be relatively shortlived um it doesn't seem but again a lot of these studies also find that the basil testosterone is already kind of high to begin with so staying in a normal dynamic range it is again it's homeostatic just like just like the endoc canabo yeah so and that's the thing I mean testosterone fluctuates across the day anyway so there already I mean there's other things that fluctuate it's like cortisol these hormones have Cycles so as long as you're in this normal range there really shouldn't be any kind of like behavioral like in terms of sex drive for testosterone or like physiological like gyom 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 I'm assuming that they the studies you referring to saw um disrupted what they call sperm quality which has to do with motility Etc yeah I mean a lot of the uh kind of invitro 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 um chuckling to myself because anytime this convers ation comes up about a substance and um 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 um but you know if people are having challenges of 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 at by than others so for some some you know various biological reasons that we don't have a biomarker for there may be some men that use cannabis and it has a profound effect on their sperm quality their sperm capacit and so their ability to maintain fertility and for the bulk majority of man i' say 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 um um but you tell me what you know about this um which is that up to 15% of pregnant women in the US have used cannabis during pregnancy that just seems that number just seems too high and yet you know it exists out there yeah it's very I mean I've heard higher numbers lit no I've heard higher numbers than that as well on the low end of this well I mean so I've heard as low as two and I've heard as high is 20 okay two sounds like okay I that I could imagine um but as high as 20 and do we know what the effects on the developing fetus are there's a lot to unpack there so first thing going back to the 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 have varied so some of the higher numbers actually come from blood levels where they've taken blood samples and found THC but the women have reported not using cannabis and so they're the idea that it's like the self-report numbers tend to come in around two or three my guess is the real number is probably somewhere around 10% but that also is 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 they're pregnant now that can be all the way up to almost the end of the first trimester typically stop using cannabis that seems to be the norm I would say important point there yeah and I think also the number that carry on through the entire gational period is is going to be a lot less I would guess now the motivations for this quite often are more in the capacity of the kind of anti- nauseant um 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 antinauseant Drugs that had profound teratogenic effects on the fetuses women have said that they would rather use cannabis than one of these other compounds because they're less concerned about the impacts of cannabis than they are because of the you know the theide effects that happened and theide effects are um malformation of the limbs and and other uh bodily structures in fetuses it was a absolute tragedy of medicine that um this occurred and even even one um birth but um yeah the reason why thalidomide is now I believe banned as a as a drug for use during pregnancy yeah I I would I actually have no idea but I would imagine um 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 itself could present some problems um in terms of that thought process now there was also a study that I thought was like some of these things just frustrate you it's where they actually decided to call this was done in Colorado where they called dispensaries and just acted naive and asked what their recommendations were and it was something like 80 to 85% of them were actually recommending that people would use cannabis to manage morning sickness and I thought that was like it's just one of these disappointing things where you're like why are you being so wildly irresponsible to kind of promote these things and this is you're talking about the irresponsible that the dispensaries would say that or irresponsible that the study was carried out that way because it's a little bit of um entament you said it not me could be I mean I I mean you can you can bulk at either side of this I think it's I mean I have a lot of frustration in general with the information that bud tenders put out into the world is that what they're called Bud tenders Bud tenders that's kind of the colloquial term that people will use for someone who sells cannabis at a dispensary we see this in Canada and I've heard this throughout the states as well I personally have been a huge advocate for the fact that I think so you know I worked uh in restaurants and bars and stuff when I was younger and for me to serve alcohol I had to undergo I don't know if you do this in the states in Canada you have to do like a it's like a weekend course essentially called like serving it right or some other terminology where you learn the basics of alcohol harms blah blah blah how to tell if someone's intoxicated when you have to cut them off all these things that you have to do to be able to serve alcohol I I have no idea if this exists in the States but it it was a thing in Canada bartenders uh in the US put in the comments on YouTube do you have to undergo training about alcohol to bartend anything even if it's just like an online quiz but like so I my perspective is because um pre- legalization at least in Canada there was somewhat of I think of a misguided thought that people would leverage their Physicians for knowledge about cannabis and what's become very apparent is that the overwhelming majority of people talk to the people selling them the Cannabis and yet those people selling cannabis don't need to have undergone any form of education and so like this kind of kills me because we've worked very hard to try and create educational platforms that are like agnostic in terms of our position on cannabis that are just based on the science I'm an executive director of an organization called the Canadian Consortium for the investigation of cannabinoids the ccic and it's we've done CME courses for Physicians to try and train them about cannabis because I think it's important that Physicians understand this but I've tried suggesting that I think that anyone selling cannabis should undergo a course like this just so that there's some consensus in the informed level that someone who comes in because a lot of people going to buy cannabis are quite naive about it and they just I mean even when we're talking about dosing what we've talked about with Edibles or smoking or how people consume it like you need to have a reliable source of information at the front line that is able to relay that to people and it it becomes very frustrating to me that that they have become the main source of information that people go and I'm uncertain of what their level of training is you're certainly doing your part to provide the public education about cannabis now so we all appreciate 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 really on the teeter totter with MDMA where we await the decision from the FDA but the early recommendation to um to the FDA was to not approve MDMA as a treatment for PTSD that's as of today in you know mid mid to late June 2024 we'll see what happens but this is also the case for um ketamine uh which is has legal status but many people are accessing ketamine not through a physician but through online sources so what you're speaking to here is is a much larger issue um and uh I absolutely agree with you I mean I think most people are probably not aware except by experience positive or negative in some cases about the differences in blood concentration as it relates to number of tokes versus concentration versus edible I me these are critical themes especially for where we're going to go next which is you know all the discussion about high THC and psychosis yeah yeah exactly so I think that I I I just wish I mean again even if this was just like an online course that wasn't that much but at least had some consensus of information that was the basics about how to you know have conversations and I I mean some of the our our system at least is somewhat provincially regulated so like you know our organization has worked with like the Ontario group that deals with cannabis distribution the Ontario like the OCS which is antario Cannabis stores um 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 something like Edibles how long you should wait just stuff like this like it sounds like the take- home message is uh proceed with caution go you know low and slow I mean that's the yeah the don't don't ingest too much too quickly like really you know if one is going to explore this legally of course um you know take a little bit wait take a little bit wait um because otherwise you're going to get the who was the reporter I think it was Morin D but I right you're gonna I don't know actually when I say that is she still on the floor in a Colorado Hotel she may have recovered reporting from the floor in Colorado um but like it yeah it's it can become very frustrating it's just the kind of lack of understanding that exists in this space and so I think this is one of the reasons why we've really kind of tried to push the public health side of this a lot more and we have I mean there was um the center for addiction of 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 onlines it's called the lower risk cannabis use guidelines they kind of tried to create a framework that is similar to how people have done stuff with alcohol um that just kind of goes through and a lot of it is this low and slow approach but it's like obviously you want no risk you abstain if you're going to use these are the different ways to engage in harm reduction um you know like obviously oral consumption has you you avoid the issue of lung damage that you could get from smoking um but then you know with oral consumption you have to be aware of dosing and timing and all these other considerations but what about vaping um Can people self-regulate their THC concentration in the blood by vaping as well as they can by joint or bong or other form of depend on exactly what you're vaping so in the states I've noticed when people say vaping they almost exclusively refer to some kind of oilbased product that's in a pen so in those situations um 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 ENT hit the lift point to vaporize THC in the canid a big bag yeah yeah like a volcano um yeah um but it doesn't create any plant combustion and so there are studies that have been run on that that have shown that you avoid the combustion byproducts so people don't like exhale carbon monoxide or these other things that we know can be damaging um if they're vaping plant matter that was actually somewhat approved as like a medical device pre- legalization when can cannabis in Canada was only under medical authorization um because of the reduced harm associated with vaporizing the plant matter versus smoking it um that is I would say a safe guideline for harm reduction that if you're going to try and avoid you know there's still going to be some issues that happen with vaporization of plant matter but it's not the same as combustion so you avoid like some of the other issues that come out when we're talking about um oil-based Vapor Products or whatever they're in they're usually in some kind of oilbased solution um 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 had been some pretty big errors of like the things that happened in the states like there was that problem where all those people developed um kind of I don't know popcorn lung or that lung inflammation where several people died from vaping products which seemed to be like a byproduct I believe of them adding like vitamin E acetate or something into the because again everyone just assumes it's a nerd but then when it when it combusts through the vaporization process it creates a massive irritant on lung tissue and so that was just you know again in my mind this is a problem with a lack of a federal um 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 there's not really a lot of like regulation of things well if you go overseas it's even more wild I mean then there's I mean then you have no idea what you're consuming anywhere I would say just because outside I mean again Netherlands is a little bit of a different situation um they're not legal they're decry alized 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 know you got people flying out of country do stem cell injections people were getting them down in Florida who went blind from the injections of stem cells into the eye in an attempt to save what little vision they already had probably don't want to get me started on that one um I I'm in total agreement with you um by the way I want to make sure that I ask about psychosis and paranoia yeah um I've previously said and I was sort of I wasn't joking but I have um observed um in my history that uh when people started to uh experience some degree of anxiety or paranoia when um 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 um terrible idea baffled that you heard that I have no idea let's say I did more than hear it um see I I've observed it I I cannot even understand that that is the strangest thing I've ever heard but okay yeah well usually the advice of of of people in terms of that was recreational drug taking is um is rarely excellent advice that's that's so I I mean I agree with you on that point for sure that you should not be consuming more if you're having a bad reaction to it because that will just like Grease the wheels going downhill for sure yeah um I also am aware that there are some very high-profile papers that been published in the last really 5 years or so pointing to potential increased risk for psychosis of lasting duration um 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 I want to make clear that what I just said is not a statement of absolute fact it's my understanding of the conclusions of these papers um there are other conclusions in these papers also but that particular conclusion seems to be important enough that they place it in the abstract and it's reached major press headlines so I guess the simple question which probably doesn't have a simple answer is does THC cause psychosis so yeah there's not a simple answer to that and I think that also is a question over whether you're talking about acute drug induced psychotic episode versus the development of a chronic um psychotic disease like schizophrenia so um the first arm of that is just can people acutely have a psychotic episode to THC or cannabis and the answer to that is yes it's not common I would say in terms of Adverse Events that happen with people consuming cannabis it's on the rarer side um but it definitely can happen so less than 5% of people that oh much less than that I mean certainly I mean it's if something like this was happening at a regular frequency it would be very well known what about anxiety attack yeah anxiet attack is I'd say more of a standard uh indication that someone's kind of gone overboard like that's not dosage overboard or does it carry the same set and setting considerations that um you know psychedelics like psilocybin have uh both so I think there's some contextual component to it there was like I mean back in the 70s when they did more let's say interesting studies there's one where basically they dosed people on THC and then had them undergo oral surgery which seems like in hindsight a very bad idea and I think virtually everyone in that study had a panic attack like so it really potentiated the stress of what they were undergoing and had they been given that same dose in a different setting I'm not sure it would have evoked that kind of response but there is definitely a dose effect to this in terms of like you know the kind of classic lowd do aspects of like of THC or cannabis like that are usually considered more the positive pleasurable responses that are why people use like it reduces anxiety it relaxes blah blah blah um that is more of like a low to normal-ish dose let's say of what someone consumes to produce those responses if they start going upwards though it's not like it's graded it's like a full flip like it's not linear at all it's almost like it goes in the opposite direction so you know someone can use cannabis to reduce anxiety but then cannabis can also trigger anxiety in other people and even in the same person if they consume too much and a lot of this at least we think has to do with the ability of it to regulate both excitatory neurotrans and inhibitory and so for reasons that we don't totally understand there's like way more cannaboid receptors on inhibitory neurons than there is on excitatory neurons but in the early days of creating the genetic lines um gavan Marano and beat Luts over in Europe created um like deletion of CB1 only from excitatory neurons or only from inhibitory neurons okay so to just clarify for people these are um 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 um which is basically impossible to do in a typical Mouse what's called a wild type Mouse um or a human um because when one ingests the drug or when the mouse is given the drug it affects any sight in the brain potentially any site in the brain where the CB1 expressor recept do like a full body deletion of CB1 and you give a mouse THC doesn't respond to it at all not surprisingly that's a comforting experiment you want to see that result yeah exactly so that's how we know CB1 drives all the kind of psychoactive effects of THC so if you delete CB1 off of inhibitory gabin neurons even though that removes like 70% of the neuro of the CB1 receptors in the brain those animals look just like wild they still get like they still exhibit all the classic signs of intoxication in terms of how that would respond to like pain sensitivity or Locomotion or these other like assays we use in mice to tell if they're high if you delete the CB1 only off of excitatory neurons the glutamate neurons then you see um what looks like the full knockout so now the animals don't seem to get high so even though the majority of CB1 receptors seem to be on these inhibitory gabin neurons it's the CB1 on the glutamatergic exy neurons that mediate most of the classic signs of what we would consider intoxication from THC or cannabis but what's interesting is um uh bat worked with the Spanish group 10 12 years ago then they showed they're looking at anxiety that if you delete CB1 only off of excitatory neurons you lose the anti-anxiety angiolytic effects of THC but you still have the you know panicky angiogenic effects of hos if you delete CB1 off of only the inhibit at gaban neurons you still have the lowd do anti-anxiety effect but now you don't have the high do angiogenic panicky effect so what that was suggesting was that for some reason CB1 like THC will initially hit CB1 on kind of glutamatergic neurons and essentially the thought is this will reduce excitatory transmission and probably quiet down circuits and if we're talking about something like the amydala this is probably how it's reducing anxiety whereas as dosing starts to increase and you start to saturate the CB1 on the gabin neurons and turn off inhibition then the network effect is more of an amplification and that seems to result in the development of kind of an angiogenic uh pro- anxiety response that's obviously undesirable why there's this differential shift it's not exactly clear I mean it's probably either due to some of the like biology of exactly where the CB1 receptors sit uh on excitatory or inhibitory neurons relative to all the Machinery that regulates transmitter release I mean bat loots has definitely done some stuff looking at the ability of uh cannaboid receptors to evoke signaling responses in a cell and on glutamate neurons they're much more sensitive than they are in gabin neurons so there's probably a dose threshold so it does look like this kind of you know low dosing what most people are trying to achieve I would assume when they consume cannabis is probably these effects mediated by quieting down excitatory transmission and then the adverse effects when someone consumes too much and they have a negative response that's probably due to the the higher starting to saturate on the inhibitory neurons now we obviously can never test something like that in humans because we can't know but based on what we've seen in animals that's my theory of kind of how this is working and why we see these kind of classic biphasic effects so yeah too much THC not a good thing because then you start maybe disinhibiting things like the amigdala producing these kind of panicky angiogenic like outcomes on that scale though I mean paranoia obviously that's a hard I don't know how you study that in a rodent I mean that's just a strange thing 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 um someone once asked me a question about you you know have you know what happens in the brain um like Imaging wise when someone's having like a psychotic episode from Cannabis and I was kind of thinking like how would that study get done like probably on accident because somebody takes cannabis is in the scanner and then starts having a psychotic episode but chances are they're going to try and get 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's sometimes even a bite bar you know like this is a very controlled environment not not an environment that you would want to be in during a psychotic episode no I can't actually even imagine how that would go down so I'm like we this is something I don't think we're ever going to have an answer to because I don't think I don't think you can actually ever test it but in terms of people having this kind of psychotic response it is pretty rare I mean and I say this because I can think of 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 it's certainly not a frequent thing because we would hear about this a lot more if we did and there's also the issue of polypharmacology which is simply when people take one drug then there's often the tendency to take another drug either because it's available in those conditions or because they threshold to say yes is a little bit lower um do most people who take cannabis and achieve the the High um have a tendency to do other drugs it doesn't seem like a drug that people combine with a lot of other drugs um I wouldn't say part I mean there's certainly cannabis is used in tandem with other drugs alcohol psychedelics at times for sure but that being said um I mean it's I there are is clearly a population of people that use cannabis as their only drug that they use I don't think that's that uncommon um but in the context of the psychosis stuff I would definitely say sure you know if someone mixed it with amphetamine or something you could have a very unpredictable response there but I mean I think the psychotic responses that have been documented are usually purely due to cannabis like it's not it's not necessarily due to some kind of uh 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 talking about what that means in the context of like an actual disorder like a chronic disorder like schizophrenia which is characterized by psychosis I think we're talking about a whole different ball game here and this is an area that is I mean I think it's an important thing to discuss in the context of science because you can't establish causality like in my view it's 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 individual 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 um using cannabis and having the uh initiation of the development of schizophrenia uh and this is where a lot of the statistics that have uh been used to develop the risk assessment essentially like so that you have a greater risk if you know like you were saying if you've used cannabis as a teenager use high potency as a lot of the research has shown though they've done these studies and they say it relates to um a greater risk of schizophrenia essentially this is just a statistical Association that they found that people who use cannabis the conversion into schizophrenia happens at a higher rate and there's more people with schizophrenia who are using cannabis is there a bias towards uh males developing psychosis I know there may be a bias initially toward males in schizophrenia that could confound this so we want to be careful to be honest in 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 than females so that could lean towards any bias that may be out there in the media the popular um 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 male biased per se they usually just report numbers or proportions of people um the the issue is so yes there's this relationship that exists and yes we know that um cannabis can trigger psychotic episodes so if there's an individual who has schizophrenia we know for certain that cannabis can lead to the onset of you know uh increases in positive symptoms like hallucinations and delusions um 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 um 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 uh same with bipolar I would say if there's bipolar or SCH and a family to me those are the people who should avoid cannabis um 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 its presentation in some capacity I think where things get really complicated um 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 um and they attribute a proportion of people who have schizophrenia to only having that schizophrenia because of the fact that they used cannabis um and I think You' had some discussion about this in the last podcast I can't remember exactly the way that you described it yeah I was um looking toward um some of the recent studies in uh Lancet jamama Psychiatry I believe I we can provide links to these again and now more recently there's been a lot of um let's just call it mainstream media coverage of this potential yeah I think is the right way to refer to it potential linkage between um adolescent teen and young adult use of high TC cannabis and Lasting psychosis but um the more I hear you talk about this the more I'm wondering if that idea is being uh Amplified more than than perhaps we ought to let it be Amplified I mean I think this is what happens when you have I mean obviously you're familiar with this in science there's different some things that we can be a little bit more definitive about and then there's some things that we just can't know for certain it's just the way it is because of the way that we gather data and because of the way humans are and this isn't a question I believe we can ask from an animal model perspective in the same capacity um so I don't think anyone would deny at least anyone who's read the literature that there's this relationship between cannabis use especially in adolescence 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 will make it kick in faster and harder so um if there is a genetic vulnerability for for um developing schizophrenia or some biological predisposition that's there I would say in that situation cannabis can trigger an initial onset of the first episode and it can make the prognosis of the disease in the long term a lot worse let's say as I recall and I may have this incorrectly but as I recall from my undergraduate years what you just said is also true for military service for people that have a predisposition to develop schizophrenia that active military duty can exacerbate it as well I mean I've never heard that but that would be a stressor and stressors are other ways I mean a lot of you know there situations where uh IND I mean some of it's the age but like you know for example if someone is prone to develop schizophrenia they move away to college even that stressor can be something that brings on an episode but cannabis very specifically like different than any other drugs like alcohol or cigarettes as far as I understand it at least the temporal relationship between cannabis use and the development of of a first episode can be pretty linked um 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 um we have a few things that like I would leverage as kind of real world evidence that makes this questionable so the first one is like I was saying earlier in the episode I mean we really didn't have cannabis use in the west like as a normal thing as one of the drugs that was part of the repertoire of what people use recreationally until like the 60s so unlike alcohol which has like been there for centuries we have a little bit of a before and after what we can look at the Grateful Dead yeah so um now granted we don't have like really good prevalence data of what schizophrenia was in the era prior I mean even even nowadays our prevalence stat is not perfect but if cannabis as a solitary variable was driving the Genesis of schizophrenia denovo in the absence of any kind of biological predisposition or genetic predisposition I find it very hard to believe that we wouldn't have seen a shift in the prevalence of the disease as cannabis became more mainstream and more widely used and generally schizophrenia rates have remained largely stable people can make arguments about that better care other things that to challenge that argument sure so another modern perspective would be okay well let's look at Canada and the states let's say where we have as I said earlier teenagers in Canada and the states by grade 12 35 to 40% of teenagers have at least used cannabis somewhat sporadically and somewhere around 5% is are probably using almost daily so we have a concentrated group of what would be the high-risk population here that are using at a pretty high rate and then we compare that to somewhere like let's say Norway or Sweden or any of the Scandinavian countries where cannabis is like not a thing certainly not at a recreational level and not in teenagers and I mean the rate use rates there are probably under 5% globally for teenagers like probably closer to two or 3% so you have two countries that have pretty similar social structures and other capacities of things we're both Western countries and yet our schizophrenia rates prevalence wise are relatively comparable and yet in Canada and the states our cannabis use rates in 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 I hear your point loud and clear I seem to recall that there is a higher incidence of schizophrenia independent of cannabis use um closer to the polles you know and less so at the equator I don't know if those statistics still hold up but I have no idea yeah interesting for us to look into that because then then it would argue that you know since uh you know we're comparing very Northern locations to less Northern locations that um perhaps cannabis was you know sort of exacerbating you probably use Greece or Italy I mean they going to have cannabis use higher than Scandinavian countries but it's going to be way lower than North America still because it's just what is it about North Americans and cannabis use I have no idea I mean I think it's just part of the culture here it's just evolved totally differently I mean Grateful Dead no I'm not picking on the Grateful Dead I like the Grateful Dead Rick Rubin convinced me to start listening to them again and uh cuz my sister used to listen to them and there're some great songs and they're from Meno Park pal Alto so I've done I've done uh my duty to listen they're some great songs so I'm not picking on them but but I mean like you also have like in Europe though alcohol is also much more normal normalized in general like kids will drink it's not abnormal for kids who 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 it's sure it's there to some degree in Europe but it's nothing like it is in North America we are just a different Beast for a lot of drug use do you see differences between United States and Canada with respect to either cannabis or opioid use I don't think dramatically I think we're pretty comparable from I mean for cannabis rates I would say they're almost the same I I've not seen sure you might get some Regional differences like we I think Quebec has much lower rates of cannabis houst than some other parts of Canada and you guys probably in some Southern States maybe are a bit different than other states so I don't know about that but again overall at a federal level I think the which is where more of the most of the data Aggregates I would say that they're pretty comparable with each other so they're not they're not wildly different at all and again even if you talk about climate a lot of the US is a lot warmer than Canada and you guys are certainly closer to the Equator than we are so I I I mean we know like you do see higher rates of schizophrenia in urban settings than you do in rural settings and so I me a stressor there's other you also have more like there's just yeah there's a lot of transitory populations that come in and out of cities that you don't see as much in rural communities there's a lot more Mental Health Services there's other variables that can influence that and no one's really I think sused out a mechanism to explain why you see that but um 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 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 the gws level or just even just looking at um 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 um that do look at this from an somewhat let's say unbiased perspective where they see you know there's some there's certainly some genetic architecture that relates to people either initiating cannabis use or people developing cannabis use disorder and there's clearly some genetic architecture that relates to risk for schizophrenia uh 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 a biological vulnerability to develop schizophrenia and some factor that relates to people using and or liking and or excessively using cannabis I've spoken to many psychiatrists in an effort to find someone expert in ADHD we've done two episodes on ADHD focusing on everything from behavioral to nutritional but also prescription drug treatments for ADHD and what's interesting is that all of them have relayed the fact that many people not just young people but adults with ADHD will often use not necessarily abuse but will use stimulants like coffee and other forms of stimulants to a high degree and then of course you can say well perhaps the stimulants are causing ADHD but they actually argue for the opposite which is that people are attempting to self-medicate and then it's perhaps no surprise that most not all but most of the medications that are approved for the treatment of ADHD are variants of amphetamine or similar so it it's another case where you know depending on whether or not you look through the lens of the drug leading to the condition or the condition leading or through the lens of the condition leading to the the use of the drug you can end up in um two very different places but it looks exactly the same um through each lens so to speak I think you so I mean and this is you know I've debated with other researchers in the area in print and in person about the different interpretations of this and one of the possibilities is again the this idea of self-medication I mean independent of there being some underlying biological thing that just is a third variable that explains the relationship between cannabis and schizophrenia the other possibility is self-medication and there there are some studies that suggest this and others that don't support it um anecdotally from um having done work in the community and talk to individuals who have schizophrenia who use cannabis what their perspective on is what I've heard from a few of them is um 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 is somewhat well managed but then there's another component which is the negative symptoms which is kind of like things that you know avolition I don't like engaging in stuff um there's some anxiety some depression some social withdrawal and a lot of the medications don't manage that component of the disease and they have said that they find Cannabis helps that side of it or it helps them de arouse a little bit even though a lot of them recognize it may trigger the development of some of the positive symptoms they feel that they don't have any tool in there kit to manage the negative symptoms and so it could be in my mind when I look at that it could be a bit of a vicious cycle where someone's using it to kind of Band-Aid one aspect but making other aspects of the disease worse at the same time so it can get very complicated but so I mean there are various ways of looking at this in terms of you know so it's either you could say there's a causal argument which is made by many saying cannabis causes schizophrenia and therefore if we eradicated it um and I think you had alluded to something like that in the last podcast that if you removed it would have this big effect in terms of reducing schizophrenia rates and that's similar to the argument that a lot of the researchers in Britain have made and I'm not personally convinced of that and I say that simply because I look at the data from Scandinavia and I'm like well there you have a population that barely uses any cannabis and yet their schizophrenia rates are the same so the only way in my mind if I look at this kind of scientifically from a data perspective that cannabis could be causing schizophrenia denovo in a subset of people is that there must be an equal proportion of people for whom for some reason and somehow cannabis is preventing them from developing schizophrenia so that it's a zero sum game at the end of the day and there's no change in rates like I can't actually understand any other model that could explain this yeah no I the way you you're explaining it now makes perfect sense I do want to make sure that we distinguish between um schizophrenia like psychosis or schizophrenia itself induced by cannabis yeah and manic bipolar um episode so people who have a predisposition or full-blown manic bipolar sometimes called manic depression but that's you know there's a lot of nuance there we did an episode about this um that people can uh also find Linked In the show note captions but in any case is there any evidence for the fact that people who suffer from or have a predisposition to manic bipolar conditions like bipolar depression for instance should avoid high THC cannabis um so well first of all I mean for in like hered ability family trees for example where you look at something like bipolar schizophrenia the two do kind of track together sure so it's not I mean I think it's hard to separate these in some capacity because um you know I remember years ago at Society for Neuroscience Glen Close was one of the I don't know if you were at that meeting but Glen CL was one yeah she was one of the public speakers and she had talked about schizophrenia in her family tree and she kind of put up this family tree of like you know her family and the the one uh the previous relatives in her family and showed like the individuals who had schizophrenia and bipolar as well and this is something I think that's been seen a fair amount is um there is some co-relationship in the way that these track at a hered ability level and so I don't know that area really well enough to to be able to comment on and from the Cannabis perspective bipolar is definitely much less stud studied and focused on than schizophrenia is but I think also to the comment about the high-thc thing I think this is the other part of the argument that's emerged out of this and this is the other part where I see a lot of the um causality arguments kind of crumble onto themselves to some degree and there's been others who've made these very similar arguments to what I'm making here which is um the push that came out of this out of the UK at least was much more that it's this High potency kind of skunk cannabis they referred to which first of all was based on a smell which they didn't really hadn't done a lot of analytics on so it was people make the Assumption if it smells stronger it's more potent cannabis that's not really true because THC doesn't dictate the odor that's as I was saying more of a tarpine thing but certainly I'm sure some of the skunk cannabis they were referring to is high potency cannabis and so the analysis on this if you actually go back to those papers and read is they often use like hash or low potency cannabis as their control where they show no association with cannabis and so that's what's use 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 um answer that fits in with the data like what's that's the most parsimonious explanation here that everything can be explained by and so the problem with that argument is if you look at the Cannabis schizophrenia literature everything goes back to this one 1987 Lancet paper out of Sweden where in that paper they essentially looked at um they have really detailed life records and health records and this was Swedish conscripts and they essentially found that if someone had used cannabis the rate the risk of developing schizophrenia had gone up and up and so this was based on a cohort of people when it was published in ' 87 that the data would have been collected through like the 60s 7s early 80s so we're talking about Sweden and cannabis it's not a country that has high cannabis use rates and an an arrow in cannabis was hovering in a 2 to five% THC range that was the initial finding that provided this association between it and yet the Cannabis in that study that they would have been referring to would have been incredibly low potency compared to what has happened or like what it is today so if the argument is that it's only related to high potency how would that initial finding have ever been found because it doesn't make any sense whereas the alternate explanation that others have put forward which I agree with and is far more sound is that there is some biological reason why individuals who 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 7s in Sweden that would have been 2 to 5% THC cannabis nowadays it's higher potency cannabis or maybe they seek out lots of different forms of recreational drugs and cannabis just happens to be one that they land on which raises the other question which is it's hard to imagine that these people who develop psychosis who happen to be using cannabis are only using cannabis it could be but I mean they also there's there's no question there's a a lot of nicotine consumption I mean individuals with schizophrenia use they smoke a lot of cigarettes I mean that's also much higher than the general population rates which is known to stimulate dopic and and other pathway and there could be other reasons you know again there may be some reason why they like it um 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 SCH schizophrenia and that may be why they like it I think it enhances cognition in everybody it just carries certain health concerns and by the way it doesn't enhance all forms of cognition but there 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 um one of the more um quickly uh uh abuse drugs nowadays because of the non-smoking delivery routes that are becoming really popular pouches and and things in fact I was chewing a little bit of Nicorette gum to kind of do experiment I liked it a lot and then um I decided to stop completely recently because it just um it wasn't having the same effect and I found myself reaching for more and that's the time when I usually back out well um yeah no nicotine's a whole other thing which I yeah uh we'll have you back to talk about n no I would definitely don't not know enough about that to have any kind of informed conversation but um so I don't know I I would say it to me at the end of the day if I put all the data together what I would kind of the perspective that I have on this is for some reason be it genetic architecture biological predisposition individuals who are prone to 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 um using cannabis if someone is prone to develop it may initiate or trigger the onset of the disease um and I think in the long term it will likely make the prognosis of the disease worse so if you were a psychiatrist in a clinic and you consistently see patients presenting saying I didn't have psychosis I used cannabis now I have psychosis and it converts into schizophrenia I can understand why the association would be made regularly that there's kind of a domino effect here and causality becomes attributed but I think when we take a step back and look at the larger data in its kind of entirety to me it's a very tricky argument to make because there's a lot of things that you just can't explain from that perspective and this is also one of the things that I find absolutely bizarre about cannabis in general is uh it's a wildly polarizing topic of conversation and people have incredibly Dee rooted opinions on both sides of the spectrum and for some reason if I don't say cannabis is the devil and causes disease that means I'm an advocate and then on the other side of the coin if I don't say cannabis cures everything I'm a prohibitionist so like I'm in this fun position where I get hate mail from both sides and everyone just generally depending on their perspective thinks that I have a bias kind of going in one way or the other and I'm very you know want it this way or want it this way 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 as I can with data 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 and 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 um opinion that a lot of people just take up I think can have a lot of influence and so that's why like there's literally no reason I should have a dog in this fight I don't study schizophrenia in any capacity um and it's not my area of research but because I'm in the Cannabis field I always feel very strongly that we need to maintain Clarity over what the data says and not get caught in these opinion-based arguments and I feel like this is one of these areas that has just kind of the amount of people I talk to that regularly tell me that they know that cannabis causes schizophrenia and they're terrified if someone uses it cuz it's going cause them to become um schizophrenic I am just kind of shocked by so this has clearly permeated you know the general population that there's a widespread belief of this yeah I think it's because of these uh very high-profile papers and the way those were picked up by traditional media um and this seems to be something that every couple of years is's a Resurgence of this idea um clearly people are curious about it and so not I just want to say thank you for clarifying um what is now to me obvious that it could be that there's a relationship there um it's clearly not the case yet and it may never be the case that there's a causal relationship there and it could just as well be that people who have a predisposition to schizophrenia are seeking out cannabis use and engaging in cannabis use and I think that's a very important principle for our listeners and viewers to just hear and understand anytime we're talking about a substance and a condition yeah and I mean I think again this is again no endorsement that that doesn't mean that it's safe and that that's without harm I'm just strong of the opinion that I don't think individuals with schizophrenia who are or who have you know first deegree relatives should use cannabis because I think there's a high degree of risk there but that's a very different argument than making saying cannabis causes schizophrenia and if we remove it from society we'll see drops in rates of schizophrenia I don't believe there's any evidence that actually could support that um 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 so yeah absolutely let's talk about strains of cannabis um I've spoken before uh about the sativa versus the indicia 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 um when I talked about this before um in the Cannabis episode I leaned on a paper that took those subjective reports of arguably many many people um push those subjective reports through what was known about the strains they claimed to have used so this is you know people are reporting their use we assume honestly but you always have to assume that they I guess people could be lying about which strains or misinformed but and then using machine learning to couple their subjective experiences as they report them to indicia versus Sativa strains and then by looking at the chemical composition of those different products because these were products that they had consumed trying to attack chemical composition to to strain in this case the mainly the Inda sativa discrepancy to subjective experience and I know that you and presumably others in the field of cannabis research take real issue to that sort of approach and perhaps I have the the feeling this is what you're going to say um rest on the idea that we at least at this point in time really can't say anything about the different biological effects of sativas versus indicas and yet at the beginning of the episode you said that there are many many different cannabinoid compounds in cannabis so three questions and I'll keep these um very short one um do you think that there are different subjective effects of different strains of cannabis that can be attributed to the different strains right not just to individual differences in experience and then the second is do you think that there will ever be a time in which we can understand this plan 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 um yes so going back to uh just the idea with the Indica sativa thing so the Inda sativa names at least from everything I've understood from everyone that I talk to and being in this field is it's those are are Botanical terms that largely refer to shape of the plant the you know the way the bud grows blah blah blah they do not track with chemical composition in any way um in fact Nick jacomas has done like a lot of analysis of like thousands and thousands of different kinds of canab cannabis that have been submitted for kind of um biochemical analysis to understand THC CBD Tarpin minor canabo content and essentially um his his work as well as from all the people that have done the genetics on this is the variability that exists within what someone calls an indicia or a sativa is uh 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 indicia is it possible that there's a chemical profile that relates to the most common indicas or most common sativas I mean I think in Nick's analysis there was like a couple of tpin that may have loaded on a little bit onto things that were sativas but there was tons of sativas that didn't fall into that bracket okay well then that immediately to me uh negates the sort of premise of this paper that I was referring to that divides according to indicia sativa and yet the paper is also trying to distinguish among all the different types or products of cannabis meaning is there some other feature of the cannabis plant that does relate to these different subjective effects because people do seem to get different subjective effects from different products that relate in some way to things other than the concentration of THC yeah I would my honest opinion is this is expectancy bias this is all expectancy bias I mean I see so they purchase something that they think is going to make them calm and it makes them feel calm if 20 people tell you that taking this makes you calm you cannot remove your expectation bias from the fact that when you consume it you feel calm like and this has been I think one of the most common things with with cannabis is like this whole area is so ripe with these expectancy biases that people have about what they assume if you go someone goes into you know and a bud tender tells them this is a sativa it's going to energize you there's no way to remove that expectancy bias from from what you get and I mean like from talking to a lot of people that kind of study this more explicitly they always say the biggest predictor of what someone feels when they consume cannabis is what they're told on the label it's going to do to them I mean and a lot wild it speaks to you know I did an episode on the placebo effect and a lot of people hear placebo effect and they go okay well then everything's a place placebo effect is amazing there's dose response to the placebo effect of nicotine on cognition dose response if you're told you got a high dose when you actually got a low dose you will exhibit the high do neurocognitive enhancement effect and by brain Imaging it shows a high do like enhancement of the relevant brain areas in other words the expectancy drives changes in brain activity across 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 uh and I just asked Ryan Vander this as far as I know I don't believe there's actually ever been a clinical trial that has blinded people and given them sativas or indicas and actually had them predict what they are or been able to characterize any kind of phenotypic description of what that intoxicated State feels like and because all the like the paper that you were referring to where it was users who had got the product they can't remove their own inherent biases from their own experience it's 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 Inda 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 Inda 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 um lore or perhaps it's real that different alcohols produce different drunks um you know I mean I've heard of you know i' I've got friends who will swear that whiskey makes them feel aggressive and vodka you know is mellow and that white Tequilas feel different than than the other Tequilas and you know for people listening to this they go okay well that's not science I agree that's not science that's just anecdote yeah and yet um you know the chemical composition of these different drinks is different but ultimately we're talking about alcohol right different sugar contents you know different hangover propensity I mean I have to believe the majority of that's an expectancy bias I have a hard time believe 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 tpin or minor cannaboids May influence that effect that is a theory that's not a thing that we know definitively in any way in fact there's virtually no research that's ever been done to test this there's some stuff that's starting to come out now like Ryan vandry at Hopkins recently published a paper where they kind of in a dose dependent manner added lemon which is one of these Tarpin like I said I think gives it like a citrusy odor into the THC and did find that a really high dose probably a dose that I don't think you could actually find in cannabis it's a little bit higher than what you would have gotten there but lemine did seem to be able to curb the ability of high do THC to make someone feel anxious and this was was done in a blinded manner so um there's I think some validity to the interaction whether that's occurring in cannabis naturally because of the levels of THC toonine I don't know but it really was one of the first demonstrations that adding in a tarpine could actually influence a a component of the intoxicated state in a in a blinded manner I think is interesting and Zea Cooper who's here at UCLA is doing some work with beta caropine which is probably probably the second most abundant tpine I think from Nick jom's work I think mercine may have been the highest prevalent tpine across all types of cannabis beta carry offing is probably the second and limine I think is probably the third um and so I think they I mean and so they're looking at I think Zea's work is in the context of pain so they're trying to look at if a fixed dose of THC if you add in varying levels of beta carry offlane does this influence this so because again you do see this in patient communities where they say well this strain helps my pain better than that strain and so it's like okay is there actual legitimacy to this or again is this just an expectancy bias because someone who sold this to you told you that this strain is better for pain and the problem is these are all subjective end points I mean this is like pain sleep anxiety these are all it's how someone personally experiences it we know from all the clinical trials that study pain sleep and anxiety there's massive Placebo effects that happen in all these conditions and so it's very difficult to actually make any kind of sound statements about this in the absence of there being kind of clinical trials that have clearly started to do this but it's like as you can imagine when you start doing the math given the amount of Turpin and 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 that's happened in the last few years that has really started to try and look at if these tpin or minor cannaboids act at the cannabinoid receptor which none of them seem to so this isn't like you've got things that modulate how THC is binding to CB1 if they're doing something else it's probably through an interaction with another neurochemical system that's influencing what THC is doing so I'm not against the idea that like different choar or what people call strains of cannabis could do different things subjectively I just am remiss to believe this until I see some blinded data because I think outside of that we know how powerful an expectancy bias is so it makes it very very challenging to make any kind of firm statements and so kind of in the context of like how you introduced this that was again I think like one of the issues that I took with the other podcast was because as you've said I understand the thought process you went through like you 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 said okay this is what that was and that was what sativa did and versus this is what Indica did um so I think it's important that you explain that because I do think that like well that's how that's what the data pointed to but now what I'm realizing is that anytime we're talking about cannabis because of the 70 plus cannabinoids present that could modify or join uh so work in parallel with the effects of THC we're really talking about polypharmacology it's not a pure sub it's not like giving anandamide or or it's not like you know adjusting levels of indis and anide you know this raises I think an equally important issue for us to resolve which is um CBD which we didn't talk about earlier when um Nolan Williams who's a psychiat he's he's one of these phenom triple board certified Psychiatry neurology um colleague of mine from Stanford School of Medicine who mainly works on ibigan and transcranial magnetic stimulation but we talked about uh cannabis a bit when he was on the podcast and he mentioned a strain of cannabis that is available in Colorado which is pure CBD I think it's called Charlotte's Web um and the parents of children who have epilepsy MH will move there or there just to get this strain because it seems to help their epileptic seizure 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 um could you tell us a little bit about the biology of the CBD receptor um mainly as it relates to CB1 or not you know does it bind CB1 as well um if not um how is it working and you mentioned that people will not report any subjective effect of taking a pure CBD compound so lacking THC but it sounds like it may have some usefulness for uh treatment of epilepsy and what are some other established meaning clinical trials and or lab um data to support the use of CBD for any type of either um 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 meaning there's no CBD in there there's some there's very very low levels of CBD and the reason that is is because THC and CBD are both made from the same precursor molecule and which direction it goes in is based purely on which synthetic enzyme converts it to either THC or CBD and so as people have clearly chased THC and wanted cannabis that's rich in THC and so cannabis has been bred to become higher content in THC by default CBD has been bred out of the plant and it has largely been bred out of the plant for quite some time uh and so this I 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 I'm always like that's bizarre because historically there's always been like THC has been what people have bred cannabis for and so kind of any medical benefits that people have reported from Cannabis per se usually are THC and CB1 driven CBD is this other molecule that we can go to the pharmacology in a second but again it's just it's I mean I think in the in the analysis that Nick jomas did of all these strains and types of cannabis that exist uh in the United States when they went through their thing of thousands and thousands of kinds of cannabis it was like 3% of them maybe had like more than 1% CBD like it's very low like there's almost none and in Canada to get a CBD Rich strain you have to basically explicitly buy it because it has to be bred to make CBD and so this is the kind of choar Distinction I think you did allude to this last time which is the type one type two type three so type one is high THC type two is like somewhat balanced and type three is high CBD and now I think like 90 to 90 something low percent of all cannabis that are out there are type one like they're all high THC because that's what's been bred there's a few that have been mixed um and so are kind of equal proportions but you're never going to get high equal proportions so like a high THC cannabis is like 20 to 30% if you go for Ty two which is mixed they're both going to fall around 12% uh maybe a little more but in that range and then same if you got a type three it's high CBD it's going to be 20ish per CBD and very low THC and so no one has ever kind of grown CBD Rich cannabis outside of this recent boom in the last decade that's happened about people wanting CBD because of the charlott's web which was popularized by uh I think sanj Gupta on CNN in like 2012 or something it was a while ago but that was what got a huge movement going around this idea of CBD and yeah so the charlott's web was I I believe that was what they had named that kind of cannabis that they had extracted it from and so it was this it was a tincture that they were using that was very high CBD content that they were finding was controlling um pediatric seizures and kids now this has actually been studied pretty effectively uh most of it's come out of Boston um Elizabeth teal um has been one of the main leads on this and she's a neurologist there that has done a lot of the work on this and so they have I think very clearly and the data is incredibly compelling their research is one of the reasons why CBD has been descheduled or changed in its scheduling down to a u what is it five what is it class like CBD yeah like CBD CBD I mean given the uh availability of CBD everywhere in gummies and drinks and I mean you can get it in a convenience story so it's been kind of a lot of it's been like shifted in its classification status um 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 DVA syndrome now I there's other forms of uh 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 uh are relatively effective at um calming down the seizures in some kids it's profound like in some kids talking about kids that were having dozens of seizures a day to essentially none and so um and I can understand I mean that's super impr from a Grassroots perspective I can understand if you were a parent who had a child with a disease like this that was largely intractable and not that well controlled from the medications they on and then something came around that showed this level of efficacy you would gravitate towards it like that makes sense to me and I think the work that Elizabeth and her colleagues have done has been really important to establish the efficacy of this of CBD in these in these um disease States and so I don't think at this point there's a lot of controversy around that the question that comes out though is so how is it working and we don't have a mechanism so as you said like CBD receptor there is no CB like there's no receptor that CBD binds to I was under the impression that CBD also bound to the CB1 receptor no I I mean certainly or that it or that under some conditions it can modulate the shape of the receptor to adjust THC binding but now you're telling me that these two things rarely coexist together so I guess the question you can dose them like you can certainly I mean you can have products that are made that are like oilbased products at least that have a certain amount of CBD and a certain amount of THC and people do go for those and there's this I mean one of the arguments people make is they say oh introducing CBD reduces the adverse effects of THC and like well if you're using it in a strain that's simply because the strin of cannabis has less THC now so you sprad it out but I mean like a lot of this was based on some that came out a long time ago from Brazil where they showed that like um giving CBD with a relatively high dose of THC could curb some anxiety that came out from hios THC I thought the explanation for that was that c CBD can modify the CB1 receptor in some way that makes THC less able to engage with the some evidence to support that that like we would call these aleric modulators there's some evidence that suggests that CBD May interact with a aleric site on the canono receptor that makes THC bind less doesn't sound like you're particularly convinced by that evidence I think I mean like at the look on your face for those listening I'm looking at Matt and he's I think he's he's being generous here let me ask you a little differently does anyone know what CBD binds to no and so the most convincing thing that I've seen that CBD binds to is the work that CC Hillard has done looking at its ability to um essentially block adenosine uptake and so it can inhibit the adenosine transporter so it causes people feel more alert no because you're getting more adenosine so you get an accumulation it blocks the adeny transport mechanism I see so you get an accumulation of adenosine which is more sedative um and that I mean in the pnas paper that um CC's lab had from 2006 they showed that that also mediated it was the adenosine I think 2A receptor that drove the um anti-inflammatory effects of CBD so it was a secondary effect by sort of the opposite of uh caffeine of caffeine yeah I know if I remember the way you're describing this it sounds like the the anti- caffeine that's kind of how I describe to people if they ever ask me for what the pharmacology of CBD is I'm like that's not the only mechanism but the thing that was important in CC studies that I think is relevant is that it was not super high concentrations of CBD that caused that so you could get this adenosine accumulation at you know you're not talking like micromolar levels of CBD which is what a lot of Studies have done and so even when we're talking about the alisic modulatory site like yes there's evidence for it and it it is convincing evidence it's just the dose range in there you're kind of like who's getting hit with CBD at that level where you're getting these effects and more so when they've done the blinded work like when Ryan Vander at Hopkins again who is one of the main people who's done a lot of this work has actually blindly given people CBD dosing with THC finds the opposite that it actually amplifies some of the effects of THC and this was something we learned from the Pediatric epilepsy world was that when you start giving CBD relatively high doses one of the things that does is saturate a lot of liver enzymes and so some of the efficacy in the Pediatric epilepsy space may be a secondary effect due to an accumulation of some of the anti-epileptics as well because they're not being metabolized the same way and this has now been very well replicated we know that once you start taking CBD when they hit doses that are at the clinical level you're going to start having hepatic effects so it's going to affect the liver and it's going to affect the ability of the liver to chew up other drugs good and there's very specific um uh sip enzymes like the cluster of enzymes that metabolize things there's very specific ones that CBD hits and so as a consequence one of them is what 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 described before that it's sort of the what we're calling just for sake of discussion the anti- caffeine how do we explain the preponderance of CBD added to energy drinks that also contain caffeine there's like no logic there bias there you go everything everything can't be expected I have a feeling it's going to be interesting to see in the comment section on YouTube I mean presumably there's some um Regular pot smokers uh 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 um 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 uh you know someone someone gave them their weed and someone else and then they got a completely different effect right they're not expecting something um different necessarily um or in a particular direction but they get a very different effect but that to me just speaks to the idea that again cannabis sounds like polypharmacology 70 different cannaboids THC being among the more powerful components but it's um it's yolked 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 T is being held constant and then there's this constellation of other things around it that are modified and people eventually Veer towards what they like what they can afford what works with their lifestyle and then they come up with a bunch of theories based on packaging what they're told but presumably also some real effects of these Turpin the CBD component Etc it can't all be just psychological expectation 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 tpes and minor canab 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 um but one of the things with CBD that's interesting unlike THC is you can actually do pretty clean blinded studies because it's really hard to give someone THC and them not know they're on THC right this was the big problem with the MDMA trial that happened recently is that people who got the placebo knew they got Placebo people got the drug knew they got the drug it's very hard you could do a dose response but it's very diff it's very challenging to give someone a psychoactive drug and a placebo and them not know which one they have whereas because CBD doesn't produce an intoxicating state it's not really perceptible from the person who's taken it um that it's doing anything that actually does make it far more amenable to do blinded trials with and so I mean the interesting thing with CBD and this is where I get a lot of people that get angry at me as well is that I would argue that the overwhelming majority of the effects of CBD that people report are all Placebo effects and I say that because people Leverage The epilepsy stuff and some of the clinical work and say but we know it does things and my response to them is do you know what dose those people are getting because this is something that for some reason has not made the transition from science into pop culture this is a similar Phenomenon with glp1 um I and other people have pointed to the fact that certain food products or certain um drinks or certain activities can increase gp1 Glon like pepti which is now becoming more um commonplace knowledge uh because of OIC monjaro Etc as um very powerful weight loss tool although there's questions about muscle loss Etc and then we had Dr Zachary Knight on who explained that even a four-fold increase in glp1 brought about through a prescription drug or ingestion of a particular food or drink does not lead to any appreciable weight loss however when one achieves thousandfold increases in glp1 through the use of things like OIC monjaro you see profound weight loss meaning that you need enormous effects in order to see the the clinically relevant changes in in that case weight loss so it sounds like a similar thing with with CBD so so if somebody um takes a CBD gummy and they feel that they sleep better you would argue that that's entirely expectation bias I think that's a placebo effect and I say that because the majority of gummies are what like two migs five migs 20 migs maybe I I've never taken a CBD product I know a few years ago they were all the rage I just I was never tempted to do it um 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 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 um but sure a lot of people report this with CBD but again so most CBD Edibles or things that people take that are sold through commercial markets are in the range of two to 25 Megs of CBD so then I say to them so you're aware that in the pediatric epilepsy studies the dose ranges are like 1,500 to 2,000 M and then you're talking about a child who weighs on the order of what 20 kilos maybe you know like 40 60 pounds somewhere in that range versus so if you start dosing by weight which is how most of these things are done well they'll say 20 Megs per kig or whatnot um so so someone my size so I weigh a bit over 200 pounds for me to take that dose of CBD uh and let's say 20 migs per kig at like 90 odd kilos I mean you're talking about me taking a liver damaging dose an insane or maybe I wouldn't say damaging um it's definitely influencing how the liver metabolizes other things because it's going to saturate those enzymes but you're taking a very high dose so if for instance you were to take a high dose of CBD and then maybe uh have a couple alcohol containing drinks that could be problematic right because now you're talking about the two- hit model yeah I I can't speak to that because I actually do not know the metabolism of alcohol well enough I don't believe so cuz that's alcohol dehydrogenase so that would probably be a separate enzyme pathway than the sips this is more like separate enzyme pathway but you're but you're um challenging the liver yeah but I don't know if it would have an effect in that capacity I mean they've definitely seen this like they know the list of medications that this is a problem for so it's things like warin um and like blood thinners uh in the anti-epileptics funnel into the same metabolic pathway as this THC so there's certain things that this would influence I don't know if I would say this would be in the context of alcohol but I think more so I mean what I try and point out to people repeatedly is I have yet to see a blinded clinical study that has found any effect of CBD that's efficacious that's under 300 to 500 milligrams and yet in in the wild and people who are using it on their own we using doses of 10 to 20 milligrams and Reporting these effects and the thing is that I think a lot of people don't also realize is CBD has absolutely horrific bioavailability like so if you take it orally in a in an oil or in a gummy or whatever you consume it in now this might be different with some of these beverages that are out there I don't know if anyone's actually ever done the pharmacokinetics on them at least I've never seen it um but standard Roots we're talking 4% like very very little actually leaves your gut into your bloodstream now we do know from the studies from GW who created the pharmaceutical version of CBD that was used for a lot of the Pediatric epilepsy studies that they did I don't know if it was random or intentional find that opposite to something like alcohol if you had just eaten a fatty meal that actually enhanced the bioavailability of CBD dramatically so then it went up to like maybe 20% got into the blood but that's probably because again CBD is a fatty molecule it likes fatty environments and for some reason having fat in the stomach and in the gut seems to promote its ability to get into the bloodstream you can see it now it's the steak in CBD or the the CBD with omelette uh protocol 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 have very poor bioavailability and then people really stand by the effects of these and so I'm like you know what I would always say is if it works for you there's no reason to stop it but because you're having benefit from it but would I ever recommend someone to do this no I wouldn't because I 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 could interact with there's a couple receptors people have said you know it might interact with a serotonin receptor there's some of these like random orphan receptors that we don't know a lot of what they do that CBD might interact with but like the concentrations you need to hit those are reasonable and you're not getting that in the blood and certainly not in the brain of people from consuming incredibly low doses of CBD so the whole Market that exists for CBD to me is is a little bizarre and I think for a lot of us in the Cannabis field this has been one of the most bizarre social experiments we've ever watched because like you know if you asked me in 2010 to walk into a room and ask how many people knew what CBD is like maybe one out of a hundred like no one knew what CBD was and now it's like 80 to 90% would know what it is because everyone you can't walk down a street in any city in North America and not see CBD products whether it's some kind of cream or like a shake or some random like concoction that people have added CBD because now it's going to you're saying the energy drinks like it's just it's bizarre to me how much has taken off because it seems to have somehow migrated into being a health product in some capacity so yeah I've never tried any of these CBD containing products I think uh a lot of what you're describing speaks to the fact that um you know people are eager for things that can help them adjust their anxiety and sleep better you know which is a large um reason why a lot of this podcast has focused on respiration based tools and other based tools that um can help people with anxiety I think that many people suffer from um just too much uh activation in their autonomic nervous system and um I I would argue there are much better things that are not of a ingestible type you know things that one can do that are science supported right there are clinical studies um meditation breath work any not so much breath work I would argue but um certain patterns of breathing meditation cognitive behavioral therapy there are a whole bunch of different things as you know um 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 I I mean again it's I think from my point of view it's an ethical thing as well because like this isn't covered by insurance people are spending their own money on this and so I find it really challenging to recommend someone to be spending what can I mean if you're especially if you're talking about an actual clinical dose I mean for someone to take CBD at the level where it could actually be shown to have some benefit in some condition of which currently it really is just Pediatric Epsy like this idea with sleep pain anxiety there's not a lot of super conclusive data and I'd say most of the trials that have been done have not found really good evidence of benefit in any capacity so it makes it very challenging to recommend this in any capacity especially I mean if someone if finances aren't an issue sure go for it but um you know I understand people are like you say looking for Solutions so ites doesn't sound like CBD is the solution I I would I 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 uh we talked about psychosis and the lack of evidence for a direct causal effect um 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 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 um we talked about the potential for addiction and the evidence potentially for and against that right um there's also this the big black or gray box of you know all the things we don't know about what regular cannabis use could do um and yet I know a lot of people who've used cannabis for years mainly as a replacement for alcohol at least that's how they describe it well it's not as bad as alcohol that you hear that a lot okay um but what are some actual if any um what are some actual harms of cannabis use that people need to take into account and just weigh against the fact that every compound caffeine even water can kill you if you drink too much of it um 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 about uh these days um is driving yeah um so Health harms I mean someone smoking obviously there's risks for lung damage I would say the evidence for things like lung cancer certainly don't hold the way they do with cigarette smoke um because people are smoking less of it or there's just fewer carcinogens in there I don't think you could make the argument about fewer carcinogens per se I think probably it relates more to the frequency I mean Donald tashkin who's in California here I think he was at UCL 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 inv vitro animal work with really high dosing suggests it could have anti-proliferative effects for tumors whether that's real or not I don't know but like I think more likely it's because most people who smoke cigarettes at least that were um you know the relationship with lung cancer were people who 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 empyema things like that are on par if you have any combustion product you're going to have damage there there's no question about that so again harm reduction perspective would be you know oral roots of administration bypass lung damage they come with their own issues with dosing and whatnot but if you're talking about physical harms that's one thing to avoid that you could bypass that aspect of it with um there is some I don't think we are at a point where we can say the 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 we're 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 it was can can this um potential I want to highlight potential um relationship between cannabis use and cardiovascular issues um be bypassed no pun intended by using Edibles not inhalant or is it related to THC itself I would probably guess and this is a guess um that the you know any 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 would make it worse but THC itself has a very complex effect on cardiovascular function because it tends to cause um typically vasod dilation so you get widening of the blood vessels which is why it relates to a lot of people will experience postural hypotension so sometimes when what that is is if you stand up and your blood pressure doesn't catch up with you so you get really laded 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 um but when they've consumed cannabis in some capacity there are some people that seem to be very sensitive to the vasod dilating effects and so when they stand up their blood pressure can't match the shift and gravity that happens and so not enough blood peruses the brain and they go down and that can be transient they'll come to a minute or two later but it happens um but but as a consequence of the Vaso dilation is it triggers Tachi cardia 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 um it's a bit of a tricky thing because obviously if there is some underlying heart or a cardiac sensitivity or issue the tacky cardia itself can be a problem I mean So like um you know if someone has like an underlying heart condition where at rest it may not present itself but the shifts into that kind of beating faster to compensate for the fact that you've got a drop on blood pressure um can do put strain on the heart in a way that could unmask a vulnerability or an event and again this is me theorizing what I think it could be based on what we understand to some degree about how it affects cardiovascular function um there are occasionally people who um have reported having like elevated blood pressure I mean some of that also could be from like an anxiety state or whatnot coming around but the typical response and this is usually driven by cannabinoid receptors that are in the um the vascular beds themselves that it causes a vasodilatory response and so that is usually the first step the second is the the uptick in the in the heart rate so you get these kind of effects over time there's some work looking at like um you know vascular stiffness that can evolve over time and cannabis users there's some evidence that suggest that you might get more of that emerging and so again that could relate to uh 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 the timeline of this I mean you know cigarette smoking was an easier thing to establish in that context because you know once antibiotics and Medicine advanced in like the 40s and the 30s and stuff and people started Living longer you started seeing a lot of these effects of cigarette smoking emerge because and yeah it took a while for the um medical community to adopt the idea that cigarette smoking was bad oh I know it's wild Physicians would smoke in clinic the ashtrays in the doctor's office I mean my grandparents grew up in Belfast they had smoked for years and they had even said like when they were younger doctors would say oh have a cigarette after a meal it promotes digestion so it it's kind of wild to hear that stuff when you think of how cigarettes are viewed nowadays but um it is I don't think we've we've kind of been able to track this long enough to be able to say with certainty what we're seeing but I think there's like if people ask me about risks and harms of cannabis the 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 um and I would also say if anyone has cardiovascular issues they should avoid cannabis just because that's more of like I would say a being safe because I don't know how to actually explicitly say what I would say the harms associated with it are but I think there is something there I've seen enough evidence that's like starting to coales into um a story that's like there's something here so I would that's where I would say that I think there's risk there's also things like um this bizarre cyclic vomiting syndrome which is this really strange thing that has become really apparent uh we've seen this in Canada a bit more now with legalization again because people are going into ERS more where it's this somewhat strange phenomenon where it's usually people who are pretty excess cannabis users um 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 um like one of the things that seems to Cur it is a hot shower which is I can't even begin to understand this I mean there's also the I'm chuckling at the example because you are so very clearly rooted in science but that just came out of nowhere like okay cool a hot shower deliberate deliberate heat exposure folks there it is I have been trying to understand how I'm 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 um you know smoking being uh a regular part of the the the medical community behaviors up until you know a few decades ago um and then you know a hot shower being the treatment for this like chronic vomiting and it it speaks to the fact that like with science and medicine we do know a ton it's amazing how much we progresses especially in the last 100 years last 25 years even but it's also astounding how um the seemingly surprising um antidotes to uh uncomfortable conditions can hold up over time with in the absence of any randomized control trials or mechanistic data I mean I I've really struggled to understand because certainly I don't think it was doctors that figured this out this was people I think who were experiencing this and then they started telling doctors this and then I think and I could only imagine I'm like maybe they're going in the shower CU they're like vomiting on themselves 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 capsacin cream and that also seemed to provide benefit something about activation of the the something with thermal regulation because the other thing that seems to have shown some benefit is propanolol which again would suggest some kind of sympathetic which is a beta Block it's a beta blocker so yeah it's your effect so there's something with autonomic it must be messing up some kind of autonomic balance or something with thermal regulation why that results in this kind of bizarre vomiting syndrome I have no idea but I remember when I first started hearing the the stories of this years ago and I was just like how cuz I mean it is again surprisingly counterintuitive because one of the um Medical uses that people have used canabas for is as an antinauseant especially in the context of chemotherapy and so something that typically has antinauseant qualities suddenly triggering a vomiting syndrome is kind of a paradoxical and yet we started off today's conversation with you explaining beautifully how activation of these um CB1 receptors are are homeostatic in some sense the thermostat analogy and you know maybe after you know chronic use there there's some you know the Seesaw sort of get fli to one side get stuck I think that's how most people have tried to uh kind of conceptualize what's going on is maybe like and it seems to involve the insular cortex at least the antinauseant effects of cannabinoids are involved through the insul cortex um and so maybe you like have burned out those receptors from chronic use and so that endogenous mechanism isn't working or it's somehow flipped in the other direction now and 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 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 a for so interesting so a hot shower yeah so apparently if it happens hot shower is what people claim so yeah so for me I would say the the the main harms that people need to be aware of the schizophrenia bipolar um 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 Bonafide health issues associated with cannabis that people should be aware of I mean and if you I mean I know we're not going to probably go into depth with it on the other side with the medical stuff it's a little bit more challenging I mean a lot of this is just because we really don't have good studies that have been done in any capacity that have really definitively told this of cannabis has like really Bonafide medical benefit yeah I was going to ask you about that it's always nice to end on positive side and you know we don't want to demonize cannabis nor do we want to glorify it it um but you know the examples that I've heard of medical uses for cannabis include appetite stimulation we talked about that um for glaucoma lowering eye pressure and glaucoma the age and age related increase in eye pressure um are two of the major risk factors for glaucoma which is the most common blinding disease second to cataract um more than 70 million people suffer from from it everybody regardless of age get your eye pressures checked there are drops for this but okay cannabis can reduce eye pressure glaucoma um nausea you mentioned and then anxiety um it sounds like if people get the um the dose right and it's right for them that in some cases it can help them with their anxiety and the reason I raised that one is because it seems that most people who decide to use cannabis regularly are using it as perhaps for its euphoric effects but as a kind of a mild sedative a way to relax in the same way that they would use a glass or two of wine what are your thoughts on that because I think this is the most common use case yeah it I mean you look at I mean the other one that that wasn't on there but you've mentioned this before and I have as well as pain so chronic pain pain is I would say the number one so pain is certainly the one that there's the most amount of evidence for and um I I would say when you talked about this in the previous podcast you were mostly correct about this component of it in the sense that it's not that cannabis is a profound analgesic it's that cannabis it has some analgesic properties but it's not like super Sledgehammer in that sense but what it does seem to do is it seems to strip away the affective component of pain to some degree and so what I have consistently heard from chronic pain patients when they use cannabis is they say yeah my Pain's still there but now the Pain's background noise so I can sleep at night and just being able to sleep I think is actually providing a huge amount of the benefit to that Community um but it's the day-to-day like they're able to function with the pain because it doesn't um they don't become focused on it the same way because they're able to kind of push it to the background that seems to be the main ability of cannabis I mean yes there's some mild analgesic properties to it to some degree but it really seems to be much more of that component of it and I think you'd alluded to something like that in the previous podcast you'd said something about it's changing the emotional state of pain so and we know from the biopsychosocial model of pain that emotions and interpretation of the sensation of pain is a huge component of what people refer to as chronic and acute pain yeah so so the pain thing I think is is a central one and that's one of the only ones that there's a little bit of actual research on most of it's either with isolated THD I think there's one or two studies that have actually looked at smoke cannabis and found small signals of benefit but so um 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 endoc canabo in that space um and yeah you look at questionnaire based um studies about why people smoke cannabis and like 85 % of them will say because it reduces stress and it makes me feel less anxious I mean that was like a big impetus as to why we started studying endoc canabo regulation of it because similar to feeding and pain where we know endoc canabo are involved in regulating feeding circuits and endoc canabo are also integrated into pain circuitry and can provide some endogenous analgesic signals um we figured the same was going to be true for Stress and Anxiety which to some degree it is um but it's very complicated because it can be like I said before basic where some you know lower doses or angol higher doses can promote anxiety but for the majority of people who use cannabis regularly it's because it helps reduce anxiety now whether that would hold weight in a clinical trial is a different story there is some old evidence from like I'd say the 70s or early 80s where they were using synthetic forms of THC like naalone which is something you can get in Canada or Marinol or dronabinol which I think is what's accessible in the states where they did find some evidence to suggest it was on par with like a benzodiazapine like diazapam or something I can't remember exactly what the comparator they'd used there but there was some evidence for there being some anti-anxiety properties of THC um and that tracks generally well with um the self-reported literature that's out there um 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 um and again there's very little research in this space there was one really really small study done by the Canadian military um first they did one version of it that was an open label uh 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 um cannabis helping especially with sleep and the big thing that they reported was that it suppressed 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-experience 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 um and there does seem to be some suggestion that because they're remembering it and maybe changing the details because they're in a Dreamscape space that they reconsolidate it a little bit more and there's often a high degree of sympathetic activation and arousal that goes on with these nightmares and some of the belief is that this is part of the sensitization process that can happen in in PTSD where the disease can work person over time because the reexperiencing and the reconsolidation and the sensitization of the disease that happens over time in this kind of sleep State can make it worse and so the majority of veterans who have used cannabis and Report benefit if you actually talk to them about it um as I've done in a few different situations and also just look at the anecdotal data almost all of it talks explicitly about sleep and they say oh we 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 naalone this um synthetic version of THC it very in like a large proportion I think like 85% of them almost stopped having these nightmares and this was a like a treatment resistant population that was pretty severe so this was a big benefit so they then took the open label and did what you should and moved forward to do a double blind Placebo control now it was a very small sampled studies and that is obviously always a problem with human work is if this was like 15 or 17 people so not powered enough to really make any kind of firm conclusions but interesting in the sense that at least it was done in a proper crossover design where they got Placebo at one point they got nablo at one point it was switched they didn't know which one they were on um because they're taking it right before bed maybe that will remove some of the subjective bias again you can't totally remove it but like if someone's taking it within you know an hour or so if we to sleep they may not feel the high the same way but even under the double blinded conditions they found a very effective suppression of the of the nightmares and the reexperiencing and then they also at the same time found this increase in kind of quality of life measures which tracked with the fact that they were probably sleeping better um I don't think they actually reported any change or even looked at maybe the overall PTSD score they only reported or really focused on the nightmare component of it because that was the primary outcome of the study 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 kind of I wouldn't maybe call it a sleep aid because it's really more of a modulator of the dream state and I think this presumably because it's reducing the amount of rapid eye movement that you're getting which most people will probably hear and interpret as bad but you know uh REM deprivation is actually one treatment for depression so there are certain um case conditions where um dreaming and REM is not advantageous and you're describing I mean depression and PTSD are both two two disorders that are characterized by changes in Ram like they have earlier onset to Ram so they go into RAM faster they tend to have some altered architecture of the REM component of their sleep so in those States maybe suppressing REM isn't actually a bad thing at least certainly for PTSD I would imagine in terms of the context of the nightmares that's providing some benefit whether or not it globally is is changing the disease severity or improving the disease I don't think we really have any evidence to say um but again I can understand the um 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 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 I don't think we have any strong data that we can leverage in that capacity to be able to say it but um to me it's one of the more interesting areas I think anxiety disorders in general um there's definitely some potential so as IID mentioned earlier um the the fall inhibitor that elevates anandamide levels so Johnson and Johnson did do a trial in social anxiety disorder it's published I think from a few years ago 21 or something I can pull up the reference for that where they did find some benefit it wasn't huge and some of this had to do with the design of the study because they kind of underdosed the patients a bit and so not everyone actually showed the elevation in an anide when they went back and looked but when they actually isolated the group of people that had higher anandamide in that proportion of the patients they did see some symptom Improvement so it did support it and this is I mean very similar like for us this is a big thing because all of the work that we focused on is looking at how stress and stress hormones regulate largely anandamide signaling and I mean one of the main things that we've demonstrated that's been replicated relatively well over the years is that stress exposure um can actually cause a rapid loss of anandamide signaling and it's that loss of anandamide signaling that seems to facilitate some synaptic strengthening in the amydala and promote activity in areas that are involved in these anxiety circuits and so um the thought has always been well if an emide you know it's that job is its kind of tonic housekeeper at keeping things in that homeostatic range let's say we're talking about explicit an anxiety circuit you know there's individual variation that exists in humans across everything so one of our predictions has been maybe people who are on the high end of the anxiety Spectrum might be on the low end of their tonic and anomid 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 endoc canabidol and found lower anandamide that's extremely interesting because um it squares with u my uh 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 um kind of let's just say Baseline circuit activation within the amygdalin related structures in mice in humans presumably in other animals also if people take a compound that adjusts the sort of homeostatic level of what's considered low moderate and high activation of those circuits that include the amydala then perhaps they're bringing their anxiety into range um in a way that perhaps is different than with alcohol which is more acute you know people have a couple drinks they'll feel relax but then there's this phenomenon of of anxiety you know the next day um feeling a little anxious when they're not drinking whereas um it's interesting that many people who use cannabis for this purpose are not using it all day long they are perfectly able to wait until the night time or evening and of course people can wait for happy hour for a drink as well but it's far and away different than the way we envision something like Al alol use disorder where somebody discovers that alcohol really helps with their anxiety and then they're drinking you know maybe one at lunch maybe a couple at dinner and then in the evening to fall asleep at night um I'm describing extremes here but I find your hypothesis um to square really well with the real world observations yeah it's an interesting one there is some evidence to actually support so my buddy S Patel who's at Northwestern now but he was at vanderbelt when he did this study um they basically played with these drugs that you can use to prevent endoc canabo synthesis so you can create a state of like um impaired endoc canabo function and in humans and they did this in rodents 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 endoc canabo function produce states of anxiety and they did demonstrate that so you could deplete endoc canabo levels and you got the emergence of an anxiety state so then you could give drugs that would boost the endoc canabo to normalize this um so again it kind of fit with the idea but then they did one key study where then they gave THC and saw could THC fell in the Gap and they found that like boosting endoc canabo giving THC on a background of low endoc canabo 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 there's some foundation for making a theory that's similar to what you're saying which is maybe some people are trying to fill in a gap of something that's icient 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 endoc canabo function or something else might be at play there so very interesting yeah I think it could explain some of the heterogeneity that exists out there for sure yeah so perhaps genetic differences in s Baseline levels of anxiety perhaps map to endogenous levels of anandamide and might predict propensity for THC use yeah I mean we have definitely found uh in human population through work I've done with a lot of clinical collaborators and others like you know we look at endoc canabo in the blood and it's not in the brain but they are lipids that can move pretty easily back and forth um and we have found relationships between peripheral endoc canabo levels and mood States both anxiety and kind of depressive measures which does you know somewhat relate to the the possibility that this could be real we don't know um it's it's it's been hard obviously for various reasons to really track this but we've never looked at an anxiety disorder population we've done some work with post-traumatic stress disorder populations there's been work in depression populations that have found some relationships that are pretty similar so it's certainly a possibility um 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 uh for what has been an incredibly clear precise and in many cases actionable whether or not it leads to a yes or a no um actionable information here because cannabis and CBD as you pointed out are kind of everywhere around us yeah and people are making decisions about um 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 uh introduction that I gave um has evolved into a collaboration that I'm certain based on the uh exquisitely clear and generous information that you've provided um 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 uh clarifying points that were unclear before um and and also pointing the fact that this is a complex system a complex bi ology um you know there are a lot of things about psychosis about negative effects about potential um positive uses of cannabis that just are not yet clear and thanks to excellent researchers like you are likely going to be clarified in the years to come so um thank you ever so much for your time for your research and for your attention to the public health education effort around cannabis thank you and I think it's also important I think it's good as you had said that like uh for people to see that scientists can have disagreements absolutely I think it's important um I think it's good that you kind of provided me an opportunity to correct the record um and did so in a very appropriate manner I think this was a great discussion for people to understand um different perspectives also good to highlight where it was that I had had issue with your previous podcast and um I think the discussions that came out of that were for the better so that's all the best and Hope hopefully if there's other contentious issues that happen down the road similar things move forward and you chat with people are well yeah if somebody who is expert in a particular area takes issue with something specific and can substantiate it with something that um can foster better understanding um without fail I'll reach out to them now how quickly we're able to get them here uh Etc is is always an issue sometimes uh we can put an addendum to a podcast um now nowadays that's easier using um 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 uh if we had been in a meeting and you presented data I presented data and we disagreed what we would probably do would be to head well traditionally it' be to the bar but we'd grab a cup of coffee or go for a walk and we would um 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 um and certainly during today's podcast is to do something uh to that effect so and I think it's really good for people in the public to know this is how science progresses this is you know someone says something someone disagrees with it you get an opportunity to clarify things and I think that that's really good uh just to move things forward so I think that was a a good process that we've gone through yeah likewise and it's certainly within the spirit of the podcast in no way shape or form do I um purport to get everything right and where I've made mistakes I I really strive to correct them and listen it's been a real honor and privilege to have you out here thanks for coming all the way from Canada and I do hope to have you back again as the research evolves and we can learn more about these topics and more so thank you so much Matt appreciate you great thank you for joining me for today's discussion about cannabis with Dr Matthew Hill I hope you found the discussion to be as informative as I did if you're learning from and or enjoying this podcast please subscribe to our YouTube Channel please also subscribe to the podcast on both Spotify and apple that's a terrific zeroc cost way to support us 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