The Effects of Cannabis (Marijuana) on the Brain & Body

1. 0:00 – 4:46

   Cannabis (Marijuana)

   1. AHAndrew Huberman0:00

      (peaceful music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, we are discussing cannabis, also referred to as marijuana. Cannabis includes many different compounds that have profound impact on the brain and body. So while many of you have probably heard of THC, there are also compounds in cannabis such as CBD, and of course there are different types or strains of cannabis, including sativa strains and indica strains and hybrid strains. And believe it or not, nowadays, there is also an entire literature, meaning a scientific and medicinal literature, about type one, type two, and type three strains. I'll explain what all of that is and how they work. I'll talk about some of the medicinal applications of different strains of cannabis and combinations of cannabis strains, as well as some of the potential health hazards of cannabis use. I want to emphasize that any discussion about cannabis has to be framed within the context that the legality of cannabis varies tremendously depending on where you are in the world. So depending on which country you're in, and even which state you're in or which area within a country, possessing and using and certainly selling cannabis can be either highly illegal or entirely legal or decriminalized or largely overlooked. You, of course, are obligated to know what those local laws are for you, where you live and where you travel. With that said, today's discussion really will include a full picture as to where cannabis and the various and even very specific compounds within cannabis can be extremely useful in the treatment of some ailments, and where certain compounds in cannabis can be extremely dangerous for certain individuals to use, in particular, individuals that have preexisting genetic propensity for psychosis. That theme is going to come up again and again, but we are also going to talk about the role of cannabis in anxiety, in depression, both positive and negative effects. We'll talk about sex differences in terms of women versus men and how they react differently to cannabis. And I would be entirely remiss if I didn't include a conversation about cannabis, meaning THC, CBD, hybrid strains, et cetera, in creativity and different modes of thinking, because as many of you probably know or at least have heard about, cannabis can impact the way that we think, the types of memory systems we can access, and what's called convergent and divergent thinking, which is one way of conceptualizing what is commonly referred to as creativity. So, today's discussion is going to include a lot of information, but I promise to make it clear and accessible to all of you, regardless of whether or not you have a background in biology or not. And today's discussion will also be quite nuanced. You'll find me routinely reading directly from specific research papers, something that, of course, we always do on this podcast. But today, I'm really going to dig into some of the finer points of the methodology in papers and some of the statistics that were used and the specific populations of people that were studied, because as it turns out, there are instances that we will discuss in which the use of cannabis can be immensely beneficial to one group and yet can be entirely detrimental to another group, even at equivalent dosages and depending on a number of different factors, so we will discuss what those factors are. Just to give you a brief overview of the kind of structure I'm going to put on today's episode, we will review, of course, cannabis in its various forms. I'll talk about some of the biology. But we are going to really drill into how dosage, that is, the concentration of THC relative to CBD, impacts whether or not cannabis is going to have one effect or another. We will also talk about the frequency of use, daily use, multiple times per day use, weekly use or monthly or occasional use. We will also talk about different professions and how some people may have a little bit more leeway in terms of whether or not they decide to use cannabis or any of its various component chemical constituents, that is, CBD or THC, et cetera. And for other professions, it might be entirely inappropriate because of the particular kinds of cognitive tasks those professions demand. We will also talk about genetic predisposition, again, sex differences, hormone effects, and I will also touch on what I think is the most important variable in determining whether or not cannabis is right or wrong for you, and that is your age at which you are considering starting or continuing use or ceasing use. What I can assure you is that by the end of today's podcast, you will have a quite thorough understanding of cannabis, how it works, what it does, what its potential benefits can be, what its potential hazards are, and whether or not it's right for you and the people that you know.

2. 4:46 – 7:03

   New Huberman Lab Premium Membership

   1. AHAndrew Huberman4:46

      I'm excited to announce that the Huberman Lab Podcast has now launched a premium channel. The purpose of the premium channel is severalfold. First of all, I will be hosting regular AMAs, Ask Me Anythings, where you can ask me anything, and I will provide answers in-depth to your specific questions about science and science-related tools for mental health, physical health, and performance. Now, there is a nominal cost to the premium channel. It's $10 per month, or you can pay $100 for the entire year. I should mention, however, that a significant portion of the funds raised through the premium channel are going to support not just the Huberman Lab Podcast, which we will continue to release every Monday on schedule, of zero-cost-to-all-consumers content on mental health, physical health, and performance, but proceeds from the premium channel will also be used to fund research, in particular, research done on human beings, so not animal models but on human beings, which I think we all agree is the species that we are most interested in. And we are going to specifically fund research that is aimed toward developing further protocols for mental health, physical health, and performance, and those protocols will be distributed through all channels, not just the premium channel, but through all channels, Huberman Lab Podcast and other media channels. So the idea here is to give you information to your burning questions in depth and allow you the opportunity to support the kind of research that provides those kinds of answers in the first place. Now, an especially exciting feature of the premium channel is that the Tiny Foundation has generously offered to do a dollar-for-dollar match on all funds raised for research through the premium channel.So, this is a terrific way that they're going to amplify whatever funds come in through the premium channel to further support research for science and science-related tools, for mental health, physical health, and performance. If you'd like to sign up for the Huberman Lab Premium Channel, again, there's a cost of $10 per month, or you can pay $100 upfront for the entire year. That will give you access to all the AMAs. You can ask questions and get answers to your questions, and you'll, of course, get answers to all the questions that other people ask as well. There will also be some premium content, such as transcripts of the AMAs and various transcripts and protocols of Huberman Lab podcast episodes not found elsewhere. And again, you'll be supporting research for mental health, physical health, and performance. You can sign up for the premium channel by going to hubermanlab.com/premium. Again, that's hubermanlab.com/premium.

3. 7:03 – 10:08

   Tool: Non-Sleep Deep Rest (NSDR), Sleep & Anxiety

   1. AHAndrew Huberman7:03

      Before diving into all of that, I'd like to highlight a new, what I think is very useful and zero-cost resource. This resource is what's called Non-Sleep Deep Rest, or NSDR protocol. I've talked many times before on the Huberman Lab podcast about Non-Sleep Deep Rest, AKA NSDR. NSDR is sort of an umbrella term for a variety of different practices, so these are behavioral practices, that allow you to direct your brain and body into a particular state, and most typically, that state is one of deep relaxation, but also one in which you can access your bodily and brain systems for teaching yourself how to relax in real time, and how to recover some of the sleep that you may not be getting at night, and to restore levels of dopamine in particular areas of the brain that are involved in motivation and cognitive and motor control. Basically, NSDR is a wonderfully restorative tool. This has been demonstrated many times over now through quality peer-reviewed science, and there are neurochemical benefits, and there are physical benefits, and there are certainly psychological benefits. I highly recommend NSDR to anybody that has trouble falling asleep or that wakes up in the middle of the night and needs to get better at falling back asleep, as well as to anyone out there that has issues with anxiety or s- self-regulation of any kind. And if you don't have any of those issues, it's also immensely beneficial just as a restorative for leaning back into focus work of any kind. Now, a number of people have reached out about finding NSDR protocols, and there are a number of different good ones out there floating around. I've decided to put a zero-cost NSDR script out there on the internet for people to access. So, you can find it by going to YouTube and simply put my last name, Huberman, and NSDR into the search function. This is a YouTube channel that's hosted by Virtusan, which has a terrific app that includes NSDR and a number of other health and wellness protocols. But they've been quite generous in hosting a 10-minute NSDR read by me. This NSDR is distinct from, although I should say similar to, yoga nidra, which some of you are familiar with. This NSDR is different than yoga nidra in the sense that it doesn't have intentions. There's no mystical component, and I describe a little bit of the science and why specific components of the NSDR are included, things like long exhale breathing. I talk about perceptual shifts and how to move from thinking and planning to pure sensation. If none of that makes sense right now, it'll b- make total sense after listening to the NSDR script. Again, it's a 10-minute NSDR script read by me. You can do this first thing in the morning when you wake up, especially if you didn't get enough sleep that night and you're feeling a little bit fatigued and you need to lean into the day with full vigor. You could do it at any point during the day, or if you wake up in the middle of the night. Again, this is a zero-cost resource for you. You can find it by going to YouTube, put my last name in and NSDR. I encourage you to try it, and if you like it, or frankly, if you don't, you can just put that in the comment section there on YouTube. And I've put it there as a free resource to you so that you can benefit from the research-backed peer-reviewed studies that point to NSDR as a very useful practice. Before we begin,

4. 10:08 – 14:01

   Levels, Thesis, InsideTracker

   1. AHAndrew Huberman10:08

      I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Levels. Levels is a program that lets you see how different foods affect your health by giving you real time feedback on your diet using a continuous glucose monitor. One of the most important factors in your immediate and long-term health is how well you're managing your blood glucose or blood sugar. I started using Levels about a year ago as a way to see how different foods and different lifestyle factors were impacting my blood glucose levels. So, for instance, it allowed me to see how different foods and particular macronutrients and combinations of macronutrients would either peak or trough my blood sugar or keep my blood sugar steady. It also allowed me to see how working out with weights or running, how that impacted my blood glucose. So, for me, it was a fascinating experiment unto myself as to how my meal schedule, the specific foods I was eating, different combinations of food, as I mentioned before, and exercise were combining to regulate this thing that we call blood sugar and that's so vital to our health. I think anyone that tries Levels will find that you learn an immense amount about what you're doing and what you ought to be doing differently in order to optimize your immediate feelings of well-being and your health trajectory. If you're interested in learning more about Levels and trying a CGM yourself, go to levels.link/huberman. That's levels.link, L-I-N-K, /huberman. Today's episode is also brought to us by Thesis. Thesis makes custom nootropics that are designed for your particular needs. Uh, I am not a fan of the word nootropics because nootropics literally means smart drugs or smart drug, and frankly, as a neuroscientist...I know, and every other neuroscientist knows, that there, there is no neural circuit or chemical in the brain for being smart. There are, for instance, neural circuits and chemicals that increase your ability to focus or your ability to task switch. Thesis understands this, and therefore has designed custom nootropics that vary and are tailored to you, so that, for instance, if you want to achieve focus and clarity for one particular type of work, there is a nootropic for that. Or if you'd like to have more energy and have more focus, there's a different nootropic for that. If you'd like to get your own personalized nootropic starter kit, you can go online to takethesis.com/huberman, take that three-minute quiz, and Thesis will send you four different formulas to try in your first month, and then they'll work with you and iterate to find the best formulas for you to take ongoing. Again, that's takethesis.com/huberman and use the code Huberman at checkout to get 10% off your first box. Today's episode is also brought to us by InsideTracker. InsideTracker 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. 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 with a quality blood test. With a lot of blood tests and DNA tests out there, however, an issue is you get information back about lipids and hormones, et cetera, but you don't know what to do with that information. With InsideTracker, they have a personalized platform that makes interpreting your data and then acting on that data very straightforward and very directed toward specific protocols. What I mean by that is you'll get information back about hormone levels and metabolic factors, lipids, et cetera, and then you can look to nutritional changes, supplementation changes, exercise protocol changes, and other lifestyle features that combine or work on their own to so- to try and shift those numbers into the range that's appropriate for you. If you'd like to try InsideTracker, you can visit insidetracker.com/huberman to get 20% off any of InsideTracker's plans. Just use the code Huberman at checkout. Again, that's insidetracker.com/huberman to get 20% off, and use the code Huberman

5. 14:01 – 15:08

   Momentous Supplements

   1. AHAndrew Huberman14:01

      at checkout. On many episodes of the Huberman Lab Podcast, we talk about supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them, things like enhancing sleep and the depth of sleep, or for enhancing focus and cognitive ability, or for enhancing e- energy or adjusting hormone levels to optimal range for you. The Huberman Lab Podcast is now partnered with Momentous supplements. We partner with Momentous for a number of important reasons. First of all, the quality of their ingredients is exceptional. It's really second to none. Second of all, they ship internationally, and that was important to us because a number of you reside outside of the United States. Third, we've worked with Momentous very closely to develop single ingredient formulations. Now this turns out to be very important, because if you're going to take supplements, you want to know what's working for you and what isn't. And of course, you want to optimize the cost efficiency and the biological efficiency of those supplements. To find the supplements we discuss on the Huberman Lab Podcast, you can go to Live Momentous, spelled O-U-S, livemomentous.com/huberman. And I should just mention that the library of those supplements is constantly expanding. Again, that's livemomentous.com/huberman.

6. 15:08 – 19:34

   Cannabis Strains, Psychoactive Compounds: THC & CBD

   1. AHAndrew Huberman15:08

      Let's talk about cannabis. And when we refer to cannabis, we are indeed referring to marijuana or the marijuana plant. Now, cannabis plants come in different strains or different varieties, and those different strains are indeed different genetic strains. Just as animals and humans have different genetic backgrounds, and they can be crossed to one another to yield further genetic variation in the offspring, plants can be hybridized to one another in various ways, through grafting or through the use of different types of seed combinations, et cetera, in order to generate different strains. There are also naturally occurring differences in the strains of plants, and the cannabis plant is no exception. So for instance, in the context of a discussion about cannabis and its medicinal uses and recreational uses, we need to distinguish between the sativa variety, the indica variety, a variety called ruderalis that's not often discussed, and hybrids of sativa, indica, and ruderalis. Before diving into the different strains of cannabis and how they impact the brain and body both similarly and differently, I want to emphasize that the cannabis plant contains a number of different psychoactive compounds. Now, the most powerful of those compounds is THC. The technical name for it is delta-9 tetrahydrocannabinol. But THC, as I'll refer to it, is just one of the psychoactive and biologically active compounds within cannabis plants. There's also CBD, which is technically referred to as cannabidiol, and cannabidiol, CBD, is known to be used for things like pain management, anxiety management, and other medicinal purposes. We will talk about the efficacy of CBD for those purposes, as well as some of, believe it or not, some of the dangers of CBD depending on where it's sourced and the dosage, et cetera. So we've got THC, CBD, and also CBN, or cannabinol. CBN is less often discussed. You're going to hear a lot less about CBN-containing products out there, CBN-containing medicines. But it is relevant to today's discussion, so it will come up a bit. Now, I will be sure to provide more specificity to what I'm about to say, but very broadly speaking, THC is largely responsible for the psychoactive effects of cannabis, that is, the changes in mood, the changes in bodily state and sensation, et cetera. Whereas CBD, and to some extent CBN, have profound effects on the brain and body, but they don't tend to give people the sensation of altered perception, altered mood...... et cetera. Some people might say they are not the component of cannabis that, quote-unquote, gets you high, although today we will really drill into what the high itself represents in terms of chemical systems in the brain and body. And what we will soon learn is that what we think of as being high actually includes a number of different changes in the brain and body, some of which can be best explained by CBD, not by THC, which runs counter to what most people out there know and believe. So broadly speaking, we have THC, CBD, and CBN, but I want to point out that the cannabis plant has over 70, 7-0, 70 different psychoactive compounds, many of which still have not been studied in isolation and in detail. So there's a big future of research for cannabis and for THC and THC-related psychoactive compounds, as well as for CBD and CBN. Today, we're mainly going to focus on THC and CBD, as I mentioned before. I should also point out that the cannabis plant has over 400 biologically active compounds. So these are biologically active compounds that may or may not have psychoactive properties, that may or may not be useful for pain relief, et cetera. Again, there is a vast landscape for exploration of the cannabis plant and of hemp for what they include that could be beneficial to us or detrimental to us, so again, a lot more work to do. Today we're going to really try and stay on target with what we already know and where there are certain exciting mysteries or intriguing mysteries about what we ought to explore more, I will certainly highlight those.

7. 19:34 – 25:55

   Sativa vs. Indica, Stimulant vs. Relaxation Effects

   1. AHAndrew Huberman19:34

      Let's go back to the different strains of the cannabis plant, sativa, indica, and ruderalis, and explore how each of those differentially impacts the brain and body, because therein, I think we can start to learn a lot about this incredible plant that is the cannabis plant. And whether or not you are a user of cannabis or whether or not you are entirely opposed to cannabis use, understanding how cannabis works in the brain and body itself is absolutely fascinating and can teach you a lot about how your brain and body work at a basic level, and can tell you a lot about how your brain and body will react to different life events and how your mood is established and stabilized and how your appetite is established and stabilized, and so on. So we have the three major strains of cannabis, sativa, indica, and ruderalis, and for sake of today's conversation, we can pretty much cross off ruderalis. It's not often consumed and components of ruderalis are not often consumed for medicinal or recreational purposes. Let's focus on sativa and indica. People will consume the sativa variety of cannabis either by edible or by smoking cannabis, or they will consume the indica variety of cannabis, again, by edible or by smoking cannabis, or sometimes they will take it in a transdermal form or a sublingual form. There are a bunch of different ways to get the cannabis into the body, but there is a clear distinction between sativa and indica that actually shows up first in the structure of the plant. At their extremes, meaning in a pure strain of sativa, it tends to be a taller plant, a longer stalk, believe it or not, and actually the length of the leaves is quite a bit longer, whereas the indica plant tends to be more short and stout. And for those aficionados out there, I'm sure you know a lot of the other specific features of sativa versus indica, but already what we're talking about is the same plant, cannabis, with two very different morphologies or shapes. You might say, "Well, why is this interesting or important to, you know, how it affects me or affects other people for medicinal or recreational purposes?" Well, turns out that even though they are the same plant, these two different genetic varieties, because of the way that they grow and the way they capture sunlight and the way, believe it or not, that the different plants (laughs) within that strain interact with one another, 'cause believe it or not, plants are interacting with one another, they actually bring different elements of the psychoactive compound to different components within the leaves and the so-called buds. The takeaway is that when consumed, and when I say consumed, I want to be very clear, I don't necessarily just mean oral consumption or eating cannabis sativa by edible. I also mean smoking it, and that could be, you know, people will, just like with tobacco, the way that they bring the psychoactive components into their bloodstream and into their brain and body is to essentially heat the dried leaves of the cannabis plant, then the heat liberates some of the psychoactive components that when inhaled into the lungs, because the lungs include a lot of vasculature, a lot of basically blood vessels and capillaries, that the psychoactive components are actually directly absorbed from the lungs into the bloodstream and then can cross into the bloodstream and permeate throughout the body and cross the so-called blood-brain barrier. So in other words, burning the plant liberates the smoke that contains the psychoactive compounds and those are inhaled into the lungs, and then get into the brain and body, and act on the brain and body. And the major effect of sativa varieties are to create a high, if you will, and I'm putting this in air quotes for those of you that are listening, but to also act as a stimulant. The sativa varieties tend to make people feel kind of invigorated, somewhat alert. It doesn't tend to be as much of a sedative as some of the other varieties. Some people report heightened sense of focus or heightened sense of creativity. We'll talk a little bit later on as to whether or not they actually are achieving heightened levels of focus and creativity or whether or not they just perceive themselves to have heightened levels of focus and creativity. The sativa varieties tend to make people feel a little bit less susceptible to pain and noxious stimuli, which are basically stimuli that you don't like. So the sativa varieties are often prescribed or are used in the recreational context for pain management and relief.Basically, the sativa variety is known to include a sort of head-biased effect. So, uh, here we're talking about subjective effects, and of course these will vary from one individual to the next. Some people will smoke cannabis sativa or ingest cannabis sativa orally and will feel an entirely different array of effects, but most people, the majority of people experience a sort of head-centered high, alertness, focus, and a sense that they're more creative. Contrast that with the indica varieties of cannabis, and when people smoke or eat or ingest indica varieties, the psychoactive components of indica, and again, this is pure indica, so not hybridized with sativa at all, but just pure indica, tend to lead to more full-bodied effects. People report feeling more complete full body relaxation, more of a sedative effect. Indica cannabis is often prescribed and/or used recreationally in order to achieve a state of sleep or to help relieve anxiety, so less of a stimulant effect. And we will talk about why, literally the underlying neural circuits that lead to the sativa variety causing more of a elevated mood and a head high, if you will, and the indica varieties being more full body relaxation. One of the ways to remember the distinction between the effects of cannabis sativa and cannabis indica was relayed to me by a friend who actually was a chronic, meaning every day all day, uh, consumer of marijuana s- he basically smoked marijuana for 20 years before quitting about four or five years ago, and he said that, uh, indica is often referred to as in da couch, meaning laid back in the couch. Um, and that can help you remember that the indica varieties of cannabis do tend to be more sedative in their effects. Okay, so there's sativa and there's indica, and then now

8. 25:55 – 30:41

   Hybrid Cannabis Strains, Type 1, 2 & 3 Strains

   1. AHAndrew Huberman25:55

      there are hybrid strains. So, marijuana growers and people who specialize in creating novel varieties of the cannabis plant, again, I'm using the words cannabis and marijuana more or less interchangeably here, they are very good at creating new strains of plant that might be 25% sativa and 75% indica or vice versa, or 50/50, or 90/10. Essentially what's happening nowadays is that through plant biology, plant genetics I should say, growers are getting quite efficient at creating a variety of different strains of the marijuana plant that give rise to very nuanced and distinct effects on brain and body. In fact, so much so that there's now a new nomenclature, a new language emerging around cannabis and the development of novel strains of cannabis for medicinal and/or recreational purposes. And while this might sound a little bit medical or a little bit clinical to some people, believe it or not, this is the nomenclature that is now typically used. People still refer to the sativa, indica, and hybrid strains, but there's now also a description of so-called type one, type two, and type three strains for any given sativa, indica, or hybrid strain. Okay? So just to put this clearly in your mind, you've got sativa varieties, that is pure sativa varieties, you have indica varieties, again, pure indica, and then you have hybrid varieties, and beneath each o- those, you have type one, type two, and type three strains of indica, sativa, or hybrid varieties. What are type one, type two, and type three? Well, type one, type two, and type three strains are strains that have varying amounts or ratios of THC to CBD. So for instance, type one strain, so for instance, you could have a pure sativa type one, or a type one pure sativa, or a type one indica. Those are going to have the greatest amount of THC relative to CBD. And I really want to emphasize this. Understanding the ratio of THC to CBD can help explain a lot or even predict a lot about how a given strain of cannabis will impact somebody. For instance, because THC is largely responsible for the typical psychoactive components of cannabis, so what I mean here is, if somebody's ingesting sativa and, and it routinely makes them, uh, feel more energized, elevates their mood, eh- gives them a heightened sense of creativity, if that's what they experience, and they're taking a type one version of that, that means that it's quite rich in THC and very little CBD. However, if they were to take a type one version of sativa and it feels far too strong, like too much energy or they felt like they were too much in their head, nowadays there are strains of sativa that have been genetically engineered, and I don't mean by an engineer tinkering away with, uh, you know, gene engineering and, uh, kind of CRISPR, mute- creating mutants, but literally by hybridizing, crossing different plants to one another, (laughs) okay? Creating in a, in a natural context, the same way plants in the, in the outside world would sometimes hybridize to one another, creating a variety that's perhaps type two, which is going to have less THC and more CBD, or a type three, which is going to be very high CBD and very little THC. And the same is also true for the indica varieties. So I want to make sure that everyone understands this, because it becomes very important for understanding the biology of cannabis and predicting positive versus negative effects of cannabis. Sativa has this kind of stimulant-like effect and tends to be more of a head high, if you will. Indica tends to be more full bodied and lead to more in da couch, as I referred to it before, (laughs) um, pun intended, deep relaxation, reduced insomnia, et cetera. Now, within each of those, sativa and indica, you have type one, type two, and type three, and that has everything to do with how much THC, which is the dominant psychoactive compound.... versus CBD, which has other effects mainly on the body but not so much on the brain and modes of thinking and mood, et cetera, how much THC versus CBD is present. And again, type one is THC dominant, type two have equal ratios, if you will, of THC and CBD, and type three tend to be high CBD. Okay. So already, we've got some categorization here that hopefully isn't overwhelming to you. But this turns out to be extremely important if you want to understand how cannabis works and predict the effects of cannabis.

9. 30:41 – 31:56

   AG1 (Athletic Greens)

   1. AHAndrew Huberman30:41

      I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic Greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking Athletic Greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens and the reason I still take Athletic Greens once or usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long-term health, and those probiotics in Athletic Greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins, and minerals that make sure that all of my foundational nutritional needs are met, and it tastes great. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman, and they'll give you five free travel packs that make it really easy to mix up Athletic Greens while you're on the road, in the car, on the plane, et cetera, and they'll give you a year's supply of vitamin D3 K2. Again, that's athleticgreens.com/huberman to get the five free travel packs and the year's supply of vitamin D3 K2. Okay.

10. 31:56 – 40:35

    Naturally Occurring Receptors: Nicotinic & Cannabinoid Receptors (CB1)

    1. AHAndrew Huberman31:56

       So somewhat surprisingly, we're going to set aside cannabis. We're going to take what we know about sativa, indica, type one, type two, type three CBD, et cetera, and we're just going to set that aside for a moment. Why would we do that? Well, we have to ask ourselves, why would any of these plants, why would any of these compounds, THC, CBD, sativa, indica, et cetera, why would any of that have any effect on us at all? And this discussion that we're about to have very much resembles the discussion that we had on a previous episode about nicotine, because as many of you know, nicotine is a commonly used substance. In fact, if we were to look at the three most commonly used drugs, alcohol would be at the top of the list. Many billions of people regularly use alcohol or occasionally use alcohol. Many billions of people also use nicotine. It's the second most consumed drug. So more than one billion and probably closer to two billion people consume nicotine. And then the third most consumed drug is cannabis in one form or another. And many of you are probably shouting, "What about caffeine? What about caffeine?" Well, in the context of drugs, and in particular addictive drugs, caffeine doesn't quite rise to the list. But if we were to look at caffeine and include it in that list, caffeine would be above all of those. Okay? But the most commonly used drugs are alcohol, second after that is nicotine, and then cannabis. Nicotine, as some of you may know if you listened to the episode on nicotine but even if you didn't, nicotine comes from the tobacco plant, and there are a few other plants that include nicotine, and typically it's brought into the brain and body by smoking tobacco, dipping tobacco, snuffing tobacco, or vaping nicotine. Nicotine exists in the outside world in these plants, the tobacco plants, but the reason it has an effect on the body is that there are so-called nicotinic receptors in the body. Now, those nicotinic receptors were named after nicotine the compound, but they existed in the brain and body not because of the existence of a tobacco plant but because there are other chemicals in the body that naturally occur, namely acetylcholine, that bind the nicotine receptor. Those chemicals, such as acetylcholine, that bind the nicotinic receptor in your brain and body create an enhanced sense of focus, et cetera, et cetera. But nicotine from tobacco binds that same receptor but with much greater affinity, and therefore also creates a state of focus but a much greater one than we can achieve without nicotine. Okay? So you can see the nicotine episode if you want to learn more about that. In a very similar way, all of our brains and bodies from the time that we are conceived, believe it or not, very shortly after conception if we want to be accurate, very early conception when you are in the womb, and still now if you're listening to this, you have what are called cannabinoid receptors because you also have endogenous cannabinoids. What do we mean by that? You have receptors which are like little parking spots that are present on cells in your brain and body, and what we call a ligand, which is basically just a chemical that's released, parks in that receptor and causes a number of different biological effects. Cannabis contains compounds that also bind to those receptors, but here I want to make a really clear distinction. We have what are called endogenous ligands. Those just mean chemicals from within us that we make naturally. Even if we never go near the cannabis plant or any other source of cannabis, we have chemicals that are created in us that park in those receptors and cause biological effects on mood, on perception, on the immune system, on hunger, et cetera, again, without ever going anywhere near cannabis. We have these endogenous cannabinoids. So endogenous cannabinoids are floating around in us, or I should say they are released in us in particular ways, bind to these receptors, and cause changes in mood, appetite, et cetera. They have many different effects on the brain and body. We will talk about those. But just like with nicotine, there are substances in the outside world, in this case cannabis contains these substances, so things like THC and like CBD, that when ingested by smoking or vaping or by ingesting edibles...... also will park in those same receptors, the cannabinoid receptors, and lead to biological effects. Now, it's a little bit misleading, because we call them cannabinoid receptors, as if they were there to bind cannabis. Or just like we call the nicotine receptors, nicotinic receptors, it makes it seem as if they were there in order to bind nicotine from tobacco. But that's not the way our brains and bodies evolved. Our brains and bodies evolved for these receptors to make use of chemicals that exist within us called in- again, endogenous chemicals. And those endogenous chemicals lead to certain effects, as I mentioned before. The key thing here, if you haven't understood anything I've said up until now, please understand this. The key thing is that THC and CBD and the other components of cannabis bind to those receptors, those endogenous cannabinoid receptors, the ones that we naturally make, with much greater affinity and exert a vastly greater potency and effect on mood and perception, et cetera, than do our endogenous cannabinoids. Another analogy that one could take in order to understand this would be hormones, like testosterone and estrogen. Many people, I would say all people, make testosterone and estrogen to varying degrees. It's going to depend on whether or not you're male, female, your age, whether or not you've gone through puberty, et cetera, et cetera. But let's just take testosterone, for example. There's testosterone circulating in your body, that's true if you're male or female, and there are receptors called androgen receptors. We could even call them testosterone receptors. And the testosterone binds to those receptors and has effects on cells. It causes hair growth, changes the voice, it can affect libido, it affects all sorts of things in the brain and body, depending on which organ and tissue you're talking about. But, of course, there are people that take synthetic testosterone or derivatives of testosterone. And some of those derivatives, for instance, in the bodybuilding community and the sports community, they will take things like Dianabol. These are modified versions of, of testosterone that can bind to the testosterone receptor with much greater affinity, or I should say the androgen recep- receptor with much greater affinity, and have supraphysiological effects, effects that would essentially never be seen from testosterone that was endogenely- endogenously- excuse me, endogenously released within the body. We could say the same thing for estrogen. There are estrogen receptors, they bind estrogen, okay? But if someone were to take synthetic estrogen or to ingest a plant compound that contains various estrogenic compounds, and those plants certainly exist out there, they can have supraphysiological effects on those receptors. Why am I telling you this? Well, many people believe that because cannabis, marijuana is a plant, and plants grow out of the ground, and they're naturally occurring, and because we have receptors in our body that are there without the need to engineer them from some external source, right, they're in our genome, we're programmed for it, and we're born with these things, and we keep these things our entire life, many people mistakenly think, "Ah, you know, these plant compounds are safer for us, or better for us, or are somehow appropriate for us to ingest." But that's simply not true. And here, I'm not saying that cannabis is always a bad idea for people. There are certain populations and certain people for which it can be relatively safe recreationally, that's the truth, and there are other populations for which it can be downright dangerous, recreationally or medicinally. And, of course, there are medicinal purposes that are being explored, and we'll talk more about that. But this is vital to understand, because I think that when we hear, "Oh, it's from a plant, it's natural," and then you also have a receptor for these endogenous cannabinoid receptors, and therefore the marriage of those two, right? (laughs) The coming together of the chemical THC and, or CBD or both with these receptors is somehow supposed to happen, as if this was a, uh, a purpose of having these receptors. But it's simply not the case. In the same way that the nicotinic receptors are not there because nicotine is good for us. They're there because there are compounds that exist within us that are good to bind to those receptors from time to time. Now, here's the key

11. 40:35 – 43:14

    THC, CBD vs. Endogenous Cannabinoids, Dependence

    1. AHAndrew Huberman40:35

       thing about... I guess today I'm saying there are a lot of key things. But here's another key thing about understanding cannabis and the way that it works, which is that THC and CBD, when they're brought into the brain and body by smoking or, you know, a edible, et cetera, they bind to those receptors, those endogenous cannabinoid receptors, and they tap into the same systems that your endogenous cannabinoids would tap into, the ones that affect mood and energy and creativity and relaxation, et cetera. But they do so with thousand-fold greater potency. And as a consequence of that, your endogenous cannabinoids are out-competed. They really get no opportunity to interact with those receptors. And understanding that can lead to a very clear understanding of why, for instance, when people use cannabis to relieve anxiety, or they use cannabis to enter a certain brain state for creativity or to enter sleep, why a dependence on cannabis starts to emerge. Because if they don't ingest cannabis, and again, ingest could mean smoke to bring THC in, or CBD in, or ingest orally, or even transdermal or tincture, or one of the other varieties, if they don't do that, then what happens is not only are the receptors not stimulated to the same degree or with the same potency that they normally are, but the endogenous cannabinoids can no longer have their effect. So people experience heightened levels of anxiety, disrupted mood, disrupted brain state, and so on. Now, again, I want to be very clear that I'm not trying to paint a picture of cannabis as all bad, or even partially bad. What I want to do today is give you as much information I can...... as to how cannabis works, how its different component parts work, how the different types of cannabis work, and point to some of the valid medicinal uses and some of the recreational uses, and then lay out the landscape for you as to who is really most at risk in terms of psychoactive components, immune components, and so on and so forth, so that you can make the most informed choice for you. I am not here to tell you what to do or what not to do. As I like to say, you know, "Do as you wish," right? I mean, don't do as you wish if it harms other people or yourself, but do as you wish, but know what you're doing. So that's really my goal here. So as we begin to dive further into the biology, I think you'll start to get a clearer picture of why cannabis is so effective in some contexts, but also why it can create such massive suffering in other contexts because of the way that it out-competes your own natural endogenous cannabinoid systems.

12. 43:14 – 53:07

    Endogenous Cannabinoids, Cannabinoid Receptors & Nervous System Function

    1. AHAndrew Huberman43:14

       So let's talk about those endogenous cannabinoid systems, what they are and how they work, because that will give us a lens into what the higher potency, or maximum impact of the various cannabis plant varieties and strains in THC and CBD and so forth, how and why those work. So what are the endogenous cannabinoids, these chemical substances that everybody makes? All right. You make them. I make them. You've been making them basically s- from the time that you were conceived, and you are going to make them until the time that you die. Whether or not they have the impact and the biological functions that I'm about to describe will depend a lot on whether or not you are using your own endogenous cannabinoids to park in those receptors that you also have from birth until death, or whether or not you are tickling those receptors or strongly activating those receptors using some external source like cannabis, THC, et cetera. The two main endogenous cannabinoids that we want to consider are anandamide, which we will refer to as EAE, so anandamide, and another one which is arachidonoyl glycerol, arachidonoyl glycerol, which we will abbreviate 2-AG. So let's just take EAE and 2-AG, lump them together, and talk about the endogenous cannabinoids just to make it simple. But if you want to do the deep dive on anandamide versus 2-AG, please be my guest. The endogenous cannabinoids are released from neurons. What are neurons? Neurons are nerve cells, and nerve cells should be conceptualized like this. You have presynaptic neurons and postsynaptic neurons. Presynaptic neurons basically contain little vesicles, little bubbles full of neurotransmitter, which are chemicals, and when neurons are stimulated electrically, and that could be from a thought, it could be from the desire to move, it could be because of a drug, it could be because you're hungry, the relevant neurons will vomit out or will fuse, as we say, those neuro, little packets, those little bubbles of neurotransmitter into the gap between the pre- and post-synaptic neuron. We call that a synaptic cleft or the synapse. It's a little gap, a little space, and the neurotransmitter flows across that synapse, and some of it will park in little parking spots that we call receptors on the postsynaptic neuron side. Depending on which neurotransmitter it is and a bunch of other things not worth going into right now, the parking of that chemical in those neurotransmitter receptors will either cause that neuron on the postsynaptic side to itself release neurotransmitter elsewhere, or it will quiet it down, so-called excitation and inhibition. That's kind of neurotransmission in a nutshell. If you don't understand it, no big deal. It's not going to prevent you from understanding today's discussion. If you understand even a small fraction of what I've just said, then it's going to allow you to understand not just today's discussion, but a lot of neuroscience with a lot more nuance and depth of understanding. The key thing to know about the endogenous cannabinoids is that unlike most neurotransmitters, they are released from the postsynaptic side. So what happens is, neurotransmitter goes from presynaptic neuron to postsynaptic neuron, but under certain conditions, the postsynaptic neuron itself releases a chemical, and that chemical goes backward, what we call retrogradely to the presynaptic neuron, binds to receptors there, and changes the probability that the presynaptic neuron will release a neurotransmitter. Put simply, endogenous cannabinoids tend to decrease the probability that the, a neuron will release a neurotransmitter. They are sort of a break on the system. They are a way of shutting down the communication between neurons, regulating it, not to make it completely quiet, but to adjust the levels with a lot of nuance. Now, the other thing that the endogenous cannabinoids do is sort of a mind-bender, because we're talking about cannabis, and a commonly known feature of cannabis and marijuana consumption is disruptions in short-term memory. And there is essentially zero debate as to whether or not that occurs, and we'll talk about the mechanisms a little bit later. And yet, endogenous cannabinoids, the chemicals that you naturally release from these postsynaptic neurons that travel retrogradely back to the presynaptic neuron, actually can lead to strengthening of connections between the presynaptic neuron and the postsynaptic neuron through a process called long-term potentiation, or LTP. They can also cause what's called depression of communication between a presynaptic neuron and a postsynaptic neuron. Long-term depression has nothing to do with depression as a psychological state or as a illness. Long-term potentiation and long-term depression simply refer to the probability that one neuron will be able to stimulate and activate another neuron, and as I just told you-... the endogenous cannabinoids can either turn up the dial or turn down the dial. They can either increase the probability or decrease the probability that a given connection between neurons will function more or will function less. So if you think about the communication between neurons as crosstalk, as a conversation, well, the endogenous cannabinoids can dictate whether or not that conversation is likely to occur or not to occur. Think of them as either, um, you know, putting someone at the top of your text chain in your phone, which would be long-term potentiation, or essentially blocking their number, which would essentially be long-term depression. So if you're getting the impression that the endogenous cannabinoids are working in a number of different ways and it's not very straightforward, you're right. In fact, that's the message that I'd like you to take away. The endogenous cannabinoids are sometimes increasing neuronal communication. This can lead to increases in mood or increases in the likelihood that someone will talk a certain way or behave a certain way or feel a certain way. They can also lead to decreases in synaptic transmission, that is communication between neurons, in ways that will make somebody's mood lower or will make them less hungry or more hungry. And here's the really key thing, there are two kinds of endogenous cannabinoid receptors, referred to as CB1 and CB2, and we can say with confidence that CB1 is highly enriched in the nervous system and especially within the brain. It's found not everywhere, but almost everywhere in the brain and elsewhere in the nervous system, so spinal cord and other aspects of the nervous system. CB2, the cannabinoid receptor, CB2 is largely located in the tissues of the body, including the immune system, the liver, even the genitals, et cetera. So what this means is that the endogenous cannabinoids are having these sorts of effects on neurons that I talked about, but they are also having effects on immune cells, on reproductive organs, on liver, on digestion, on hunger, et cetera, through mechanisms that are divorced from the function of the nervous system of neurons. Now, in reality, no system of the brain and body is divorced from the nervous system, because the nervous system is controlling everything, it is really the master controller, and everything's feeding back to the nervous system, so it's a two-way street. But the simple way to think about it is CB1 receptors are mainly in the nervous system and CB2 receptors are mainly in the body, and endogenous cannabinoids, again, EAE, anandamide, and 2-AG, arachidonoylglycerol, are impacting CB1 and CB2 receptors. Today, we're mainly going to talk about CB1 receptors, 'cause they are the ones that are responsible for most of the familiar effects of cannabis, but the key takeaway at this point is to really understand that the major effects of your endogenous cannabinoids on these receptors, in this particular CB1, are very nuanced. It depends on context, depends on which neurons, it's, you know, sometimes increasing communication between neurons, sometimes decreasing it. And then along comes cannabis, and that cannabis, again, can arrive by smoking, by vaping, by edible, and cannabis contains THC and CBD that potently bind the CB1 receptor. And now, the effects of the CB1 receptor being occupied by THC or being occupied by CBD are not very nuanced. In fact, they are very predictable. And especially important is to understand that they are so strong and they park in that receptor with such affinity, with such force and precision and stubbornness and refusal to leave that receptor, that they completely out-compete the endogenous cannabinoid system. In fact, they leave the endogenous cannabinoid system essentially dysfunctional, which, in some cases may be a good thing, but in most cases, is going to lead to problems of various kinds. And we'll talk about what sorts of problems. And again, I feel obligated to say, this is not me saying, "Don't ingest cannabis or THC or CBD." That's not what I'm saying. What I'm saying is, if you evaluate the potency, that is, in technical terms, it would be the affinity with which these compounds, THC and CBD and CBN, bind to these endogenous receptors, that would be like a howitzer gun, like a cannon going off, as compared to endogenous cannabinoid, whether or not it's EAE or 2-AG, which is more like a cap gun level of activation, at least in this analogy. So now you have what at least I would like to think is a fairly complete understanding of the different varieties of cannabis, at least at a broad sweep, and the different biological effects that they can have, at least in terms of the major receptors and in retrograde signaling, et cetera, et cetera.

13. 53:07 – 56:29

    Biological Effects of Cannabis

    1. AHAndrew Huberman53:07

       Now let's take a step back into the real world and evaluate or think about what happens when somebody smokes cannabis or ingests cannabis by way of edible or a tincture or something of that sort. Cannabis is very fast to enter the bloodstream. In fact, within 30 seconds, it's going to enter the brain and permeate throughout the brain and body. That's very, very fast. I mean, when you contrast that with something like alcohol or even nicotine, depending on how the nicotine is delivered, that is a very fast delivery of the psychoactive and biologically active compound, which in this case is THC and CBD and probably some other things as well. So within 30 seconds, it reaches the brain and bodily tissues, and within 30 to 60 minutes, it's going to reach its peak concentrations and have its peak biological effects. Those aren't always the same thing, but in the case of cannabis, again here I'm using cannabis as a kind of umbrella term for THC and CBD, the effects are going to peak at about 30 to 60 minutes after bringing those compounds into the body in some way or another. And the effects tend to last anywhere from three to four hours, although there's some variation on that depending on individual metabolism, whether or not somebody is, uh...Familiar with the compound, believe it or not, psychologically familiar, but also biologically familiar, or whether or not it's a first time use or occasional use, and so on. THC and CBD and other components of cannabis are highly what we call lipophilic. That is, they have an affinity toward, and they can actually pass through fatty tissues. Now, every cell in your body, but especially neurons, have a double layer of fat on their outside, and then, of course, when people say- f- hear fat, they always think, "Ooh, fat's bad. Fat's whatever..." You know, most of the world seems to want to lose fat or bodily fat. Here, we're talking about the fatty membrane, the barrier around each tissue. In this c- case, we're talking particularly about neurons. And THC and CBD and the other components of cannabis are highly lipophilic, so they can get into essentially all cells just simply by flowing into them. They will also remain in those cells for a long time. So I know that a number of people, depending on whether or not they get tested for work or for sport or otherwise for cannabis or CBD and THC, don't take this as a strict number, but typically s- if one ingests CBD or THC, smokes cannabis, ingests by orally, et cetera, doesn't matter, it's going to stay in that fatty tissue and can be detected for at least as long as 80 days after ingestion. And there's a whole industry as to, you know, how to accelerate the clearance, and, um, uh, I should just tell you that just losing bodily fat isn't going to, um, eliminate it from your system, uh, maybe partially in those fat cells, but, uh, certainly in, uh, intraviseral fat and other fatty tissue that's, uh, in and around the brain and body is going to harbor that, uh, THC molecule and the CBD molecule for quite a long while, at least 80 days. Okay, so if someone smokes cannabis or they ingest cannabis, very rapidly gets into the bloodstream, and the components that are psychoactive get into the bloodstream and are immediately able to access neurons and other cells and start having these effects of parking at those endogenous cannabinoid receptors and impacting the signaling between neurons,

14. 56:29 – 1:04:58

    Cannabis Sativa & Subjective Effects: Mood, Stress, Alertness, Paranoia

    1. AHAndrew Huberman56:29

       which leads to the subjective effects of cannabis, including THC and CBD. So let's talk about what those different subjective effects are. Again, this is going to vary depending on whether or not people are ingesting sativa varieties of cannabis, just to remind you, those tend to be elevated, mood, alertness, talkativeness. People who take sativa varieties tend to talk a lot more than they would otherwise. Again, there are exceptions to this. Of course there are exceptions. I'm sure there are people out there shouting, although I guess if you're the quiet people who don't talk too much, you're probably not shouting, or if you're not, you're not doing it on sativa, joke intended. But in any event, there are exceptions, but there are also general rules, and the sativas tend to mean people sort of mood elevated, energetic, again, the sort of head high, and indica varieties tend to do the opposite, more of a sedative, relaxant, et cetera. Why and how would they do that? Okay, well, without going into an extensive deep dive into the different neurotransmitter systems of the brain and body, what we know for sure is that CB1 receptors are present on an enormous number of different neurons and brain structures and neural circuits, so that the sativa varieties that act as sort of a stimulant, making people feel happy, 'cause in general, they do tend to elevate mood, at least at certain dosages, talkative, uh, tend to make people feel, um, like they have ideas that are interesting that they might want to share, um, tend to narrow their context, so we tend to increase focus. This is something that's not often discussed about cannabis, but it can, especially the sativa varieties, can increase people's level of focus to particular things, uh, something they're watching or something they're doing or music, allows them to narrow their sense of focus. That's going to occur by activation of CB1 receptors in the so-called prefrontal cortex, which is just behind the forehead, and the prefrontal cortex acts as a strong modulator of so-called limbic circuitry and other circuitry that is more stress-oriented. Uh, the way to think about the stress and limbic circuitry such as the amygdala, which many people have heard about, is that they aren't really circuits for fear and stress. They are circuits that are constantly evaluating one's own internal state, heart rate, et cetera, and what's happening externally, and sorry to say, but the default of those systems is to detect danger, the sort of threat detection systems, and then the prefrontal cortex largely acts as a brake on those systems, sort of like the reins pulling back on a steed of horses that would otherwise just kind of take off. And so the sativa varieties tend to increase CB1 activation in the prefrontal cortex and in other circuitry that then leads to a kind of overall reduction in stress because of the way that prefrontal circuitry can reduce activation of the amygdala. Now, that, of course, does not explain why some people become very stressed and very paranoid when they smoke sativa varieties or other varieties of cannabis or ingest other varieties of cannabis. We will talk about the paranoid effect and why that occurs and who might predict that would occur to them in a, in a little bit. But just want to give you a sense of how this is working, because as I mentioned before, THC and/or CBD are going to bind that CB1 receptor, let's say in prefrontal cortex, so neurons of prefrontal cortex is going to bind there, and then there will be a retrograde signaling back to the presynaptic neuron, and in the case of prefrontal cortex, what's happening is it's increasing transmission, increasing the release of neurotransmitter in prefrontal cortex. However, at the same time, the very same THC and CBD that was brought into the system is binding s- the very same type of receptors, CB1 receptors, in other brain structures, such as the amygdala, and causing retrograde signaling back to the presynaptic neurons in the amygdala, but it's quieting the activation of those neurons. So this is interesting, right? We have the same compounds, THC and/or CBD, brought into the body and brain, binding the same receptors, in this case, the CB1 receptors, but depending on where those receptors are located...... and which brain areas we're referring to, they are e- either causing heightened levels of alertness and activation of systems that are designed to make you talkative and alertness and mood, et cetera, focus, or they are causing suppression of those circuitries. So, we have kind of a see-saw effect here, where the same compound is increasing mood and alertness and focus in the prefrontal cortex and is decreasing stress and threat detection in the amygdala, and that's one of the reasons why, especially the sativa varieties of cannabis, allow people to enter these states of focus. Some might even say flow, although I don't want to go into what flow states really are. That's, uh, for a different discussion, and it's very poorly defined, uh, as it is. And I certainly don't want to give people the impression that cannabis increases flow states, because that's not always the case, and certainly most often is not going to be the case. But the idea here is that this molecule comes into our brain and is shifting everything towards a state of focus, elevated mood, of heightened sense of importance about whatever it is that we happen to be doing. And now, of course, whatever we could happen to be doing could be writing a song, writing poetry, communicating with somebody, but it could also be something as trivial as watching cartoons or watching a movie, which is, you know, not trivial in its own right, but in terms of thinking about the creative aspects or the creativity-stimulating aspects of cannabis, not, um, sort of productivity oriented. So, narrowed focus, elevated mood, more relaxed and yet energetic. That's the major effects of the sativa varieties, except, and this is a really big boldface triple underline except, except in some individuals, depending on dosage but also depending on preexisting neural circuitry and propensity for anxiety, some people ingest or smoke sativa varieties, and regardless of whether or not it's a type one, type two, or type three variety, okay, regardless of the ratio between THC and CBD, people will experience intense anxiety and paranoia. Now, how do you predict who will experience intense anxiety and paranoia and who will experience intense relaxation, focus, and sense of creativity from ingesting or smoking a type one, type two, or type three sativa? Well, there is no way to predict that. And there's a lot of kind of what I would call street lore or dorm room lore or kind of, um, peer, not peer-reviewed (laughs) , uh, but, uh, sort of peer-discussed, I mean, among friends and people and acquaintances, lore out there that what one needs to do is simply smoke more, right, (laughs) or just ingest more. You hear that. "Oh, well, listen, if it makes you paranoid, you simply need to use more." That is absolutely categorically false. Everything we know about the way that THC and CBD work is that they tend to potentiate, that is increase, the effects of these different systems at given synapses and in different areas of the brain and body. That is, if someone e- experiences paranoia or anxiety from a given strain of the marijuana plant or from ingesting an edible in a particular way or particular kind of edible, that person is very likely to experience the same effect every time they ingest that strain or variety. This is part of what's led to this enormous industry ... I mean, there are a number of different reasons, but this is part of what's led to this enormous industry of highly customized cannabis, where people will spend some time really seeking out the different strains of cannabis and hyb- hybrids of cannabis that work best for them and work best for them in particular contexts. I wish I could tell you that if you are a person who is, you know, between five foot seven and, uh, six feet tall and, uh, you have blue eyes, uh, or brown eyes, that the sativa varieties are going to be right for you or that the s- sativa varieties are going to give you panic attacks. I can't do that. The only way to determine it would be to actually experience ingesting those or smoking those, which is certainly also not what I'm suggesting, (laughs) right? That's up to you. I'm not telling you what to do or what not to do. But there are no good predictors. In fact, if you look in the literature, it is not at all clear that people who have a heightened level of anxiety when they do not smoke cannabis will experience cannabis as less paranoia-inducing or more relaxing. That's simply not the case. Now, what we can say for sure

15. 1:04:58 – 1:09:41

    Cannabis Indica & Subjective Effects, Memory, Dosage

    1. AHAndrew Huberman1:04:58

       is that, uh, general categories of effects, such as increased focus and reduced anxiety, are largely due to activation of areas like the prefrontal cortex. Now, unlike other compounds, like nicotine or alcohol, or neurotransmitter systems, like dopamine, when we talk about the cannabinoid system, and I say effects, biological effects, psychoactive effects, I want you to keep in mind always, please, please, please, keep in mind that those effects can be varied and often opposite in direction. So, let's just give an example of that. I just mentioned that when people smoke or, or eat sativa, that it tends to lead to one specific set of, or generally leads to one specific set of effects, heightened focus, mood, et cetera, whereas when they ingest or smoke indica and its components, right? Again, we're still talking about THC and CBD in varying ratios, but now indica cannabis, and you say, "Well, why would it improve the transition time to sleep, or at least give people the impression that it improved their transition time to sleep?" We'll talk about what indica actually does for sleep in a little bit. But indica also tends to suppress activation of the amygdala and threat detection centers in the brain, again binding the same CB1 receptors and those retrograde signaling mechanisms I talked about before, but it also tends to shut down the hippocampus, an area of the brain associated with memory, which is why indica varieties lead to pronounced, or I should say profound defects in short-term memory and sometimes in long-term memory as well if it's consumed.... over long periods of time. We'll talk about short, medium, and long-term consumption, occasional consumption going forward. So what I'd like you to take away from this component of the discussion is, first of all, (inhales) the mechanism of action by which cannabis impacts the brain and body, but in particular, the brain is going to be through CB1 receptors. And those CB1 receptors can lead to either an acceleration or a break on particular biological mechanisms. And there are going to be a constellation of different accelerations and breaking of different neural systems in the brain and body, depending on whether or not people ingest Sativa or Indica or some hybrid strain. And perhaps most importantly, even if you didn't understand anything that I said about the biology of these different strains and their receptors, please do understand that there is no way to predict what the effect of a given strain will be on an individual. There has been extensive exploration as to whether or not people who are so-called mellower or more anxious or any e- number of different personality dimensions will respond in one way or the other. But in fact, there is no way to tell. Layer on top of that the fact that dosing THC and CBD can be fairly straightforward in the form of edibles, right, because there can, there can be, at least if it's a controlled source, a defined number of milligrams of THC, a defined number of milligrams of CBD. That's true for ingestibles. It's much harder to gauge that from the smokable forms of cannabis, especially if those smokable forms of cannabis are obtained through sources where there isn't a lot of clear information about the total amount of THC in that product. Now this is all changing quite a lot nowadays because of the commercialization of THC and CBD products and cannabis in a number of different areas, including in the United States. But still, many people are ingesting cannabis, THC, CBD through sources where they don't really know how much they're bringing into their system. And so, whether or not someone gets incredible anxiety relief, enhanced sense of mood and focus and well-being, pain relief, et cetera, or whether or not they have full-blown panic attacks, et cetera, is very hard to predict based on dosage information alone. Now of course, we can create broad categories, and we are going to talk about studies that create broad categories of low dose, moderate dose, and high dose, frequent use and infrequent use. But unlike alcohol, unlike nicotine, we can't really point to specificity of X amount of alcohol, grams of alcohol per week which is safe, or X amount of alcohol which is not safe. And so I know a lot of people out there are wondering, you know, how often can they smoke cannabis? Or how often can they eat cannabis or THC or CBD in any number of its different forms and products safely? Well, we have to really define what safely means, and we have to really acknowledge that there's a pretty loose set of controls over what one is bringing into their brain and body as they ingest THC and CBD. But even under conditions in which it's very controlled, it's very hard to predict what those effects will be.

16. 1:09:41 – 1:16:08

    Brain Areas Affected by THC & CBD, Side Effects

    1. AHAndrew Huberman1:09:41

       So before moving into specifics of taking cannabis or not taking cannabis, who should, who shouldn't, what the medicinal purposes are and what some of the newer exciting data point to, I just briefly want to make a list. And I promise very briefly. I know I'm not often concise, but I do try to be thorough for your sake. I want to make a very brief list of the different brain areas that are impacted by THC and CBD and why THC and CBD have the various effects they do. (smacks lips) When somebody smokes or ingests cannabis, doesn't matter what the THC or CBD ratio is. If they experience deficits in memory, and that's almost always present, that's going to be because of reductions in electrical activity within this brain region we call the hippocampus. Okay? Hippocampus means seahorse. It's shaped like a seahorse. Anatomists like to name things after what things look like. But hippocampus memory, memory is reduced, in particular short-term memory. That's true regardless of whether or not one is using Sativa, Indica, or some hybrid. (smacks lips) In general, the prefrontal cortex is going to be activated by the Sativa varieties, which is going to increase thinking and narrowly constrain focus to some activity, and that's more commonly associated with the Sativa varieties. The Indica varieties, as I mentioned before, tend to lead to a suppression of activity in prefrontal cortex, believe it or not, and turn off thinking and planning. This is why Indica varieties are often used for relaxation and for promoting sleep. Regardless of whether or not Sativa or Indica variety, and again, regardless of the ratio of THC to CBD, there is a general suppression of neural circuits within the so-called basal ganglia and cerebellum. Basal ganglia and cerebellum are areas of the brain that are involved in action planning and withholding action, so that would be the basal ganglia, so-called go/no-go circuitry, and the cerebellum, which is involved in balance but also motor planning and motor sequencing. This is why people who smoke marijuana, regardless of the strain, will tend to be less physically mobile. Other common effects are reddening of the eyes, dryness of the mouth. That's actually caused by the same general mechanism, which is a reduction in the secretion of saliva and of sort of tears and lubrication of the eyes from the lacrimal glands of the eyes because of the presence of largely CB2 but also CB1 receptors in the mouth and on the eyes. And there tends to be, especially with certain strains of cannabis, increase in appetite, so-called munchies. And that has everything to do with very, very high density of CB1 receptors in the hypothalamus and in particular areas of the hypothalamus like the arcuate nucleus of the hypothalamus, uh-... other areas as well, of course, that have tons of CB1 receptors, bind THC and CBD, and activate the neurons that strongly stimulate appetite through two mechanisms. One is a cognitive mechanism of creating a preoccupation with food and anticipation of taste, as well as the experience of taste, so the narrowing of focus to what you want to g- go eat, right? You really crave, I don't know, pizza. It seems to be high fat, high carbohydrate foods, but really crave pizza, and narrowing of focus so that you're not thinking about anything else, but also signaling from the hypothalamus to the gut to neurons within the stomach itself that regulate blood sugar. So, there are strong effects on blood sugar of THC and CBD that generally lead to increases in appetite. So, two parallel mechanisms, one within the brain, one within the body, increasing appetite. 'Kay? So, there's an array of different effects, and as I mentioned before, CB1 receptors are present all over the nervous system, in the brain, the spinal cord. In fact, the presence of CB1 receptors in the spinal cord largely explains the fact that THC and CBD, to some extent, although it's not very well studied, can provide some pain relief. I sha- say some, because a lot of people perceive or believe that they experience more pain relief from cannabis than they actually do. It actually has a lot to do with a perceptual shift to basically focusing on other things. But there does seem to be some anti-nociceptive, meaning anti-pain, effects of cannabis, THC in particular, and that is exerted largely through effects on CB1 receptors in neurons of the spinal cord. So, a broad array of effects are taking place regardless of what strain you take and wha- whether or not you eat the cannabis or you smoke the cannabis, and the broad array of effects can be explained by the fact that that retrograde signaling can lead to activation or suppression of activity in various neurons. So now, I'd like to take a step back from the biology of cannabis and THC and CBD and all the signaling and receptors, et cetera, and really just focus on cannabis use. And wherever possible, I will point to the specific strains that have been studied and the ratios of THC to CBD. But I have to say that unfortunately, most studies of marijuana, of cannabis, while they have been very careful to detail the amount of THC, low dose, medium dose, or high dose, and actually getting very specific right down to the number of milligrams or even how much circulating THC is present after somebody smokes a joint or ingests, uh, cannabis, most studies have not distinguished between sativa and indica strains. And that's unfortunate because in the real world, people are distinguishing between sativa and, and indica strains in their patterns of use and what they prefer and what they don't prefer, even what they prefer to smoke during the day or ingest during the day versus night. Believe it or not, there are people who are using certain strains during the day and other strains at night. But the science is yet to catch up to that, or I should say more accurately, the general public and the themes that are emerging and the practices that are emerging around cannabis, especially in states where it's decriminalized or legalized, are occurring at such a rapid rate that there's absolutely no way that the science could keep up. This is a naturally occurring experiment. Not to say that it's natural, like people should do it, but it's an experiment that's happening in real time in the real world much faster than con- controlled studies within university laboratories and other laboratories can keep up.

17. 1:16:08 – 1:26:41

    Creativity: Convergent vs. Divergent Thinking & Dopamine

    1. AHAndrew Huberman1:16:08

       So at this point, I think it's appropriate to ask ourselves, why do people e- even use cannabis? I mean, what are they trying to achieve? Is it always about not feeling pain? Is it always about reducing anxiety? Well, sometimes it is, but oftentimes people are using cannabis in order to achieve a particular state, and we could use a broad brush and say, "Well, they just like being high." But while that may be true in a lot of circumstances, and I have to believe it actually is true in a lot of circumstances, there are a lot of people who use cannabis in a very directed way where they get, quote unquote, "high" in order to achieve states that, to them, are particularly attractive, and one such state is a state of creativity. And this brings us to a broader theme, which is, does cannabis increase creativity, and if so, is it the THC, the CBD? What's the appropriate ratio or the best ratio for accessing creativity? This is an interesting and important discussion, I believe, because creativity is one of the more sought after and more elusive states that humans can experience, and yet if you look at human evolution, you look at our progression, uh, in terms of technology development and, uh, culture and, uh, music and poetry, et cetera, we really can look to creativity as the state that fostered so much of that evolution. So, whether or not you're into technology or you're into art or music, whether or not you're just somebody who wants to expand their understanding or their experience of life in some way, creativity is a fundamentally important state to try and access and to try and access regularly and to try and tap into in order to eventually produce something, in order to create something of meaning that exists not just in that creative state, but to yourself after that creative state has gone away, right? So, the painting that you paint in the creative state hopefully is a painting that still inspires and, um, has impact after you exit that creative state and that will inspire others, and this could be true for any number of different things, not just painting. So, does cannabis increase creativity? The short answer is, it depends. First of all, we need to define creativity, right? Here we are as, as thinking as scientists, if not already scientists, and there are basically two modes of thinking that are associated with creativity, and they don't completely explain creativity. But if you look in the research, the psychology research and the neuroscience research, you'll hear about convergent thinking and divergent thinking. Convergent thinking is taking loose ideas and kind of braiding them together, finding a common thread, synthesizing and organizing those different ideas into some common or specific framework in order to...... get or create some specific outcome. So, convergent thinking is basically, uh, the person in the room who's listening to all the ideas and taking them all in. Maybe it's a, a panel of, you know, "How should we, um, you know, how should we, uh, get a certain product out to market?" Or, you know, "What are the, what are the different motifs that we should include in a piece of music?" Or, you know, um, "W- what should we do in terms of re- uh, re-architecting a given, uh, physical space?" Taking in those different opinions, those different ideas from different people, and then synthesizing them and coming up with one or a small subset of coherent ideas that incorporate some or all of the ones that they heard. Okay? So, that's convergent thinking. It doesn't have to involve a panel of people talking to you. I use that as an example of what goes on inside your own head when you're engaging in convergent thinking. You're thinking, "Well, so-and-so said this, and I think that." And you're kind of braiding them through and trying to get some common theme, some common vector to emerge from that. Divergent thinking, on the other hand, is best described as brainstorming. It's exploring ideas and continuing to move into the variation and the vastness of ideas in hopes of eventually being able to converge on some novel idea or framework. Okay? So, these are similar and related, but typically, the creativity process involves first brainstorming and divergent thinking, and then in order to arrive at something, to actually create something, right? The verb create, not just thinking about what you might create, which occurs during divergent thinking, but actually creating something, a specific painting, a specific song, a specific body of literature, a specific scientific project or experiment, and so on. That usually involves convergent thinking. Now, these can be explored in the laboratory, and they can be explored in the laboratories through sets of different types of questionnaires or even tasks that you can give human subjects, and this has been done extensively. And across the entire body of data, and by that, I mean, literally hundreds of studies that have explored the relationship between particular neural circuits and neurochemicals, convergent and divergent thinking, we can arrive at a, at a principle. And the pri- principle involves a molecule that many of you have heard about before, which is dopamine. Dopamine is a neuromodulator. It's involved in motivation, and it tends to direct our attention to things outside of us, but it's also closely related to convergent thinking and divergent thinking and to the creative process. And therefore, it should come as no surprise that diseases of the ner- nervous system, excuse me, such as bipolar disorder, of which we've done an episode all about bipolar disorder, or schizophrenia or mood disorders that impact the levels of dopamine, either make it way, way too high or way, way too low, strongly impact whether or not people will be creative. And I think the short takeaway that makes the most sense in terms of framing this, and we cover this on the episode on, on bipolar disorder, sometimes called bipolar depression, is that in professions where there's a lot of creativity required in order to succeed, so again, musicians, composers, artists, et cetera, you tend to find more manic depression. And manic depression, at least in the manic states, the hyperactive states, are correlated with elevated levels of dopamine. Likewise, it has been seen over and over throughout history that ano- that individuals that have mild forms of schizophrenia or even full-blown schizophrenia, many famous painters, for instance, or musicians, they are known to have elevated levels of dopamine, and they are quite creative. Now, that doesn't mean everybody who's creative has elevated levels of dopamine, although it's likely that their levels of dopamine are at least not diminished, and it doesn't mean that non-creative people have low levels of dopamine, so don't get carried away with the interpretation here. But the point is this. Dopamine levels strongly relate to the probability that you can engage in convergent and divergent thinking, and they do so in the following way. When dopamine levels are high, divergent thinking is more likely. That is when people have a lot of dopamine circulating in their system, they tend to be very expansive with their ideas. They tend to brainstorm a lot. They tend to be comfortable and even want to or reflexively throw out a lot of ideas that sometimes even seem a little disconnected. Some people might think of this as kind of attention deficit, but it's not. It's really the idea of, you know, throwing out disparate ideas, right? Um, you know, you hear sometimes, you know, you throw things against the wall and see what sticks. Well, these people, that's, uh, obviously a- an analogy, but people are, um, throwing lots of things against the wall and seeing what stick- and then seeing how the things that stick fit together. That's divergent thinking, and elevations in dopamine tend to increase divergent thinking. However, they tend to do this in a kind of an inverted U-shaped way. For those of you that are watching on YouTube, I'm just drawing kind of a, a hump, obviously. And for those of you listening, just imagine a U, uh, the shape a le- of a letter U, and then just flip it upside down so it looks like a bump. Turns out that when dopamine levels are very low, there's a low probability of divergent thinking. When dopamine levels are high, as I mentioned before, there's a high level or probability of divergent thinking. But when dopamine levels go very, very high, then there's again a reduction in divergent thinking. In other words, there's a kind of a sweet spot of elevated dopamine for divergent thinking. And again, divergent thinking is critical for the creativity process, because creativity by definition is taking a novel set of ideas and arranging them in a particular way or taking existing ideas and arranging them in a novel way that then you eventually converge on some new product, new idea, new song, et cetera. Now, convergent thinking follows a very different pattern. When dopamine levels are high, convergent thinking is not very likely. And when dopamine levels are low, convergent thinking is very likely. So, here using a arguably a very reductionist view, we're looking at all of this thing of we're calling creativity through a very neurosciency reductionist lens, we can say this.The creative process involves going into a state where you're willing to consider a lot of options, many of which seem distantly or not even connected to one another. And dopamine facilitates that divergent thinking state, in which you are perfectly happy, and in fact, experience a kind of a joy, a elation, a comfort, and a pleasure in organizing all these different ideas that, to anyone else, might seem not that related. But when your dopamine levels are elevated, these all seem like great ideas and that maybe there are connections there. Right? You're not accepting all of them as true and valid and interesting and combining them, but there's this idea that, you know, it's, it's worth entertaining the possibility, at least for moments. And then, as dopamine levels drop, there is the process of convergent thinking, which is taking options down off the wall, saying, "No, no, that doesn't fit with that, th- doesn't fit with that, but ah, that fits with that, and that can work. That feels right or sounds right or looks

Episode duration: 2:47:37