How Marijuana Affects the Brain & Body | Dr. Andrew Huberman

ANDREW HUBERMAN: Now, let's take a step back into the real world and evaluate or think about what happens when somebody smokes cannabis or ingest 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 if 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-- and 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 familiar with the compound, believe it or not, psychologically familiar, but also biologically familiar, or whether or not the first time use or occasional use, and so on.

THC, and CBD, and other components of cannabis are highly of 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 of course, when people hear fat, they always think, oh, fat's bad, fats whatever. 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 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 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, if one ingests CBD or THC, smokes cannabis, ingest by orally, et cetera-- it 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 how to accelerate the clearance. And it should just tell you that just losing bodily fat isn't going to eliminate it from your system, maybe partially in those fat cells, but certainly, in visceral fat and other fatty tissue that's in and around the brain and body, it's going to harbor that THC molecule and the CBD molecule for quite a long while, at least 80 days.

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 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, 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 digesting 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 meet people mood elevated, energetic, again, the head high. And indica varieties tend to do the opposite, more of a sedative, relaxant, et cetera. Why in hell would they do that?

OK, 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 in brain structures and neural circuits so that the sativa varieties that act as a stimulant making people feel happy because in general they do tend to elevate mood, at least at certain dosages, talkative, tend to make people feel like they have ideas that are interesting that they might want to share, tend to narrow their context so it tends 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. Something they're watching, or something they're doing, or music, it 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. The way to think about the stress in limbic circuitry such as the amygdala, which many people have heard about, is that they aren't really circuits for fear and stress.

There 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 threat detection systems. And then the prefrontal cortex largely acts as a brake on those systems like the reins pulling back on a steed of horses that would otherwise just take off.

And so the sativa varieties tend to increase CB1 activation in the prefrontal cortex and in other circuitry. That then leads to 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 little bit. But I 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, the neurons in 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 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. 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 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 circuitry. So we have a seesaw 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 for a different discussion, and it's very poorly defined 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 not trivial in its own right but in terms of thinking about the creative aspects or the creative activity stimulating aspects of cannabis, not 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 I, type II, or type III variety. OK, 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 I, type II, or type III sativa?

Well, there is no way to predict that. And there's a lot of what I would call street lore, or dorm room lore, or peer-- not peer reviewed but peer discussed, I mean, among friends, and people, and acquaintances lore out there that what one needs to do is simply smoke more 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 experiences paranoia or anxiety from a given strain of the marijuana plant, or from ingesting an edible in a particular way, or a 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 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 between 5 foot 7 and 6 feet tall, and you have blue eyes, or brown eyes, that the sativa varieties are going to be right for you, or that the 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. 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 is that 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 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, all right, again, we're still talking about THC and CBD in varying ratios. But now indica cannabis and say, well, why would it improve the transition time to sleep? Or at least give people the impression that it improved the 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 that we 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, 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 brake on particular biological mechanisms.

And there are going to be a constellation of different accelerations and braking 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've said about the biology of these different strains and the 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 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 because 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 wellbeing, 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 grams of alcohol per week, which is say, for X amount of alcohol, which is not safe.

And so I know a lot of people out there are wondering, 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.

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. 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. Hippocampus means seahorse.

It's shaped like a seahorse. Anatomists like to name things after what things look like. But hippocampus, memory is reduced, in particular short-term memory.

That's true regardless of whether or not one is using sativa, indica, or some hybrid. 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 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, the 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, 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 go eat. You really crave 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. And 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 should 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 antinociceptive meaning antipain 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 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 retrograde signaling can lead to activation or suppression of activity in various neurons.