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 a 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 well-being, pain relief, etc., or whether
or not they have full-blown panic attacks,
etc., 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 the 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, the 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, an increase in appetite, the so-called munchies.

And that has everything to do
with the 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. [MUSIC PLAYING]

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

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