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 1, type 2, and type 3 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 and 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.

Before we begin,

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.

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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.

So 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, seven zero,

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.

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’s 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 how it affects me

or affects other people

for medicinal or recreational purposes?

Well, it 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 within that strain

interact with one another,

because 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 they 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 will 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 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,

consumer of marijuana.

He basically smoked marijuana for 20 years

before quitting about four or five years ago.

And he said that indica is often referred to as in the couch,

meaning laid back in the couch.

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 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’s 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 of 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 strains,

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 it routinely makes them feel more energized,

elevates their mood,

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 there 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 gene engineering in a kind of CRISPR creating mutants,

but literally by hybridizing,

crossing different plants to one another, okay?

Creating in a natural context,

the same way plants 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 body

than lead to more in the couch,

as I referred to it before, 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, kind of 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.

Okay, 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.

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 will 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 1 billion

and probably closer to 2 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 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 were 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 that 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.

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, 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 is 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, in the sports community,

they will take things like Dianabol.

These are modified versions of testosterone

that can bind to the testosterone receptor

with much greater affinity,

or I should say the androgen receptor,

with much greater affinity

and have supraphysiological effects,

effects that would essentially never be seen

from testosterone that was 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, it 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?

The coming together of the chemical THC or CBD

or both with these receptors is somehow supposed to happen

as if this was 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 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 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, 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.

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

and THC and CBD and so forth, how and why those work.

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So what are the endogenous cannabinoids,

these chemical substances that everybody makes?

You make them, I make them.

You’ve been making them basically

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 refer to as EAE, so anandamide,

and another one, which is arachidonoylglycerol,

arachidonoylglycerol, which we will abbreviate 2AG.

So let’s just take EAE and 2AG, 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 2AG, 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 little packets,

those little bubbles of neurotransmitter

into the gap between the pre- and postsynaptic 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 neurotransmitter.

Put simply, endogenous cannabinoids

tend to decrease the probability

that a neuron will release 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 a 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 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 was 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 a CB1 receptors

are mainly in the nervous system

and CB2 receptors are mainly in the body

and endogenous cannabinoids.

Again, EAE, anatomide, and 2AG, arachidinoyl glycerol

are impacting CB1 and CB2 receptors.

Today, we’re mainly going to talk about CB1 receptors

because 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, it depends on which neurons.

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 outcompete

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 CB1, 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 2AG,

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.

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 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,

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 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 of course, when people hear fat,

they always think, ooh, fat’s bad, fat’s bad.

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.

And 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 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 if one ingests CBD or THC,

smokes cannabis, ingests 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 to

how to accelerate the clearance.

And I 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 intravisceral fat and other fatty tissue

that’s in and around the brain and body

is going to harbor that 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,

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 a sativa joke intended.

But in any event, there are exceptions,

but there are also general rules.

And the sativas tend to meet 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

in brain structures and neural circuits,

so that the sativa varieties that act as sort of 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 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,

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.

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 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,

and neurons of prefrontal cortex is going to bind there.

And then there’ll 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 the 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, 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 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’re causing suppression of those circuitries.

So we have kind of 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 it’s 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 creativity stimulating aspects of cannabis,

not 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 bold face,

triple underlined 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 pure, not peer reviewed,

but 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?

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 five foot seven and six 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, 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

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, 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 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

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, 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’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,

right, 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’re 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

and 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,

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 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,

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,

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.

Okay, 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 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 antinosusceptive,

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 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 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 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 has 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 controlled studies

within university laboratories

and other laboratories can keep up.

So at this point,

I think it’s appropriate to ask ourselves,

why do people 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,

or 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

in terms of technology development and culture

and 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.

So the painting that you paint in the creative state,

hopefully is a painting that still inspires

and 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.

Here we are 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 the person in the room

who’s listening to all the ideas and taking them all in.

Maybe it’s a panel of how should we get a certain product

out to market?

Or what are the different motifs that we should include

in a piece of music?

Or what should we do in terms of re-architecting

a given 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 are 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 principle,

and the 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 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 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 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 throwing out disparate ideas, right?

You know, you hear sometimes,

you throw things against the wall and see what sticks.

Well, these people, that’s obviously an analogy,

but people are 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 hump, obviously,

and for those of you listening,

just imagine a U, the shape 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 arguably a very reductionist view,

we’re looking at all of this thing of,

we’re calling creativity

through a very neuroscience-y 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 or 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 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,

doesn’t fit with that, but ah, that fits with that,

and that can work, that feels right or sounds right

or looks right.

That’s the creativity process.

And so I think this is not just important

for understanding cannabis,

which we’ll get back to in a moment,

but it’s important for understanding creativity

and brain states in general.

Brain states are not, as we would say,

a square wave function.

You don’t just drop into a trench of creativity.

Creativity is not an event, it’s a process.

And what I’m telling you is that it’s a process

that involves divergent thinking and consideration

of a lot of different ideas.

That’s correlated with high, but not too high dopamine.

And then one has to transition

into a state of convergent thinking,

which is really homing in on the ideas

that seem to have validity or that could have validity

and getting rid of everything else.

And that’s associated with low dopamine.

It’s more about logical implementation and consideration

as opposed to thinking about and considering everything.

So let’s now return to the question

of whether or not cannabis

and its different components increase creativity.

And when you look at the literature on this,

you find studies that very clearly point to a yes,

it increases creativity.

And it’s not surprising, therefore,

that cannabis can increase dopamine transmission,

that is dopamine levels in certain brain areas,

in particular brain areas involved in thinking and planning.

Okay, so cannabis increases dopamine in these areas,

elevated dopamine increases divergent thinking,

and divergent thinking is associated with creativity.

And there are studies that support the idea

that cannabis can increase creativity.

However, there are at least as many studies

that say that cannabis does not increase creativity,

that cannabis increases consideration of multiple ideas,

perhaps through elevation of dopamine and related systems,

but that ultimately the ideas that converge from that

are not truly creative ideas.

At least they don’t meet the criteria

for creative brainstorming

and extraction of ideas that are truly novel.

So it doesn’t increase creativity.

So which one is it?

Well, fortunately, there’s an entirely

distinct set of literature

that has taken all the other literature into consideration.

And here’s where we arrive.

So there’s a really nice study

that explored creativity in cannabis users.

And we will provide a link to this study.

First author is Emily LaFrance,

and the title of the paper,

so somewhat amusing in its own right,

which is, it starts with a question,

inspired by Mary Jane, of course,

Mary Jane being one of the kind of old school versions

of our ways of talking about cannabis or marijuana.

Nowadays, people refer to it mainly as pot,

has other names too, of course.

And the title of the paper is inspired by Mary Jane,

mechanisms underlying enhanced creativity in cannabis users.

And I really like this study for a couple of reasons.

First of all, they looked at people who did not use cannabis

as well as people who use cannabis.

So they had two different groups,

but they did not evaluate creativity of the cannabis users

while they were under the influence of cannabis.

They looked at the level of creativity

in these cannabis users

when they were not under the influence of cannabis

and asked whether or not their ability to be creative

was enhanced by cannabis.

Now we’re going to compare this to studies

in which people come into the laboratory

and actually use cannabis,

and then they evaluate creativity under that context.

But this study has some unique takeaways

that I think are really interesting.

First of all, they did, yes,

see evidence for enhanced creativity.

And when I say enhanced creativity,

I mean within the context of this divergent thinking thing

that I talked about a moment ago.

And when I say enhanced,

I mean significantly greater than in non-users,

so people that don’t use cannabis.

So right now I can imagine

that all the cannabis users are cheering,

yes, cannabis increases creativity,

makes people more creative than they would be otherwise.

Well, this is interesting.

We have to ask ourselves how that was accomplished.

And it turns out that one of the major ways

in which it was accomplished is that cannabis users,

even if they are not under the influence of cannabis,

are far more open to novel ideas,

and they have a more explorative and sort of reduced anxiety

or I should say lower anxiety mode of thinking

when they explore novel ideas,

which is essential for divergent thinking.

So they observe both enhanced divergent

and convergent creative type thinking in cannabis users.

And the source of that they conclude is,

and here I’ll just quote,

cannabis users higher levels of openness to experience

are responsible for their enhanced self-reported creativity

and convergent thinking test performance.

So it’s not necessarily that cannabis

is increasing the capacity of the brain areas

that are associated with creativity,

but rather cannabis appears to be increasing an openness

and probably doing that in part through lowering anxiety

in particular people.

And that openness is leading to inclusion of more ideas

during the divergent thinking process, right?

They’re willing to consider throwing up more things

on the wall to see if they stick, so to speak.

So in their conclusions,

they have a really nice statement.

Again, I’ll just read from the paper

because they said it better than I ever could.

Quote, while mainstream media has propagated the idea

that cannabis expands the mind and enhances creativity,

our results show the link between cannabis and creativity

is largely a spurious correlation,

meaning that it’s not the case

that cannabis increases creativity,

but, and I inserted the but in this quote,

but driven by differences in personality

that are related to cannabis use.

For example, openness to experience

that are related to both cannabis use

and augmented creativity.

This is a real chicken-egg argument.

What do I mean by that?

What I mean is this paper finds

that people who are more open to experience

are more likely to use cannabis

and people who use cannabis

are going to be more open to new experiences.

And that combination of features, openness to experience

and what that openness to new experiences brings

enhances the convergent and divergent thinking

that is characteristic of the creative process.

So in short, cannabis increases creativity,

but through changes in personality

that tap into the creative process

rather than directly impacting the neural circuits

that for instance, turn on creativity.

And I have to say this study is really important

because by exploring cannabis users

not while under the influence of cannabis,

they were able to tap into this very important,

what I believe to be fact.

Because if you think about a study

in which you would have one group using cannabis

and another group not using cannabis,

and then you give them some tasks

that taps into creativity, you will see effects.

And very likely you’ll see effects

where cannabis might even increase

divergent convergent thinking and creativity

that those results have actually been published

many times before.

But given the varied effects of cannabis and THC

that we talked about earlier

through all that complex signaling stuff,

you can imagine that there will also be other studies.

And in fact, there are where divergent

and convergent thinking and creativity

is not assisted by cannabis

and might even be reduced by ingesting cannabis.

However, if one considers that divergent thinking

is absolutely crucial to the creativity process

and the range of things that one will explore

will be enhanced by openness

and by reduced levels of anxiety.

So a willingness to explore different options,

some of which might seem completely crazy,

and cannabis increases the personality types

and reduces the anxiety that create that sense of openness.

Well, then it makes perfect sense

why cannabis would increase creativity

in certain individuals, but not directly.

And this study, the one I just referred to,

which I should say was published

in the journal Consciousness and Cognition,

and again, we’ll provide a link to it,

did a wonderful job of teasing out

this impact of cannabis on personality,

which then impacts creativity.

So if somebody asks you, or if you’re wondering,

or if you feel like cannabis increases creativity,

in some sense, the answer is yes,

but the answer is yes because of the ways

that it shapes openness to new ideas.

And can, I should say can, because not in everybody,

but can in some individuals reduce anxiety.

What this means is that if you are somebody

who experiences anxiety or increased levels of focus

from cannabis, regardless of the strain,

and here I have to imagine people

are exploring different strains

if they’re exploring them at all,

exploring different modes of delivery,

smoking or ingestible, et cetera.

If you’re somebody who experiences anxiety,

it’s very likely that you won’t have the increased openness

to experience and divergent ideas

that will facilitate creativity.

However, if you are somebody

who achieves heightened levels of relaxation

and reduced levels of anxiety from cannabis,

regardless of which strain we happen to be talking about,

well then, yes, it will position you

to be in a heightened state of creativity,

at least as defined by convergent and divergent thinking.

One of the more characteristic,

or I should say stereotype qualities

of people that smoke a lot of marijuana

or ingest cannabis through other means

is their changed patterns of speech.

In fact, there’s a kind of a lore in the clinical realm

that you can predict or get some strong indication

as to whether or not somebody is a cannabis user

or pot smoker based on their voice

and their particular tone of voice

and their lack of inflection.

There’s a lot of speculation here,

but fortunately it’s been studied.

So I’d like to discuss now

whether or not cannabis can impact patterns of speech,

both acutely, meaning while under the influence of cannabis

and over time in chronic cannabis users.

And when I say chronic cannabis use,

I want to be very specific what I mean.

Chronic cannabis use does not necessarily mean

that people are smoking cannabis

or ingesting cannabis every day.

Although certainly if they are,

that qualifies as chronic use.

Chronic use is regular use over time

of anywhere from twice a week or more.

So using cannabis once a month

would not be considered chronic use,

even if it’s for many, many years.

Using cannabis or ingesting cannabis in some way or form

twice a week would be considered chronic use.

And then of course,

some of you out there are going to ask me to split hairs

and say, well, what if somebody uses it twice a month?

Well, listen, the clinical literature

and the scientific literature don’t get that specific.

And of course, there are an infinite number of ways

to arrange one’s cannabis use,

everything from zero, none at all,

to constantly every day, all day and everywhere in between.

But think of chronic use as twice a week or more.

Think of occasional use as less than that

and realize that within the realm of chronic use, excuse me,

that or more can be anywhere from twice a week

to every day to just in the evenings, et cetera.

The effects of chronic use of cannabis,

as I just defined it, on speech have been studied

because of this characteristic drawing out

of certain syllables, a slowing of speech,

and in many cases, a total change or alteration

in the way that people speak and use language,

both when under the influence of cannabis

and when not under the influence of cannabis,

if they are chronic users.

And here, we really want to distinguish

between THC and CBD and just make it really simple

and say that CBD is not responsible

for most of the psychoactive effects of cannabis,

whereas THC is.

And again, the ratio of CBD to THC

is going to be relevant there,

but let’s just think about cannabis and THC

as one in the same for this portion of the discussion,

realizing that, of course,

they are not exactly the same thing.

There’s an excellent study entitled

Adults with History of Recreational Cannabis Use

Have Altered Speech Production.

And we will provide a link to that.

First author, Adam Vogel, really liked this paper.

It was published in the journal

Drug and Alcohol Dependence.

We will provide a link to it for you

if you’d like to peruse it in more detail.

The title itself,

Adults with a History of Recreational Cannabis Use

Have Altered Speech Production,

tells you pretty much everything you need to know,

except there’s some important nuance in here

because as I mentioned earlier,

people who smoke sativa varieties of cannabis

oftentimes will become more talkative, much more talkative.

However, whether or not people tend to rely

on sativa cannabis use or indica cannabis use,

there is a very consistent finding

that people who are chronic users,

again, twice a week or more,

recreational use or medicinal use,

undergo pretty profound changes in the way that they speak,

but in a very specific set of ways.

Now, first of all,

the changes in speech shouldn’t surprise us at all

because both sativa varieties of cannabis

and indica varieties of cannabis

impact those brain centers involved in movement,

the basal ganglia.

Remember the go-no-go circuitry,

the circuitry that makes you want to do things

and the circuitry that makes you want to withhold action,

and it tends to shift the body and brain

toward more inaction.

And cannabis impacts CB1 receptors in the cerebellum,

which is involved in motor planning, execution, and balance.

So regardless of whether or not people are using cannabis

of the sativa or the indica variety,

there are disruptions in motor circuitry.

And as you may have heard,

if you listened to our episode

with Rockefeller professor, Dr. Eric Jarvis,

who works on speech and movement,

speech is movement, right?

The movements of the mouth, the movements of the hands,

those are intimately related in terms of our speech.

In fact, the centers of the brain

involved in hand movements

are part of the speech areas and vice versa.

Eric actually pointed out

that if you put your hands behind your back,

provided you normally do have use of your hands,

it actually will reduce your fluidity of speech.

And so I’m going to put them back in front of me now.

The point is smoking marijuana

or consuming marijuana by edible changes one’s speech

and does it in a very specific way.

And in this study by Adam Vogel and colleagues,

they explored a huge different variety of aspects of speech.

And this can be done using spectral processing,

which is fancy nerd speak

for looking at how much inflection there is

or looking at how long people hold vowels

or consonants, et cetera.

And again, these are people

not under the influence of cannabis,

but rather people who tend to be

under the influence of cannabis

when not participating in the study.

In other words, chronic recreational cannabis users.

So what are the two major shifts that cannabis causes

on our patterns of speech?

Well, the first one is a change

in what’s called spectral tilt.

Again, that’s fancy nerd speak

for vocal effort and intensity.

So I’m not a pot smoker, I confess.

But if I were to say the sentence,

vocal effort and intensity

are important components of speech.

That’s the way I would say that sentence

if I was striving to enunciate very carefully

and to accent certain words and syllables.

A pot smoker or somebody who uses recreational cannabis

fairly often would have reduced spectral tilt,

AKA vocal effort intensity,

and might say spectral tilt is vocal effort and intensity.

And it differed between groups

and appeared to change in line

with the duration of abstinence from cannabis use.

That I think is not a far cry

from the change in spectral tilt that they observed here.

In addition, there are changes in verbal timing.

That is pronunciation of words

and accenting particular syllables of words

in people that consume cannabis or smoke cannabis.

So rather than emphasize particular words within a sentence,

so again, I’ll just use a sentence from the paper

so that you can gain more knowledge from the paper.

Cannabis, and I’ll say it the way that I would say it

since I’m not a cannabis user.

Cannabis, marijuana,

is the most commonly used illicit drug in the world

with approximately 4% of adults aged 15 to 64 years

reporting recent use.

And the citation is from the United Nations

Office on Drugs and Crime, 2019.

So that would be the way

that I would typically read that sentence.

And having gone into the data in this paper

and of course evaluated references therein,

and listen to some of the spectral analysis

that they include as data,

you can literally go into these papers online

and hear recordings of people who are cannabis users

or non-cannabis users.

And I’ll try and give you a clear sense

without picking an extreme example

of how somebody who’s a fairly consistent

or even occasional cannabis user

might read that very same sentence.

Cannabis, marijuana,

is the most commonly used illicit drug in the world

with approximately 4% of adults aged 15 to 64 years

reporting recent use.

And the citation comes from the United Nation

Office on Drugs and Crime, 2019.

Now you’ll notice that wasn’t a dramatic difference.

And of course I could have taken the liberty

to pick an extreme example of the sort

that they did occasionally observe

in evaluating subjects for this paper.

I could have said something like cannabis,

marijuana is the most commonly used illicit drug.

But frankly, that would have been selecting

an outlier example and I don’t want to do that.

I don’t want to skew the data as they say.

Rather, if you heard the first time I read the sentence

and the second time I read the sentence,

what’s mainly different is the difference

in the amount of enunciation and accenting

of particular words and symbols within a sentence.

So the total content that’s delivered is exactly the same.

And while I wasn’t measuring my pace,

the overall rate of communication is essentially the same,

but there’s less sort of lilting and falling of the voice

and less accenting.

That’s the major consistent effect of cannabis use.

Now, of course, there are examples of people

who are using a lot of cannabis

and it impacts brain centers involved

in movement and speech.

So much so that they really do have the really drawn out

kind of, and oftentimes this will be detected in the laugh.

You know, there’s this sort of stereotypical stoner laugh

as it’s sometimes called, rather than say,

or that’s a fake laugh, obviously.

It’s hard to make myself laugh

if something’s not actually funny.

I have to think of something funny.

When people will say, like, that’s a bit more

of the way I might laugh, like,

sort of the inspiratory laugh or the,

which is expiratory laugh.

People who use cannabis chronically will often do that.

Which is sort of the back of the throat.

It’s sort of this, the,

it’s neither inspiratory nor expiratory laugh.

And believe it or not, there’s an entire literature

on inspiratory inhaling versus expiratory laughs.

And there’s also a literature on cannabis

altering the pattern of inspiratory and expiratory laughs.

It almost sounds like a sarcastic laugh

when in fact they may not be feeling sarcastic at all.

And I have a very close friend and colleague

who’s a phenomenal neurosurgeon and neuroscientist

by the name of Dr. Eddie Chang.

He’s the chair of neurosurgery at UCSF

and his lab and him are expert in the study

of neuroscience controlling language and speech.

And he often tells me that he can predict

with almost certainty whether or not somebody

is a regular cannabis user based not just

on the patterns of speech that they use,

but even just by recording specific neurons in their brain

that underlie the laugh reflex

and certain patterns of speech.

So this idea that cannabis use changes your ability

to speak and enunciate clearly does appear to be true.

And the stereotype that cannabis use tends to create more

of a drawl or kind of a, if you will, a laziness

in the laugh and some of the reflexive enunciations

that people use does also appear to be true.

And I say all that, of course, with the caveat

that many people out there will know individuals

or perhaps you yourselves are individuals

that may use cannabis,

but that have incredible articulation,

probably better than mine and better than other people

out there who speak for a living.

So I’m not saying that 100% of people

that use cannabis regularly can’t speak well or clearly,

that’s simply not what I’m saying.

And I don’t want to communicate that idea at all,

but it is the case that people who are regular cannabis

users are impacting the neural circuits involved

in movement, movement also controls speech

and therefore cannabis is impacting speech.

Now I’d like to turn our attention

to whether or not cannabis can increase sexual activity,

sexual desire and or sexual function.

So we’re going to be talking about libido,

about sexual desire and about effects

of cannabis on hormones.

And while this might sound like a discussion

that’s purely oriented towards recreational use of cannabis,

that is people using cannabis to heighten

or increase their sense of arousal for sexual activity,

it actually ventures into the clinical realm too,

meaning there have been excellent peer-reviewed studies

that I’ll describe to you in a moment,

exploring the use of cannabis or THC more specifically

for something called hypoactive sexual desire disorder,

which refers to a persistent or recurrent deficiency

or absence of sexual fantasies and thoughts

and or desire for or receptivity to sexual activity.

This is a disorder that is fairly common

anywhere from six to 9% of people, both males and females.

It used to be considered higher prevalence

in females than in males,

but now those numbers seem to be evening out.

So basically there are anywhere from six to 9%

of people out there who have very diminished sexual desire.

And so a number of those people are interested

in figuring out ways to increase

their amount of sexual desire.

And of course there are people in the general population

who may not have hypoactive sexual desire disorder,

who are interested in using cannabis recreationally

in order to increase their desire for

or their experience of sexual activity.

Now, first we have to acknowledge that sexual desire

and activity is a complex set of processes,

meaning it’s not just one event, sex, the verb,

it involves arousal, it involves sex, the verb,

and it involves a whole set of mindsets and emotional states

that vary tremendously between individuals.

But once again, we can distill out a few basic principles

and I should emphasize these are by no means

the only chemicals in neural circuits involved

in the sexual arc, as we’ll call it,

desire, the act of sex, et cetera,

but they are central to it, they are vital to it.

They would be considered what I would call necessary,

but not sufficient, okay?

So there’ll be other chemicals involved too,

but the main chemicals in neural circuits

are those involved in dopamine.

So the so-called mesolimbic reward pathway

in particular brain structure called nucleus accumbens,

which we’ll talk about more in a moment,

is vital to all motivated behaviors

and to the seeking out of all particular types

of pleasurable experiences and sex is no exception.

So when we hear that the nucleus accumbens is activated,

that almost always means that dopamine has been released

in that area and other areas of the brain and body,

and we can consider dopamine central

to the desire for, pursuit of, and act of sex.

In addition to that, there are molecules like oxytocin,

which are involved in pair bonding

and they’re going to be neural circuits

specific to the oxytocin circuitry.

But in terms of sexual arousal and sexual behavior,

it’s really the dopamine pathway in this nucleus accumbens,

which are especially vital.

That allows us to address the question,

does cannabis increase, decrease,

or have no effect on sexual desire

and or the ability to have sex?

And therein, we will find some very interesting answers

because once again, it will point to the fact

that the effects of cannabis on different individuals

can be highly divergent.

Meaning in one set of individuals,

cannabis will make them far less anxious.

And in another set of individuals,

the same strain of cannabis at the same dosage

will make them extremely anxious.

The same can be said also of sexual activity.

And this was beautifully illustrated

in the context of sexual desire

in the journal Psychopharmacology

in a paper published in 2017.

The title of this paper is

Individual Prolactin Reactivity

Modulates Response of Nucleus Accumbens to Erotic Stimuli

During Acute Cannabis Intoxication, an fMRI Pilot Study.

So I’ll give a little bit of definition

to some of the terms in the title

that will make it easier for you to understand the paper,

but then I’ll just march through the results

because they are very straightforward

and easy to understand and very interesting.

fMRI is just Functional Magnetic Resonance Imaging.

So basically subjects in this experiment

came into the laboratory.

They were either people who had not used cannabis before

or who had used cannabis before.

They were placed into a brain scanner,

one of these fMRI devices.

It looks like a tube that people are backed up into

and then they can view images in there

and their brain can be imaged

without having to remove any skull

or drill into the skull, no neurosurgery.

The participants in this study

were grouped according to whether or not

they had experienced any aphrodisiac effects

during the intoxication with cannabis.

So that would be the first group, group A.

They literally called it group A for aphrodisiac.

And then the second group,

and this is the only thing I don’t like about this study

is rather than call it group B,

they called them group non-A,

which is just gets a little confusing.

So I’ll try and simplify all this.

There are two groups and one group experiences

sexual arousal when under the influence of cannabis.

THC specifically.

The other group does not.

And it turns out this is a very commonly observed

divergence of effects of cannabis.

Some people experience a lot of sexual arousal

from cannabis and THC in particular,

and some people do not.

In fact, they experience suppression of sexual desire.

And it’s always been a little bit mysterious

as to why that is.

Well, in this study,

they showed people in both groups, erotic images,

and they measured sexual arousal

through a number of different measures.

We won’t go into all that.

It was largely subjective.

There’ve been other studies where they’ve actually

measured things like erections in males

and vaginal lubrication in females.

These are so-called autonomic responses

that people can’t lie about, so to speak,

and that tap into other aspects

of the so-called sexual arousal process.

In this study, they also took blood samples

to look at the concentration of things like cannabinoids.

So this is a really nice study

in that they actually measured how much THC

was in the bloodstream in different individuals

who reacted to these erotic stimuli in different ways.

And they measured hormones,

namely cortisol, which is a stress hormone,

which tends to negatively correlate

with sexual arousal, and prolactin.

And the interesting takeaway from the study was

that for people, and it didn’t matter

if it was males or females,

because they looked at both,

for people that experienced elevated prolactin levels

under cannabis intoxication, that’s how they refer to it,

people take cannabis, they measure prolactin.

Some people had elevated prolactin, some people did not.

For the people that had elevated levels of prolactin,

they did not observe activation of brain areas

associated with sexual arousal.

In this case, the right nucleus accumbens,

so you have two nucleus accumbi, I guess they’d be called,

one on each side of the brain,

and the activation of that brain area

is strongly associated with dopamine and with arousal

and sexual arousal in particular in this study.

And if people had elevated prolactin,

they did not experience activation of nucleus accumbens,

and they did not report feeling sexually aroused

to those pictures, at least not to the same degree

as the other group.

So some people’s prolactin levels go up

when they ingest cannabis,

and those people do not achieve elevated levels

of sexual arousal when under the influence of cannabis,

even if they’re looking at erotic stimuli.

That makes sense because prolactin

is mutually inhibitory, as we would say,

it’s kind of in a push-pull with dopamine.

When dopamine levels are high,

prolactin levels tend to be low.

And when prolactin levels are high,

dopamine levels tend to be low.

The other group, so-called group A,

that experienced elevated levels of sexual arousal

when under the influence of cannabis

and viewing erotic stimuli,

that group did not show elevated levels of prolactin

in response to cannabis.

So this, I believe, resolves a longstanding controversy

in the field, which is,

does cannabis increase sexual arousal?

Well, it depends.

If you fall into the category of person

who has elevated levels of prolactin

in response to cannabis, then no,

actually cannabis will suppress

your sexual response and desire.

If, however, you are in the category of person

that does not have elevated levels of prolactin

in response to cannabis,

well, then erotic stimuli can potentially,

and in fact do, increase sexual arousal

in the majority of individuals.

Now, many of you are probably hearing this

and wondering whether or not you fall

into one category of individual or another.

And the key thing here to understand

is that levels of prolactin heading into the study

did not predict, did not predict,

whether or not people would respond to cannabis

with elevated or non-elevated

or even reduced levels of sexual arousal.

It was whether or not people’s prolactin levels went up

or did not go up that predicted whether or not

their levels of arousal would go up or not.

So if you are somebody who, yes,

does experience elevated levels of sexual arousal

and function when under the influence of cannabis,

well, that’s very likely that cannabis

does not increase your prolactin levels,

at least not to a significant degree while you’re taking it.

And if you are somebody who does not experience increases

in sexual arousal or function

or even diminished sexual arousal and function

when under the influence of cannabis,

it’s very likely the cannabis

is increasing your levels of prolactin.

Unfortunately, there’s no way to know or predict

based on some other measure.

I think the outcome measure that is increased

or not increased or even reduced sexual arousal

is really the litmus test by which one can figure that out.

While we are on the topic of the effects of cannabis

on sexual function and hormones like prolactin,

it’s probably worth mentioning

that cannabis has been studied extensively

for its impact on other hormones.

And we can summarize those literature in the following way.

And here I’m referring to studies only on adults.

We will talk about the developing brain and body

in a little bit, but it is very clear

that smoking cannabis increases prolactin levels.

Very, very clear.

Now you might say, didn’t you just describe a study

about a set of individuals whose prolactin didn’t increase?

And as a consequence, their level of sexual desire went up?

Yes, there are a subset of individuals

for which that’s true.

But people who smoke cannabis

do experience increases in prolactin.

And that’s especially pronounced

in people that smoke cannabis more than twice a week.

So this is important.

Prolactin, as I referred to earlier,

is reciprocal or mutually inhibitory with dopamine.

One way to think about this is in the context

of the normal sexual arousal arc,

whereby dopamine is increased

when people are sexually aroused,

but then after orgasm, both in males and females,

prolactin levels skyrocket.

This is actually what creates the so-called refractory period

for males during which they cannot achieve erection again

for some period of time.

That relates directly

to how long the prolactin increase lasts, okay?

Prolactin is also increased in new parents of all species,

including humans, which at least partially explains

some of the reported or typical reductions

in sexual desire and activity in new parents.

Now there are other reasons for that too, sleep deprivation,

but nature is smart and has arranged a set of hormones

and circuits in the brain and body

such that when tending to a newborn

is the most important thing, it relegates.

It reduces the importance of producing more children

and sexual activity in those moments and days and weeks,

sometimes longer.

So when prolactin levels are up, dopamine levels are down.

Smoking marijuana more than twice a week

significantly increases prolactin.

There are fewer studies exploring

whether or not edible marijuana has the same effect,

although the preliminary evidence suggests that it does not.

I get into this in a lot more detail in a future episode,

all about hormones with Dr. Kyle Gillette,

who’s been on this podcast before,

but he verified that in my read of the literature

is that the edible forms of marijuana, cannabis,

probably again, let’s put an asterisk next to this,

but it appears do not have as much

of a prolactin elevating effect

and therefore not as much of a dopamine suppressive effect

and therefore not as much

of a testosterone suppressing effect.

And that gets to the issue of testosterone.

Does cannabis marijuana suppress testosterone?

And this is a very controversial literature and here’s why.

Some studies say, yes, it suppresses testosterone

in males and females.

And keep in mind that testosterone in females

is vital for libido and cognitive function,

cellular repair, et cetera.

So it’s not just important in males, of course.

However, other studies say that cannabis

does not decrease testosterone.

And it seems to depend on whether or not

the cannabis is brought into the system

by way of smoking or edible.

And it seems to depend on whether or not

the cannabis is used chronically by an individual or acutely.

And here, I just want to zoom out and say

that studies on cannabis or drugs of any kind in humans

are really complicated.

If you think about it,

someone has to come into the laboratory

and let’s say you want to study chronic cannabis use.

Well, you can’t keep them in the laboratory all the time.

So you have to rely on their self-report

of how often they use cannabis and in what form.

And you can’t really control from one individual

to the next of how much cannabis and THC

they’re bringing into their system.

One person might smoke cannabis out of a bong

and take big, deep, lungs full bong inhalations or such.

Other people might smoke joints.

Other people might use edibles.

It becomes very complicated to know what people have done

and that they’re reporting it accurately.

And no joke here,

especially if marijuana is impacting

the short-term memory systems.

They might not actually remember.

They might not be tracking it that well.

Contrast that with studies of the acute use of cannabis

and THC where people who are not regular users

come into the laboratory and now suddenly

with institutional guidelines and safety protocols

are under the influence of THC and cannabis.

Well, now you’re dealing with a person

who may not have experience with the elevated heart rate

and blood pressure that’s characteristic of cannabis

because it is a stimulant,

at least when initially brought into the system,

even if it might eventually lead to relaxation.

So now you’ve got someone who’s anxious

or somebody who’s not anxious, who’s deeply relaxed,

and you’re trying to study these effects.

So it’s a moving target of sorts.

It’s very complicated to study marijuana and cannabis

and its various derivatives in this way.

Now you can probably appreciate better

as to why there’s so little nuanced data

about sativa versus indica

versus different ratios of CBD and THC.

It’s really difficult to do these studies

in the first place.

That said, the general rules are smoking marijuana

increases prolactin in men and women,

which will reduce dopamine and testosterone.

Smoking marijuana chronically,

meaning more than twice a week,

does appear to reduce testosterone significantly

and elevate so-called aromatase enzymes,

which are the enzymes that convert testosterone

into estrogen.

This might partially explain the effect

that occurs in about 35% of males,

which is gynecomastia,

which is a development of breast tissue in males,

in particular, young males

who have elevated levels of testosterone

or who are taking exogenous testosterone

for testosterone replacement therapy,

or if they’re taking high doses, anabolic steroids,

or in females, the increase in breast size,

which is due to additional estrogen

from testosterone converted to estrogen.

So it does appear that marijuana and cannabis

increase estrogen, reduce testosterone,

increase prolactin, especially in chronic users.

Now, I’m sure that some people out there will say,

well, their testosterone levels are exceedingly high

or they are fine,

meaning the constellation of symptoms

associated with low testosterone and elevated estrogen

are not present in them.

That probably means one of two things, or both.

They either had elevated levels of testosterone

to begin with, so their ceiling was higher,

so bringing it down didn’t have that much of effect,

or that they have very low levels

of aromatase in their system.

There is some anecdotal evidence

that smoking particular parts of the marijuana plant,

in particular, the seeds,

can increase aromatase

and the conversion of testosterone to estrogen.

I think in the old days, the lore was

the seeds make you sterile,

and I think that was related to what I just told you,

this increase in conversion of testosterone to estrogen.

There’s a vast literature

on the effects of cannabis on fertility.

It does seem, yes, it does seem to alter sperm motility

and sperm health and function

when taken chronically more than twice per week,

in particular, high doses of high-potency THC.

This is something we will cover in far more detail

on a future episode all about fertility.

And in females, there’s an increase in estrogen

as a consequence of smoking marijuana

and increasing prolactin and estrogen in parallel.

Whether or not that’s detrimental isn’t clear,

although I point out that elevated estrogen and prolactin

can be associated, again, can be associated,

not necessarily, and certainly not causative,

but can be associated with elevated levels

of or frequency of breast cancer detection.

So cannabis and its effects on hormones

are not without consequence.

There are effects of cannabis on cortisol.

In some individuals, it greatly increases cortisol

due to the anxiety and paranoia it can create,

and in other individuals, it reduces cortisol.

Again, we have these divergent effects,

but I want to be very clear.

The effects on prolactin, meaning elevated prolactin,

the effects on testosterone, meaning,

at least most studies point to reduced levels of testosterone

and increased estrogen, that seems to be true

for most all individuals that chronically use cannabis,

whereas the effects on cortisol tend to be divergent.

Cannabis increases cortisol in some individuals

and decreases cortisol in others.

In general, increases in cortisol that are ongoing

are not healthy for us, and so on.

And then, of course, there are other effects on hormones,

and I’ll just briefly summarize those,

that THC in particular, not CBD, but THC in particular,

is known to be strongly inhibitory

for something called gonadotropin-releasing hormone.

This is a hormone that’s released from the brain,

from the hypothalamus, that then feeds onto,

or I should say signals to the pituitary gland,

which is also near the roof of your mouth,

a lot of stuff happening near the roof of your mouth,

it turns out, biologically.

And reduced levels of gonadotropin-releasing hormone,

caused by cannabis use,

reduced levels of LH, luteinizing hormone, and FSH,

which reduced levels of testosterone

and sperm production in males,

and egg health and ovulation

and menstrual function in females.

Now, I’m sure there are a number of women out there

who will say they have perfectly normal menstrual cycles

despite using cannabis.

I’m certainly not going to dispute that.

But if you are somebody who’s trying to maximize fertility

or regulate or balance hormones,

marijuana and cannabis reduces GNRH,

that is the gonadotropin released from the hypothalamus,

and thereby reduces luteinizing hormone

and follicle-stimulating hormone,

which are released from the pituitary

and travel in the bloodstream

to support normal ovarian function and health

and normal testicular function and health

in females and males, respectively.

Up until now, I’ve been discussing

the biological and psychological effects of cannabis.

Now I’d like to shift our attention

to some of the negative health effects of cannabis

and shine light on some of the individuals

or groups out there that need to be especially wary of

and probably avoid cannabis use entirely,

including ingestion of cannabis by way of edible.

And I frame things that way

because I think there is an increasingly large number

of people out there that appreciate

that smoking tobacco or smoking cannabis,

vaping tobacco, yes, vaping tobacco or vaping cannabis,

each and all have negative health consequences

on the lungs and on the so-called endothelial cells

of the body, the cells that make up the vasculature,

the capillaries and blood vessels.

If you don’t already know this,

I’ll make it very clear and I’ll make it very brief.

Whether or not you smoke or vape, tobacco or cannabis,

you are severely impairing the function

of endothelial cells that make up the capillaries

and blood vessels of your brain and body.

And that is known to decrease cognitive capacity over time,

increase probability of strokes,

severely impact lung function,

and also lead to things like peripheral neuropathies.

It leads to sexual dysfunction

because of lack of blood flow to the genitals,

can lead to other aspects of reproductive damage,

including to the ovaries and testes.

Essentially, there is no other way to state it

except that smoking and vaping

have negative health consequences

that are independent of the substances

that people are trying to get into their bloodstream

by smoking or vaping.

So people smoke and vape tobacco

and people smoke and vape cannabis.

And in both cases,

if we just set aside the direct effects of tobacco

and the direct effects of cannabis,

we can confidently say that the process of smoking,

of inhaling smoke into the lungs, and yes, also vaping,

bringing the chemicals that transport nicotine,

or in this case, cannabis into the lungs by way of vaping,

are both severely detrimental to endothelial cells.

I think a few years ago, when vaping wasn’t as prominent,

there was this question and this idea

that maybe vaping was going to be far healthier

or at least not as bad as smoking.

But now we can see a huge number

of negative health effects of vaping,

some of which are distinct from the effects of smoking.

So if you’d like more information on smoking versus vaping,

please see the episode that I did on nicotine.

We will also do an entire episode

all about vaping in the future.

But there’s really no way to slice it and dice it

or candy coat it.

The fact of the matter is that smoking has clear

and severe negative health consequences,

regardless of whether or not you’re smoking tobacco

or cannabis, THC, and vaping has negative health

consequences, whether or not you’re using the vape

to bring in nicotine or THC

or some combination of THC and CBD.

That’s simply the way it is.

With that said, now I’d like to focus our attention

on the direct effects that cannabis has,

either by way of THC action or by way of CBD action

in terms of positive or negative health effects

on the brain and body.

And we’re going to explore that first as a function of age.

And the reason we’re going to do that is related to a fact

that I mentioned at the beginning of the episode,

which is that the CB1 and the CB2 receptors,

the two receptors for cannabis to which THC and CBD and CBN

and all other psychoactive compounds in cannabis bind to,

to have their actions are present throughout development.

Believe it or not,

they are present very soon after conception

and the CB1 and CB2 receptors actually play a critical role

in the development of the fetus.

Now you might wonder why that is,

because of course the developing fetus

doesn’t necessarily expect to see cannabis

or to be exposed to cannabis and THC and CBD.

But as you recall, endogenous cannabinoids are present

in the adult brain and body and endogenous cannabinoids,

it turns out, are also present in the developing fetus.

In fact, endogenous cannabinoids are present

at much greater levels in the developing fetus

than they are after a child is born.

And levels of endogenous cannabinoids

actually go down across development.

I find this really interesting.

What this means is that endogenous cannabinoids

and activation of the CB1 and CB2 receptors

are an integral part of neural development.

And this is going to become especially relevant

in considering whether or not pregnant mothers

should or should not use cannabis or CBD.

And it also points to some very interesting biology

in terms of how the brain develops

and how the body develops.

Now, the development of the brain and nervous system

and body is a fascinating and vast literature,

certainly far too vast to cover in today’s episode,

especially at this late hour, as it were.

But we will have a future episode

all about brain development.

In terms of the effects of cannabis,

it’s sufficient to say that cannabinoid receptors

are present and active in the developing fetus.

They’re present and active in the newborn.

They’re present and active in adolescence.

And across that time, from conception until adolescence,

endogenous cannabinoids are mainly responsible

for the actions of those cannabinoid receptors.

During that time, the cannabinoid receptors

are having very specific effects

that are distinct from their effects later in life.

And those effects can largely be explained

in terms of neural development.

Again, we don’t have time for an entire lecture on this now,

but during development,

your body was a collection of a bunch of cells.

It’s actually called a blastula,

which means a ball of cells.

And then those cells actually have to grow out connections

and duplicate themselves.

And this is a very interesting process

by which neurons initially are situated far apart,

and then they grow out connections

and make contacts with one another.

They remove certain connections,

depending on what kind of life events you’re exposed to.

If you have a wonderful event early in life

or a traumatic early life,

those connections change, et cetera.

The important point for today’s discussion

is that the CB1 receptor in particular

is expressed on every neuron in the developing brain

and has been shown to be important

for every aspect of neural development,

from the proliferation of cells,

meaning getting enough cells to create a brain,

to the outgrowth of the so-called axons,

the little wires that connect up neurons with one another,

to the steering, the direction in which those axons go

in development, which is essential.

And even so far as to explain the connections

that form between neurons, the so-called synapses,

and then how those synapses work.

So the basic statement here is that endogenous cannabinoids

and CB1 receptor activation are critical

for every aspect of brain wiring and development.

With that in mind, the statement I’m about to make

is absolutely terrifying, at least to me,

and frankly, it should be terrifying to you as well.

And the statement is the current statistics

on cannabis use in pregnant mothers

is absolutely shocking.

The most recent survey of pregnant mothers

in the United States show that 15%, one five,

15% of pregnant mothers report using cannabis

in some form or another, either smoking it

or more likely ingestion of an edible,

because they are aware of the negative effects

of smoking on the developing fetus,

ingestion of an edible to increase THC

and or CBD during pregnancy, which to me,

I have to say as a developmental neurobiologist is,

frankly, it’s scary.

It’s absolutely scary because that CB1 receptor

is not just a minor player in neural development,

it is absolutely central to every critical aspect

of brain wiring and development.

Now, the long-term implications

or even the short-term implications of this 15%

of mothers self-reporting the use of cannabis

at some point during pregnancy are not yet known.

This is, as we would say,

an experiment that’s ongoing,

but I’d be remiss if I didn’t point out these data

and just implore you, please, please, please,

if you are pregnant or considering getting pregnant,

you’re a cannabis user, whether or not you’re using edibles,

if you’re a CBD user, please do whatever is necessary

to not ingest cannabis or smoke cannabis

or ingest CBD during pregnancy.

Now, there may be certain clinical indications

by which your physician and your OBGYN

and the pediatrician that will eventually be

the pediatrician for your child will prescribe CBD,

although it’s hard to imagine what those are.

I contacted a number of different pediatricians and OBGYNs

and not a single one said they would ever suggest

and in fact would strongly discourage their patients

from using cannabis during pregnancy.

But I think that the advent of edible forms of cannabis

and the combination of THC and CBD in certain products

and the fact that most people view CBD as safer

because it does not include as, or does not have,

I should say, the psychoactive effects that THC does

has led to a situation where you have 15%

of pregnant mothers using cannabis

at some point during pregnancy

and maybe even frequently throughout pregnancy

and the effects on the developing fetus

are completely unknown, but recall that cannabis

and THC and CBD out-compete, meaning they park

in the receptor for endogenous cannabinoids

and prevent endogenous cannabinoids

from having their normal level and pattern of action.

So this is absolutely critical.

I cannot encourage you enough, or rather I should say,

I cannot discourage enough the use of cannabis

and any related compounds in cannabis,

edible or smoked, certainly not smoked,

but even edible during pregnancy.

And certainly in breastfeeding, lactating mothers,

the same is also true.

Recall that cannabis and THC and CBD

are incredibly lipophilic.

They are fat-soluble and they get into cells very readily

and they cross the blood-brain barrier,

they cross the blood-placental barrier.

So when I encountered this statistic,

I had to kind of wipe my eyes a few times.

I could not believe it.

And yet I cross-checked that number

with a few other studies.

A few others have come in a little bit lower at,

you know, somewhere like 13 to 14%,

and a few have come in a little bit higher,

but the average of 15% is both striking and shocking.

So I don’t know how to make the message more clear.

I hope that is clear.

Please do not use any cannabis, THC,

or related things, including CBD, smoked or edible

if you’re pregnant, lactating, et cetera.

Now we are at the point where we need to consider

some of the negative health effects of cannabis

that have been well-documented in peer-reviewed studies.

And before I do this,

I want to return to a point that I made earlier,

which is that nothing I am about to say

relates directly to issues of legality.

If we consider alcohol, for instance,

alcohol is legal in most areas of the world.

It’s certainly legal in the US,

and yet there’s an age limit for its use.

Typically, it’s not available to people

until they’re 21 or older.

It’s not to say that certain people

don’t use it before age 21, but it’s not legal.

It is illegal to buy or possess alcohol,

consume alcohol before age 21.

And I think with good reason,

because the brain is still developing.

Likewise, we can have a informed discussion about cannabis

and its various components

that can fully acknowledge the reality,

which is that one of the major harms of cannabis

in the past has been the legal ramifications

of cannabis being illegal.

That’s a statement that is no longer controversial.

And this is not a discussion

about legalization or non-legalization.

If you look to the scientific literature,

the epidemiological literature,

there are wonderful data out of Carleton University

and elsewhere in Canada,

showing that many of the negative effects

of marijuana and THC

are due to the criminal justice system itself.

That is the creation of illicit drug businesses,

the creation of organized crime,

the creation of a number of different features

related to the illegality of cannabis.

And again, this isn’t the topic of today’s episode,

but that should be acknowledged.

And at the same time, we need to acknowledge

that when a compound, a drug,

or whatever you want to call it, becomes legal,

there’s a tendency to assume

that it’s safe and safe for everybody.

And with respect to cannabis and THC,

and perhaps even CBD, but certainly for THC

and cannabis that’s smoked or vaped

or consumed in edible form,

that is simply not the case.

There are clear data pointing to negative health effects

of cannabis use and THC use,

which again is not to say that there are not

positive effects on mood, anxiety, pain relief, et cetera.

Those are out there and they exist.

And we will mention some of those, of course,

and we’ve talked about some of those,

creativity, for instance, et cetera.

But if we do not acknowledge the negative health effects

that are documented in the literature,

then we are overlooking some very important data,

especially as it relates to the development of psychosis

in certain individuals.

So with that said, there are very strong data,

and I will provide links to these resources,

pointing to the fact that for people

who are chronic users of cannabis,

that is using it twice a week or more,

that over time their levels of anxiety actually increase.

And this is true even for individuals

that are using strains of cannabis

that while under the influence of cannabis reduce anxiety.

Over time, meaning over the course of 12 or more months,

there is a well-documented effect of the anxiety relief

that cannabis and THC initially brought

being less and less potent.

That is people need to smoke more of it or ingest more THC

in order to achieve the same level of anxiety relief.

And in some cases, a switch from anxiety relief

to increase in anxiety.

And again, that’s increase in anxiety,

not just when the drug is not being consumed,

but also while under the influence of the drug.

Why would that be?

We have to go back to our understanding

of the CB1 receptor and the potency with which THC

binds to that CB1 receptor.

When THC is brought into the system over and over again,

meaning twice a week or more,

the binding of THC to that CB1 receptor

eventually causes a sort of habituation or attenuation

of the entire process of binding the receptor

and creating the psychoactive effects.

So initially it creates anxiety relief,

but over time the affinity for the receptor doesn’t change.

Meaning it can still park in that slot

with a lot of affinity, a lot of strength,

but there are fewer receptors available.

And then the signaling that’s downstream of those receptors

becomes less and less robust.

Now, this is a topic we didn’t get into

in too much detail today

because I didn’t want to include

even more biological detail,

but the CB1 receptor is a so-called

G-protein coupled receptor.

That’s a mouthful, but a G-protein coupled receptor

basically is like a bucket brigade.

So while some receptors in the brain and body

are such that when something, a chemical binds to them,

that receptor has a direct action,

like it opens and allows stuff to rush into the cell,

increases the excitability of the cell,

so-called fast effects.

These G-protein coupled receptors,

and CB1 is a G-protein coupled receptor.

They are more like a bucket brigade

where they kick off a process through one molecule

that then is handed off to another molecule

that this then is handed off to another molecule.

It’s a long chain or cascade of events.

Those long chains or cascades of events

have a lot of opportunity for regulation, for adjustment.

You know, receptor systems in the brain and body,

especially receptor systems like the cannabinoid system

that are used to being kind of tickled, not punched,

you know, tickled by endogenous cannabinoids

every once in a while, some binds, has an effect,

but certainly not bound with incredible potency

and over and over again as they are

when THC is coming into the system.

Well, those systems eventually over time,

they adjust themselves so that the body and those cells

can achieve so-called homeostasis.

So when people are using THC more than twice a week,

what ends up happening

is those G-protein coupled receptors

in the downstream signaling mechanisms

start to adjust themselves

and it requires more and more drug.

So either higher dosages or more frequent use.

And a lot of the positive effects,

the so-called decrease in anxiety,

increased focus, increased creativity,

some of that starts to wane, it starts to dissipate

and people wonder why they have to use so much cannabis

just to achieve a fraction of the effect

that they used to be able to achieve with even a lower dose.

So anxiety is getting worse over time

and that’s anxiety during the drug use

and outside of the drug use.

Some people work around that or try to work around that

by using varying strains of cannabis

or changing the pattern of delivery from smoking to vaping

or from vaping to edible and from edible to transdermal.

Anyway, they go through a lot of gymnastics

and writhing and seeking,

but nonetheless, anxiety increases over time.

Also, it’s very clear that depression increases over time

and especially, this is surprising to me,

but especially for individuals that were not depressed

at the outset of their use.

In other words, they didn’t start using cannabis

because they were depressed,

but rather the depression starts to emerge

as a consequence of the cannabis and THC use.

So that’s serious.

In fact, we now know

based on really solid epidemiological evidence

that depression is not a strong predictor

of seeking out cannabis.

It doesn’t drive terribly many people

to seek out cannabis use,

but cannabis use itself makes people four times likelier

to develop a chronic major depression.

So anxiety is increasing, depression is increasing,

and this turns out to be especially relevant,

important to young people.

Why do I say that?

Well, if you look at the data,

and again, I think some of the strongest data

are data to come out of the Canadian system.

They’ve done some really beautiful controlled studies.

I really hope to invite some of the people

who arranged and ran those studies

as guests onto the Huberman Lab podcast.

But if you look at the data out of Canada,

or you look at some of the data

out of Northern Europe and the US,

what you find is that the probability

that somebody will use cannabis

and then go on to use it chronically

correlates very strongly with age.

So for instance, some of the highest degree of cannabis use

is among individuals 16 to 24 years old.

In fact, in individuals who are 16 to 24 years old,

and in particular in students

and people who are working, surprising,

more than in unemployed populations,

being young, 16 to 24, at least to me that’s young,

and being a student or working,

doubles the likelihood that somebody

is going to use cannabis on a regular basis,

twice or more per week.

The typical age of initiating cannabis use nowadays

is about 19 years old, so 18.7.

And about 20% of people in that age bracket

of 16 to 24 years old are using cannabis daily,

either by vaping, by smoking, or by edible.

That’s an enormous number, at least by my read,

it’s an enormous number.

And here’s why it’s of really serious concern.

During the ages of 16 to 24,

the cannabinoid receptors are still available.

They are not being as strongly driven

by endogenous cannabinoids,

but by ingestion of THC and or CBD,

there are downstream effects

on the signaling within those cells

that all the data point to creating a much,

much higher likelihood of developing major depression,

severe anxiety, or psychosis at later ages.

So to be very clear,

cannabis use between the ages of 16 to 24

in both males and females is increasing anxiety,

increasing depression in the immediate years,

and within the one year’s time or so,

so much so that people are using cannabis ongoing

in an attempt to reduce that anxiety

and reduce that depression.

But in addition to that, the cannabis use,

and because of the signaling mechanisms involved,

are predisposing those individuals

to psychosis later in life.

If you look at individuals

who start using cannabis even younger,

age 14 or even as young as 12,

the probability of psychosis later in life,

in particular schizophrenic or schizophrenic-like episodes,

more than doubles.

So this is of really serious concern.

And this is completely aside

from any so-called positive effects

or beneficial effects of cannabis

that people might derive from occasional use as adults,

meaning people older than 25.

So for the person who’s older than 25,

who eats an edible every once in a while,

or who smokes cannabis every once in a while,

and people love to make the argument,

it’s not as bad as alcohol,

which frankly is a terrible argument,

because if you saw our episode on alcohol,

alcohol is pretty bad.

But even so, it’s just not a good argument.

Saying that something is good

because it’s not as bad as something else

is simply just not a good or valid argument,

at least not biologically speaking.

The use of cannabis in young populations

is very strongly predisposing people to psychotic episodes.

And we know the mechanism by which this occurs.

This occurs by a thinning of the so-called gray matter.

And it’s called gray matter

because with neurons, nerve cells,

they have a so-called cell body.

That’s the part that contains the DNA

and manufactures all the neurotransmitters, et cetera.

And those are shipped out to the other parts of the neuron

that include the axon, the wires between axons.

And those axons under the microscope,

because they have a lot of fatty tissue around them,

and this is healthy fatty tissue

that allows electrical transmission to be fast,

that fatty tissue,

those portions of the cells are called white matter.

So you have gray matter and white matter.

Gray matter are the so-called cell bodies

where the DNA and all the stuff is manufactured.

White matter are the axons or the wires

through which all the key components are shipped out

to the synapse, et cetera.

Wonderful data.

And I do say wonderful

because this is part of a large-scale consortium

and we will provide a link to the paper.

This was published in Translational Psychiatry

just this year.

Point to the fact that adolescent cannabis use

accelerates the thinning of the prefrontal cortex

and the gray matter in particular.

So what this means is while during normal development,

the gray matter, the prefrontal cortex,

and all the cells there are indeed intended,

it’s a normal process for it to thicken

and then thin a little bit as connections are adjusted

and people learn and mature and grow up.

This is part of the normal healthy maturational process,

independent of cannabis use.

When kids, because these really are kids,

use cannabis and it doesn’t matter

the mode of cannabis delivery,

whether or not it’s vaping or smoking or edible,

that gray matter thins at a much, much greater rate.

And the reason I like this paper

published in Translational Psychiatry this year so much

is that they link the amount of cannabis use,

heavy, moderate, light, or no cannabis use

to the rate of prefrontal cortical thinning.

And it’s absolutely clear from these data

that the more often young people,

meaning individuals between the age of 14 and 25,

the more often they consume or smoke or vape cannabis,

the faster and the more extreme that cortical thinning is.

And the cortical thinning is occurring

in exactly the area of the brain

that’s involved in planning,

in control over one’s emotions, in reflexes,

in organizing one’s life in a number of different ways,

anywhere from cleaning one’s room, literally,

knowing what goes where,

to making plans that extend out through the day,

through the week, through a year,

essentially becoming a functional human being

involves using your prefrontal cortex

in a variety of different contexts

and different sort of time domains,

the time domain of an hour, the time domain of a day,

making plans and being able to execute plans

is fundamental to being a healthy human being.

And it’s absolutely clear from these data

that the more cannabis one uses,

the more impaired those neural circuits are.

There’s simply no other way to view these data.

In fact, so much so that even small amounts of cannabis use

are associated with rates of cortical thinning

and degrees of cortical thinning

that are really detrimental and concerning

for normal cognitive processes.

If you were somebody who smoked marijuana

or consumed cannabis in any form or another

during adolescence,

does that mean that your prefrontal cortex

can never be rescued, that it can’t come back?

Well, the short answer is

it probably can be rescued to some degree.

It will depend on how much cannabis you were using

and how often and what strains of cannabis, et cetera.

There’s really no traveling back in time.

As my graduate advisor used to say,

time machines are broken.

At least for now, we don’t have time machines.

So all you can really do is try and emphasize,

first of all, quitting cannabis in any form

and focusing on behaviors that emphasize endothelial cell,

blood flow, health to the brain.

So that would be cardiovascular exercise,

adequate nutrition, not smoking nicotine.

And there are a number of other things that one can do.

We will do an entire episode all about trying to reverse

the effects of cannabis and other drug use

during adolescence.

We don’t have time to do a deep dive on that right now,

but all the things that standardize

and kind of promote health, adequate sleep,

good social connection, regular cardiovascular

and weight training exercise, healthy nutrition,

what that represents to you,

healthy metabolic function and weight, et cetera.

Those are all going to facilitate some recovery

of brain function in particular prefrontal cortical function

by way of all the positive effects

that those behaviors and choices have.

But with that said, if you are in the age bracket

that I’ve been referring to,

this 14 to 25 year old age bracket,

and you are a occasional even or chronic cannabis user,

you should be very, very careful and concerned

about the long-term effects that could potentially have.

That statement is bolstered by another statistic,

which is that unlike a lot of other drugs,

the rate of cannabis use is strongly related

to how dangerous people perceive cannabis to be.

And that might seem obvious on the one hand,

if you think something is very, very dangerous,

you would expect that the probability

that somebody would use it would be very, very low.

And if they think something is safe,

the probability would be high.

But that isn’t necessarily the case.

If you think about it, cannabis is a unique instance

in which nowadays we are hearing,

yes, it’s becoming legal in a number of areas.

And we talked earlier about why that’s probably

a good thing in most circumstances,

but that we aren’t just hearing that cannabis is safe,

or it’s not just being implied that cannabis is safer,

but many more people are talking

about the positive effects of cannabis

without a lot of discussion

about the negative effects of cannabis.

And I realize that saying this is going to upset

some people out there,

because I know that there are a number of people

who fought very hard for the legalization process,

and I want to acknowledge that.

I also want to acknowledge the many known positive effects

of cannabis in adults with very occasional use,

provided it is delivered safely

and in the safe context and setting and with legality.

That is entirely distinct from the issue

of whether or not cannabis is safe

for the developing brain and body.

Again, I’m not demonizing anybody for using cannabis,

but I want to make the point very simply and very directly.

It is far and away a different circumstance for the brain,

for an individual to be 25 years or older

and using cannabis in whatever form occasionally,

or maybe even frequently,

than it is for a young person aged 14 to 25

to be using cannabis, either by smoking or vaping,

or by edible or any other form on the brain and body.

It’s absolutely clear that the brain continues to develop

at least until age 25,

and that a huge number of systems

related to mood regulation, so-called executive function,

the ability to organize one’s thoughts,

plan, and execute plans,

essentially to become a functional human being,

that’s one portion of becoming a functional human being,

but certainly an essential one.

All of that relies on the fine-tuning

of this neural circuitry

that we’ve been talking about up until now.

And it’s abundantly clear

that cannabis and THC in particular

dramatically disrupt those processes.

So if this isn’t clear enough just from my statements,

I’d like to point to a particular paper.

This is one of the more impactful papers

in this area in recent years.

This is a paper published in Lancet Psychiatry in 2022.

Title is, Association of Cannabis Potency

with Mental Ill Health and Addiction, a Systematic Review.

There are a number of very important points

in this very fine paper.

Lancet Psychiatry is one of the premier

medical journals out there.

And they evaluated a huge number of studies.

They actually looked at more than 4,000 studies.

They selected the ones that were only the most rigorous

in terms of study design and analysis

and rigor of conclusions.

And they looked at how early use of cannabis

impacted later probability of development of psychosis

and other psychiatric conditions.

And the takeaways from this study are very clear.

First of all, chronic cannabis use,

so more than twice per week,

has consistently been associated

with mental health disorders.

I’m pulling some phrases directly from the paper.

Heavy cannabis use, meaning cannabis use

more frequent than twice per week,

has been associated with four times the risk of psychosis

later in life, in particular,

schizophrenia and bipolar-like episodes.

Now, we’ve done an episode on bipolar disorder,

so-called bipolar depression.

We have not yet done one on schizophrenia,

but both bipolar disorder and schizophrenia

have a very, very strong genetic component.

There’s a 30, three, zero, 30 times greater likelihood

that you’ll have bipolar disorder

if you have a first relative who has bipolar disorder.

And then it’s also the case that using cannabis,

especially during adolescence and the teen years

and up until age 25,

create a four times greater risk of psychosis

for those that have a predisposition

to bipolar disorder and or schizophrenia.

Now, I don’t hear very much about this in the media.

This paper got some attention

and then it sort of got swept away.

I don’t think that was an intentional sweeping way.

There’s just a lot of events in the world,

as you well know.

But I think it’s a particularly important set of findings

because obviously in looking at so many studies,

it distills out the strongest findings that are out there

and really pulls the consistent messages

that are arriving from all these different studies.

And as they point out, and again, I’m paraphrasing here,

this is the first systematic review

of the Association of Cannabis Potency.

And all of the data point to a very clear conclusion,

which is the more potent the THC concentration,

the higher probability of developing psychosis

or a major depressive episode

or a major anxiety disorder later in life.

That should be of particular concern

because we know, we are absolutely clear about the fact

that with the advent of all these new strains of cannabis

and with the engineering and availability of cannabis

at much higher potency, meaning THC potency,

the risk of psychosis is going up and up

and is likely to continue going up

unless something is done to reduce the frequency

of cannabis use to zero, ideally,

or to very low frequency, very low potency

in adolescents and teens and people age 25 or younger.

I know a lot of people don’t want to hear this message

because first of all, it’s alarming.

And second of all, as I mentioned earlier,

the statistics tell us that the greatest number of people

that are starting to use cannabis

are in the age bracket of 16 to 24.

Many of them are functional in other areas of life.

They are students, they are employed, et cetera.

But when you couple that with the fact

that the most frequent adopters of cannabis use

are in this age bracket of 16 to 24,

they’re twice as likely to use as other individuals

or to start using cannabis as our other individuals,

plus the general perception out there

because of the way that cannabis is discussed in the media

and by sports figures and by celebrities

and by politicians, et cetera,

that it’s not as bad as alcohol and maybe not that bad

and maybe even has health benefits,

then you’re essentially setting up a system

where young people are far more likely to adopt

and continue cannabis use without realizing

these serious health consequences that await them later.

With all of that said, I of course, again,

want to acknowledge that there have been

well-demonstrated effects of cannabis for reducing pain,

in particular in chemotherapy and in the context

of reducing nausea in people suffering

from cancer or chemotherapy.

There is a well-known effect

that one can generally point to as positive

using cannabis for things like glaucoma,

for lowering intraocular pressure

and offsetting the loss of neurons

that would lead to blindness,

although there are other tools, of course,

that don’t involve cannabis use

that can accomplish that as well.

So-called intraocular pressure lowering drugs or drops.

There is a list of probably a dozen or more psychological

and bodily ailments that can be aided by cannabis use,

in particular edible cannabis use of particular strains.

I, of course, I’m going to address each

and every one of those in episodes where I’m talking,

for instance, about eye disease or about chronic pain.

I am in no way, shape or form trying to rob

the incredible efforts of the laboratories

and people that have worked very hard to study

and establish the valid uses of cannabis

for treating various ailments

and that continue to study cannabis

in order to try and ameliorate the symptoms

of different ailments.

But today I really wanted to emphasize

the biology of cannabis.

Some of the often discussed effects,

I guess one could call them positive effects,

things like enhanced creativity,

and really point to the nuance

and actually the divergence of people who take cannabis

and some experience heightened levels of creativity

and some do not.

Some people experience heightened levels of sexual arousal

and some people experience the exact opposite

and so on and so forth.

Rather than focus on all the potential positive

and sort of emerging positive data about cannabis

in different medical contexts.

And at the same time,

I strongly feel that it’s important

to acknowledge the shocking,

because there’s really no other way to describe it,

the shocking effects of cannabis use

on the developing fetus and the fact that so many pregnant

and lactating mothers are using cannabis.

I mean, that number 15% still has me dizzy

with kind of disbelief,

and yet we need to acknowledge this

and address this immediately.

And I think it’s vital to understand that cannabis use

through any delivery mechanism,

smoking or vaping or edible or otherwise,

is very, very concerning.

In fact, dangerous to the developing brain,

certainly for the fetal brain and for the baby brain,

but also for the adolescent brain

and for the teen and young adult brain,

not just because of the effects that it can have

in the immediate term,

those slow creeping increases in anxiety and depression

brought on by cannabis use,

but also the time release, if you will,

on the development of psychosis

and other types of major psychiatric disorders

later in life.

I acknowledge we’ve covered a lot of ground today,

and yet there’s still far more ground

that we could have covered

and that we will indeed cover in future episodes.

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So once again, thank you for joining me

for today’s discussion all about cannabis.

And as always, thank you for your interest in science.