Translator: Rhonda Jacobs Reviewer: Tanya Cushman
So, I've been asked to talk about demystifying the endocannabinoid system.
So, I started working on the pharmacology of endocannabinoids over 20 years ago,
and I had done my PhD, and then I'd done a couple of postdocs,
and then I actually had a five-year career break when I had my two children.
And I then found myself back in the lab
and in the lab of one of the world experts on cannabinoid pharmacology.
And at that time, the field of cannabinoid research
was really a relatively small group of people, scientists,
and it was not a particularly fashionable research area.
People didn't take us particularly seriously.
I think they thought we were kind of having some fun in the lab
in psychedelic lab coats or tie-dyed T-shirts, some altar piece,
but actually it's a really serious group of people
who'd been working really hard to understand the endocannabinoid system.
But now fast forward to 2019,
and everyone's interested in endocannabinoids,
and everyone's interested in how cannabis works.
So it's kind of like if you keep those old clothes that you love
and you're passionate about it for long enough,
they will come back into fashion.
(Laughter)
So let's start, as a kind of introduction,
by looking at how clever our brains and bodies actually are.
So our bodies, our emotions and our physical responses
are designed to respond to our environment.
So things change in our environment, internally or externally -
there are chemical changes,
and that initiates a change in our emotions or our responses.
And an example of this you probably all have heard of
is called the fight-or-flight response.
So what happens is something frightening happens, there's a danger,
we produce adrenaline;
it's rushing through our bloodstream, or noradrenaline,
and that causes us to either fight that dangerous thing
or to fly away and escape.
So how does this work?
So deep in your brain, your amygdala senses fear and danger,
and it sends signals to other parts of your brain and body,
and then adrenaline's produced,
and that's the little chemical structure of adrenaline there.
It then courses through your bloodstream -
that's in your muscles, your digestive system,
all sorts of things;
you're poised to fight or to fly,
and your heart rate also increases.
So let's look at the pharmacology underlying some of that.
So the adrenaline,
we think of in pharmacology a bit like a key.
And the adrenaline receptor, the adrenergic receptor,
is a bit like a lock.
So the key of adrenaline fits perfectly into this little lock.
So that's kind of background there.
So what about the endocannabinoid system?
So the endocannabinoid system, similarly,
is part of your body that is designed to respond to your environment,
either internally or externally around you,
and to then initiate various changes in response to that.
So let's do a little myth busting, first of all,
around the endocannabinoid system.
It exists throughout life,
so we're actually born with an endocannabinoid system,
and it's there before we're born.
And for example, it's very important in brain development,
in something called synaptogenesis, which is the formation of synapses,
and these are the little electrical connections in your brain
that allow neurotransmitters to send information.
It's also involved in what's called synaptic pruning,
which is the other scenario,
where actually some synapses that might be superfluous or extra
are actually pruned away.
So these are two really important functions.
The endocannabinoid system is there
in people who've never even heard of cannabis.
So if you've lived a life or in a community
where cannabis isn't a thing,
you still have a wonderful, functional endocannabinoid system.
And importantly,
the endocannabinoid system helps us understand how cannabis works.
But cannabis is not the reason why the endocannabinoid system exists.
So how does it work?
Let's have a look at the endocannabinoid system in a little more detail.
So here's the endocannabinoids - there's two of these -
and these are produced in your brain and different tissues at specific times.
This is the little chemical structure of one of them.
The endocannabinoids act on CB, cannabinoid receptors -
there's two of these: CB1 and CB2.
These are found in your brain and in different tissues
in order to respond to endocannabinoids.
When the endocannabinoids bind to these, you get a response.
So the same lock and key scenario:
the endocannabinoids are like the key,
and then the receptor is the lock that unlocks these downstream responses.
So why do we make endocannabinoids and when?
So as I said, they're really important in this responding to our environment.
And we make endocannabinoids in response to all sorts of different things,
specifically, at the right time and the right place.
So here are some examples.
When we're hungry - you might be feeling a little bit hungry now, maybe not yet,
but when you are or you start thinking about food,
your endocannabinoids and your hypothalamus will start to go up.
Exercise, when you're feeling stressed, pain, depending on the time of day,
your endocannabinoid levels are increasing in specific parts of your body and brain.
So what do they do?
They do lots of different things, and here are some examples.
They're involved, as I said, in appetite stimulation.
They're involved in de-stressing, so reducing stress and anxiety.
They're involved in pain relieving mechanisms,
so they go up in specific parts of the brain in response to pain.
So you can see here that it's very, very important in balancing things out.
So you've got an increase in stress, the endocannabinoids de-stress.
You've got an increase in pain,
the endocannabinoids produce pain-relieving effects.
Fun fact: they're also very much increased in response to singing.
So we did some singing earlier,
and endocannabinoids actually go up 42 percent in response to singing,
and also dancing,
so these are two other key mediators of the endocannabinoid system.
So I'd like to propose to you today that the endocannabinoid system is clever.
And one of the examples we can use is stress.
So in response to stress, we produce endocannabinoids,
and they produce a reduction in stress.
So here we've got a stressful event happening,
like, for example, giving a TED Talk
(Laughter)
or your toddler having a meltdown in the supermarket
or an exam or a deadline.
And so what happens,
you get an increase in stress hormone cortisol in your bloodstream.
And also you get an increase of endocannabinoids in response to that.
And very cleverly, the system actually learns from stresses.
So in response to the same stressful event a second or a third time,
you can see there in blue,
the endocannabinoid levels are actually increasing even further,
and with the third event, it's going up even higher,
so they're learning from this stressful event.
And the levels of cortisol are actually being reduced.
So you've got this de-stressor that's learning cleverly
from repeated stressful events.
And another example of how the system is really clever
is memory formation.
So in response to various events in life, we form memories,
and the endocannabinoids are really involved in that
in the most quite incredible way.
So in various parts of your brain,
endocannabinoids are released to help with memory formation.
And for example, in your hippocampus -
it's a part of your brain with lots of endocannabinoids
and endocannabinoid receptors.
So what happens is the endocannabinoids help the formation of helpful memories;
they're involved in your working memory,
like remembering dates and names and lists.
But quite remarkably, they actually help prevent the formation
of what we call emotionally aversive memories,
so things that may be traumatic.
So they prevent the consolidation and retrieval
of emotionally aversive memories.
So they really integrate the memory formation system
so that we have just enough emotional memories
that are healthy and helpful,
and also help with our working memory.
So, what about cannabis?
So, how does it fit into all of this?
So cannabis contains two primary constituents
called cannabidiol - CBD, and THC.
So today, I'm really just going to talk about THC.
For CBD, it really could be the subject of another entire TED Talk.
I'll just remain to say that for CBD,
we still have lots of questions about how it works -
its mechanism of action -
whether it works in certain illnesses,
and we have questions around its safety.
But for THC, we understand a bit more about how it works.
So again, we've got this lock and key scenario.
So THC actually acts as an alternative key for the endocannabinoid receptor,
so it fits into the lock, as it were, of the endocannabinoid receptor.
And what it does when it binds to that receptor
is it either mimics the endocannabinoid system
or it disrupts the endocannabinoid system.
Now, we could ask the question, How can this be?
How can we have something in a plant
that actually is an alternative key for a receptor in our brain?
How did this happen?
So if you imagine in your back garden you have a pile of a billion keys.
If you were to try all those keys,
there's a probability you'd find one that might fit into your back door,
and you could give that key to someone to get into your house.
And in fact, the plant kingdom
contains many, many millions and millions of little molecules.
This is the structure of THC here.
And THC is actually only one of over 100 cannabinoid-like molecules in cannabis,
and that's only one plant.
So it's a matter of probability
that in plants, there are these little molecules that actually fit into receptors
that we already have in our brains and in our bodies.
There are many examples of this.
For example, morphine is found in poppies.
It fits in perfectly to opioid receptors,
which are normally occupied by enkephalins and endorphins
in our bodies.
And clearly that example illustrates
that because something's natural and found in plants
doesn't necessarily mean that it's always safe.
So what does THC do to the endocannabinoid system?
So we've got this endocannabinoid system; it's balancing things out,
it's responding to stress and making memories.
What happens when THC's there?
You've now got two potential keys for the same lock.
So the endocannabinoid system -
another very clever thing about it which applies to most biological systems
is it's very tightly controlled and designed not to be overactivated.
If it gets overactivated,
that can be really harmful and become dysfunctional.
So it's designed to downregulate when it thinks it's active.
So when THC's on board, the system downregulates.
So what happens is you get lower levels of endocannabinoids;
they start to kind of switch off or level off.
And you actually get fewer of the endocannabinoid receptors.
So what this means is that, as you may know,
that often people need to start taking - may take higher levels of THC
in order to have the same effect as they had before
because of this downregulation happening.
So let's have a quick look at coping mechanisms.
So in response to stress,
there are a certain proportion of people who would take THC or cannabis
in order to help manage stress.
That might have a de-stressing effect and it might not.
In some people it can cause anxiety, but it might have a de-stressing effect.
What does this do to your endocannabinoid system?
So what happens is your endocannabinoid system's actually been downregulated now.
So in response to stress,
it's kind of like scratching its head a little bit in response to stress
because there's fewer endocannabinoids -
the spot for endocannabinoid's kind of occupied by THC.
So your system's not really learning from the stressful event.
So rather than kind of learning adaptive coping mechanisms
in response to stress,
like, for example, exercise that might harness your endocannabinoid system,
this spot's kind of being occupied by THC.
A certain proportion of people who use cannabis containing THC
might develop what's called a dependence.
And that means they actually want to stop using it.
It might be affecting their life in some way negatively -
they want to stop, but they're finding it hard to stop,
and that's called a dependence.
And the reason for that is THC's kind of occupying this spot
where the endocannabinoids were there.
If THC's not there, the endocannabinoids aren't there either,
so that can cause a certain amount of dependence sometimes.
So, we've got the endocannabinoid system.
You've got an environmental effect, like a stressor, like giving a TED Talk -
you've got stress.
And you've got the endocannabinoids being released in a certain part of your brain
to help de-stress things.
THC on the other hand, contained in cannabis,
isn't responding to the environment,
and it has multiple effects at once.
So your cannabinoid receptors are found in many different brain regions
and different places in your body.
So THC will activate multiple things at once.
It may de-stress.
It does affect memory and cognition in various ways -
it can impair short-term working memory.
It may make people sleepy.
It may affect motivation, increase appetite.
It can also be a bit unpredictable, so some people may feel happy or high,
but some people can feel anxious with THC, particularly with higher doses.
Some people may - with high doses of THC, there's a risk of an acute psychosis.
And it can potentially increase the risk of schizophrenia
in individuals who may be vulnerable.
So it can be a bit unpredictable depending on the dose
and depending on the individual.
So, to kind of wrap this up.
Endocannabinoids are not equal to THC.
So what we've got here
is the endocannabinoids are produced at the right time in the right place;
they're very precisely controlled;
they're responsive to the environment.
THC, on the other hand, has multiple effects all at once;
it's not precise;
it's not responding to your environment;
and it may downregulate the endocannabinoid system.
Now all that said, THC and cannabis,
also CBD,
may relieve some symptoms of certain illnesses.
But there's still a lot we need to know about potential side effects.
And what might happen is it may relieve symptoms acutely,
so over the short term,
but it may make illnesses worse over the longer term.
So these are questions we still need to answer.
Scientists are also working at making new medicines
that target the endocannabinoid system,
so potentially things that can actually upregulate the levels of endocannabinoids
at a specific place and time.
So, finishing with this cartoon -
I'm a scientist, so lots of research is still needed.
This is the chocolate co-op company.
And on the board we've got
"The conclusion is that eating chocolate will make you look younger and thinner."
And the supervisor there, saying, "Look, half the work's done.
All you need to do is fill in the top part and we can legally say the bottom part."
So actually what we need is we need more data.
We need to understand any potential harms of recreational cannabis.
We need to understand more about the efficacy and the safety
of medical cannabis for various different illnesses.
Thank you.
(Applause) (Cheers)