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)
