– How does caffeine work
to make us feel more alert? And does the timing in
which we ingest caffeine play an important role in whether or not it works
for us or against us? So maybe we just start with,
how does caffeine work? Why is it that when I
drink mate or coffee, which are my preferred
sources of caffeine, do I feel a mental and physical lift? – Yeah, so I'm going to suggest, counter to what most people
would think, drink coffee. – Or mate, is mate okay also? – Yeah, yeah, yeah.
– Or whatever form you enjoy. – We'll come onto sort
of why I suggest that, but when it comes to coffee, I would say the dose and
the timing makes the poison.
So let's start with how caffeine works. Caffeine is in a class of drugs that we call the psychoactive stimulants. So it works through a
variety of mechanisms. One is a dopamine mechanism, dopamine we often think
of as a reward chemical. But dopamine is also very much an alerting neurochemical as well. And caffeine has some role it seems, to play in increasing dopamine. But its principal mode
of action, we believe, in terms of making me more alert and keeping me awake throughout the day, is on the effects of adenosine. And to explain what adenosine is, from the moment that you
and I woke up this morning, this chemical adenosine has
been building up in our brain. And the longer that we're awake, the more of that adenosine accumulates. – Where is this adenosine coming from and where is it accumulating? – Yeah, so the adenosine
here that we're talking about that is creating the sleep pressure is a central brain phenomenon. And it comes from the neurons
themselves combusting energy. And as they're combusting energy, one of the offshoots of that
is this chemical adenosine.
And so, as we're awake throughout the day and our brain is
metabolically very active, it's accumulating and
building up this adenosine. Now, the more adenosine that we have, the sleepier that we will feel. So it really is like, a sleep
pressure is what we call it. Now, it's not a mechanical pressure, don't worry, your head's
not going to explode, it's a chemical pressure. And it's this weight of sleepiness that we feel gradually growing
as we get into the evening. – May I just interrupt
you again to just ask, do we know what the circuit
mechanism is for that? I mean, not to go too
far down the rabbit hole, but for the aficionados and for myself, we have brain mechanisms
like locus coeruleus that release things, our brain areas, locus coeruleus just being
a brain area, of course, that release things that
proactively create wakefulness. So are those neurons shutting
down as a consequence of having too much adenosine
or are there areas of the brain that promote sleepiness
that are becoming activated? Because you can imagine both
things working in parallel, one or the other would
accomplish the same end point.
– Yeah, and it's both. And so there are two main
receptors for adenosine, the A1 receptor and the A2 receptor, and they have different modes
of activating brain cells or inactivating or decreasing
the likelihood of firing. And adenosine works in
this beautiful, elegant way where it will inhibit and shut down the wake promoting areas of the brain whilst also increasing
in dialing up the volume on sleep activating,
sleep promoting brain- – Biology's so beautiful. – Oh, it's fantastic.
– It's always a push-pull.
So this is another example
where as I am awake longer, adenosine is released in the brain and my wakefulness areas
are being actively shut down by that adenosine and my
sleepiness brain areas, so to speak, are being
promoted to be more active, is that correct? – That's right, and it's a
very progressive process. It's not like a step function where, and sometimes that happens occasionally, but it's usually because you've
been sort of driving through and as we'll come on to,
have caffeine in the system, and then all of a sudden
you just hit a wall and it just engulfs you
and you go from a zero to a one of sleepiness within
a short period of time. Caffeine comes into play here because caffeine comes into your system and it latches onto those
welcome sites of adenosine, the adenosine receptors.
But what it doesn't do is latch
onto them and activate them because if it was doing
that, then it would, in lots of ways, it would dial
up more sort of sleepiness. It does the opposite. The way that caffeine
works is that it comes in, competes with quite sharp
elbows with adenosine, competitively forces them out of the way, hijacks that receptor by latching onto it, but then just essentially blocks it. It doesn't inactivate the receptor, it doesn't activate the receptor. It functionally
inactivates it in the sense that it takes it out of
the game for adenosine. So it's like someone coming into a room and you're just about
to sit down on the chair and caffeine comes in and
just pulls out the chair and you're like, well, now
I've got nowhere to sit. And caffeine just keeps
pulling out the chairs from adenosine, and adenosine, even though
it's at the same concentration in your brain, your brain doesn't know that you've been awake
for 10 hours, 16 hours, at that point when you've
downed a cup of coffee, because all of that
adenosine that's still there can't communicate to the brain that you've been awake for 16 hours.
– But the adenosine is
still in brain circulation. – Correct. – So the real question is, what happens when caffeine is dislodged from the adenosine receptor? – Unfortunate things happen, and that's what we call
the caffeine crash, which is caffeine has a
half-life and it's metabolized. – Do you recall what the half-life is? – Yeah, the half-life is somewhere between five to six hours. And the quarter-life therefore is somewhere between 10 to 12 hours. It's variable, different
people have different durations of its action. But for the average
adult, five to six hours. That variation, we understand,
it's down to a liver enzyme or a set of liver enzymes
of the class that we call the cytochrome P450 enzymes. And there are, I think,
last I delved into the data, which is pretty recently, there are two gene variants that will dictate the enzymatic speed with which the liver breaks down caffeine. And that's why you can have some people who are very sensitive to caffeine and other people who say, you know, it just doesn't affect me
really that much at all.
– These are the people
that have a double espresso after a 9:00 PM dinner
and can sleep just fine. – Well, and we'll come on to- – Or at least, subjectively, they think they're sleeping just fine. – Subjectively, yeah, and
we should speak about that, that assumptive danger too. So then the caffeine is in the system and after some time period, it will be inactive in the system. So let's say that I've
been awake for 12 hours now and it's 8:00 PM and
I'm feeling a bit tired, but I want to push through and I want to keep working
for another couple of hours. So I have a cup of coffee.
All of a sudden, I was feeling tired, but I don't feel like I've
been awake for 12 hours anymore because with the caffeine in the system, may be only half of that
adenosine is being communicated through the receptor to my brain. 100% of the adenosine is still there, only half of it is allowed
to communicate to my brain. So now I think, oh, I haven't
been awake for 12 hours, I've just being awake for
six hours, and feel great. Then, after a few hours and the caffeine is starting
to come out of my system, not only am I hit with the
same levels of adenosine that I had before I'd
had the cup of coffee several hours ago, it's that, plus all of the
adenosine that's been building up during the time that the
caffeine has been in my system.
– So it's sort of an
avalanche of adenosine. – It is a tsunami wave, yeah,
and that's the caffeine crash. – And it's interesting
because the caffeine crash at two o'clock in the afternoon
when you have work to do is a terrible thing, but
what about the person, maybe this person is me in my 20s, who says, I'm going to
drink caffeine all day long, and then I want the crash
because at 9:00 or 10:00 PM, if I stop drinking caffeine
at say, 6:00 PM, and I crash, then I crash into a slumber,
a deep night of sleep.
Is that sleep really as
deep as I think it is because given the half-life of caffeine that you mentioned a few moments ago, I have to imagine that
having some of that caffeine circulating in my system might
disrupt the depth of sleep or somehow the architecture
of sleep in a way, that even if I get eight or who knows, even 10 hours of sleep, it might not be as restorative
as I would like it to be. – Yeah, and that is the danger. Just sort of that, those
people that you described, who say, and a lot of them
will speak with me too, say, look, I can have
two espressos with dinner and I fall asleep fine, and I stay asleep because usually those
are the two phenotypes that we typically see
with too much caffeine.
I just can't fall asleep
as easily as I want to, or I fall asleep, but I
just can't stay asleep, and caffeine can do both of
those things quite potently. – How late in the day do you
think is, assuming somebody, translate this folks, if you
go to bed earlier or later, you have to shift the hours accordingly. But given somebody who
typically gets into bed around 10:00, 10:30, and falls
asleep around 11:00, 11:30, when would you recommend
they halt caffeine intake? And these are not strict prescriptives, but I think people do benefit from having some fairly clear guidelines
of what might work for them.
Would you say cutoff caffeine
by, what time of the day? – I would usually say
take your typical bedtime and count back sort of
somewhere between 10 to, eight hours is probably
getting a little bit close, but take back sort of 10
hours or eight hours of time, that's the time when
you should really stop using caffeine is the suggestion. And the reason is because for those people who even just keep drinking
up until into the evening, you're right that they
can fall asleep fine, maybe they stay asleep, but the depth of their deep
sleep is not as deep anymore. And so there are two consequences. The first is that for me,
and it can be up to by 30%. And for me to drop your deep sleep by 30%, I'd have to age you by
between 10 to 12 years, or you can just do it
every night to yourself with a couple of espressos.
The second is that you then
wake up the next morning and you think, well, I didn't
have problems falling asleep and I didn't have problems staying asleep, but I don't feel particularly
restored by my sleep. So now I'm reaching for
three or four cups of coffee the next morning, rather than just two or
three cups of coffee, and so goes this dependency cycle that you then need your uppers to wake you up in the morning. And then sometimes people will
use alcohol in the evening to bring them down because
they're overly caffeinated. And alcohol, and we can
speak about that too, also has very deleterious
impacts on your sleep as well. [light guitar music].
