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. - Whatever form you enjoy. - We'll come on to 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 principle 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, 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 then coming 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 and dialing up the volume on sleep-activating, sleep-promoting regions. - Biology is 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, you know, engulfs you and you go from a zero to the 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, you know, 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, you know, 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, you know, 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 because- - 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 was 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, I'm just, it doesn't affect me really that much at all. - These are the people that have a double espresso after a 9 p.m. dinner and can sleep just fine.

- Well, and we'll come on to-- - Or at least subjectively, they think they're sleeping. - 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, you know, I've been awake for 12 hours now and it's, you know, 8 p.m.

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, maybe 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 been awake for six hours, I 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 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 nine or 10 p.m., if I stop drinking caffeine at say 6 p.m.

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 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, 10, 30 and falls asleep around 11, 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 cut off 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, you know, using caffeine is the suggestion. And the reason is because for those people who even just keep drinking up until, you know, 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.

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