CAFFEINE & THE SCIENCE

Caffeine is the most widely used central nervous system (CNS) stimulant in the world (1, 2). It's found in many different food and beverage items including teas, coffees, chocolates, energy drinks, and of course in the form of caffeine pills for those moments you need caffeine straight to the face. But what is caffeine? Well, without getting too complicated, caffeine is a methylxanthine, specifically, 1,3,7-tri-methylxanthine. If you pronounced that correctly in your head, I'm proud of you. Just know it looks like this:

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Synthetic and natural forms of caffeine are biochemically indistinguishable so for this conversation we aren't going to discuss whether the caffeine your drinking came from green coffee extract, guarana, or some dude in a lab coat.

How does it work?

We drink it, some gets absorbed in the mouth, the rest gets absorbed in our small intestine, then water carries it around to tissue. Caffeine is readily absorbed with 99% being absorbed within ~45 minutes of ingestion and has a half-life of ~6 hours. Simply put, all 'half-life' means is the amount of time it takes for the chemical in question to be out of your system. It begins getting broken down primarily in the liver into its three metabolites which are dimethylxanthines: paraxanthine, theophylline, and theobromine (**). These various metabolites have different physiological functions in the body—all of which work synergistically to provide us with the pleasurable experience of caffeine. It acts in three ways:

1. CNS stimulation (CNS)

2. Metabolic stimulation (MET)

3. Direct muscle stimulation (MUSC).

Let's review:

• Caffeine acts as an adenosine receptor antagonist (**). Adenosine is a neurotransmitter (our body's chemical messengers) that's responsible for helping manage our sleep-wake cycle by means of sleep induction. Basically, adenosine builds up while we're awake, so the longer we're awake, the more adenosine we have built up, the more tired we get. When we consume caffeine it blocks adenosine from binding to the adenosine receptors which, in turn, keeps us from feeling sleepy. Think of this like musical chairs: there's one chair left, caffeine and adenosine are the only two in the game, music stops and caffeine sits down first—we all win cause caffeine rocks. Through the same mechanism of adenosine receptor antagonism, caffeine stimulates the secretion of other neurotransmitters such as dopamine, norepinephrine, serotonin, acetylcholine, glutamate, and GABA--all of which enhance cognitive function (**).
• Paraxanthine is the predominate metabolite of caffeine making up ~80% of the concentration of metabolites (**). Paraxanthine provides the bulk of ergogenic effects of caffeine by increasing blood flow, mitochondrial respiration, and muscle contractility through potentiating the production and release of nitric oxide (**). Paraxanthine also increases cAMP levels by inhibiting phosphodiesterase enzymes* (PDEs) in skeletal muscle and adipose tissue. This promotes lipolysis via the activation of hormone-sensitive lipase. I know that's a lot to take in. All that jargon is saying: caffeine is fat burning.
• Theobromine is a less abundant metabolite. It functions very similar to caffeine as an adenosine receptor antagonist though Its effects are less significant than caffeine—it has one-fifth the effect. Theobromine is also fat soluble and therefore takes ~2-3 hours to be absorbed, and has a half-life much greater than caffeine lasting up to 12 hours (**).
• Theophylline is one of the most widely prescribed drugs for the treatment of asthma and COPD. And it's just chilling in coffee. Nature's crazy. Though structurally similar to the others, theophylline has a unique mechanism of action acting as a potent bronchodilator (**) due to its ability to relax smooth muscle cells in our airways. The mechanism has not been fully elucidated.

How to supplement

​So the first question is, does it need to be supplemented? Well, that question can be answered easily about all supplements. No. You can do just fine without caffeine. Buuuuut we want to dominate our goals and aspirations, right? Caffeine is just the thing to help us do that.

Benefits of supplementation

There's a long list of benefits of caffeine—some of which were elucidated in the previous section, but now I want to discuss it's function as an ergogenic aid specifically. In summary, supplementing caffeine has been shown to:

1. Increase force production (increased Calcium Ion mobilization availability - MUSC)
2. Enhance muscle contractility (Na+/K+ pump activation - MUSC)
3. Reduce RPE (rate of perceived exertion - CNS)
4. Reduce muscle pain (CNS)
5. Improve mood (CNS)
6. Increase glycogen sparing (MET)
7. Enhance glycogen re-synthesis (MET)

This all sounds great, but if you're not asking yourself, "to what degree does it do all of these things? And to what degree does that have an effect?" then we're looking at research wrong. Which leads me to our next point of analysis: Is it worth it?

Yes. The impact of caffeine is significant. As we've now discussed, many of the physiological impacts result from caffeine's action on adenosine receptors as an antagonist. When caffeine non-selectively binds these receptors, the action of adenosine is blocked, not dampened (15). This results in significant impacts via central nervous system (CNS) stimulation. For the other two mechanisms—action on fatty acid oxidation and direct action on skeletal muscle—the dose can change the level of impact of caffeine to an extent. 

How much and when

Given that the literature is clear on the ergogenic effect of caffeine, organizations such as the National College Athletic Association (NCAA) and International Olympic Committee (IOC), have put limitatiosn on the amount of caffeine allowed in competitors system during competition. The maximum dose allowed is ~800mg (**). Interestingly, the ergogenic of effects have been shown to occur at doses much less with the average being 400-600mg and the lowest being 250mg (depending on weight of the individual). For dosing, a good rule of thumb is 3-6mg/kg body weight (**). 

Caffeine can be taken either before of during your workout depending on what benefit you're looking for. With caffeines fast absorption rate—into the blood 20 min after consumption and 90% absorbed after 45 min—and its half-life being ~5-6 hours, there's a decent sized window to reap the benefits. Some researchers have tested dosing through exercise i.e. Cox et al. (**) reported a small 3% improvement in time trial performance that followed 2 h of exercise at 70% V˙ O2max for trained cyclists regardless of whether 6 mg·kg1 of caffeine was ingested in a single dose before or divided into six equal doses and administered at 20-min intervals throughout the 2 h of exercise. Basically this study showed that it doesn't matter either way.

Additional note: The enzyme cytochrome P450 1A2 is responsible for 95% of all caffeine metabolism, including the demethylation of caffeine to paraxanthine [44]. Individuals with a homogenous A allele of the CYP1A2 gene tend to produce more cytochrome P450 and consequently metabolize caffeine more quickly [45]. But now we're getting to deep. All this means is our genetics play a huge role in caffeine metabolism and the effect that it will have on us. Which is a perfect segue into side effects.

Side Effects

Caffeine is great. But as Paracelsus said,“All things are poison and nothing is without poison; only the dose makes a thing not a poison.” Usually boiled down to "the does makes the poison." How much we take will determine what experience we have with the chemical in question. Many people can experience headaches, irritability, anxiety, insomnia, etc. But this is something that each person needs to determine themselves. Start on the lower side of the recommended 3-6mg/kg body weight and adjust from there. 

The LD50 (amount that will kill you) is 150-200mg/kg body weight which for me would mean drinking 44 Bang energy drinks (**). In all reality that wouldn't be possible because I could never consume that much liquid. So if you're worried about overdoing caffeine by drinking it, you're good. Withdrawal systems can be pretty gnarly and if fact at the time of writing this, I am 21 days sober of caffeine. Fun little challenge a few friends and I took on. I didn't think I would survive the first couple days given the monstrous headaches, feelings of nausea, and severe lack of energy. After a few days I felt much better. The worst part now is my occasional decaf coffee. It's like dirt water. 

Summary

Now to put this all into one paragraph:

Caffeine is a plant alkaloid so it's ~natural~ for all those who enjoy that label. It's a methylxanthine with three major metabolites: paraxanthine, theobromine, and theophylline. Think of it like caffeine is the mom and paraxanthine, theobromine, and theophylline are the kids. These three compounds work synergistically in different capacities to bring you the benefits of caffeine—feeling awesome. Caffeine acts in three ways: 1. CNS stimulation 2. metabolic stimulation 3. direct muscle stimulation. The predominate mechanism of action is as an adenosine receptor antagonist which just means it blocks adenosine from functioning. Think of it like taking a pain killer: you get a headache, you take Ibuprofen, Ibuprofen inhibits the COX2 pathway which keeps you from feeling pain. Simple. You should take about 3-6 mg per kg of bodyweight (kg = your weight in pounds divided by 2.205) before or during your workout. The exact right dose varies person to person, so dabble in this range and find what makes you feel good. If you give yourself a full blown anxiety attack, scale back just a bit.

Pro-tip: I don't just share this one with anybody. Caffeine takes ~20 mins to get absorbed by the GI and start taking effect. If you're ever down bad (cramming for an exam, need to lift but don't want to, went out the night before brunch with the parents). I've come up with what I call 'Caffeine naps®'. This is where you chug your favorite caffeinated beverage then immediately lay down and take a 20 minute power nap. You get to rest your eyes and then wake up right as the caffeine is starting to work it's magic. You'll feel like a new person.

References

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