Beyond a few cups of green tea, I tend to get a bit anxious. But despite how caffeine affects my individual biochemistry, I find its widespread use fascinating. Besides a unique pharmacology, caffeine has many benefits. It’s energizing. It can help aid in focus, cognition, fat loss, and athletic performance. Most of all, tasty beverages everywhere contain caffeine! Cautiously eager singles even use caffeine consumption as an excuse to go out on dates. I admit: I’ve used the line myself. Eyes glued to the ground (in an attempt to not stare at her breasts), I’d utter the magic words, “So you wanna go get a cup of coffee sometime?” Responses to this technique have varied.

So while it might not improve your game, understanding caffeine pharmacology is important. Due to its social acceptability and mass consumption, the finer points of caffeine’s effects on human biochemistry are often taken for granted. To remedy this, Chemically Correct: Caffeine Part I will give you the run down.

Chemistry

Caffeine (1,3,7-trimethylxanthine) is a member of the xanthine family. Xanthines are found naturally throughout the plant and animal kingdoms. Xanthine itself is a part of human metabolism. Other naturally occurring xanthines include theobromine (found in chocolate) and theophylline (found in plants and isolated as a drug for asthma).

Xanthines are a part of the purine family. Purines such as adenine and guanine make up the base pairs of DNA. Despite the resemblance of caffeine to aspects of our DNA, xanthines don’t get mixed up in our genetic code. Rather, they are a product of purine degradation. The enzyme xanthine oxidase efficiently metabolizes xanthines

Pharmacokinetics

Caffeine is 99% orally bioavailable. Levels tend to peak within 30-60 minutes, passing through all biological membranes including the blood brain barrier (36). The half-life is around 5 hours. 80% of caffeine is metabolized to paraxanthine by CYP1A2 (37). A small percentage is converted to theophylline. Both of these metabolites are pharmacologically active and have similar half-lives to caffeine (38). Only 5% of ingested caffeine remains unchanged, the majority being excreted as 1-methyluric acid (39).

For the same amount of caffeine ingested, plasma levels can vary by a factor of 15.9 between individuals (40). This could explain differences in individual sensitivity to caffeine.

Despite variations in human absorption and metabolism, a useful estimation is that 10mg/kg of caffeine in the rat equals out to about 250mg of caffeine in a 70kg human (1).

Pharmacology

Several direct pharmacological effects have been ascribed to caffeine. These include adenosine receptor antagonism, release of intracellular calcium, phosphodiesterase inhibition, and GABA(A) receptor antagonism. The fact of the matter is that with the exception of adenosine antagonism, all of these effects occur at dosages that would be toxic to humans (1). Thus, only antagonism of adenosine receptors is regarded as relevant. It is possible that caffeine has other unknown mechanisms. And some phenotypes using higher dosages might be more vulnerable than others to caffeine’s “upper limit” effects such as phosphodiesterase inhibition. However, this article will concentrate on pharmacologic effects related to adenosine antagonism.

Adenosine and Adenosine Receptors

Adenosine. You’ve heard of it before. It’s the “A” in ATP. Since adenosine is a main component of THE energy substrate, it should come as no surprise that adenosine receptors concern themselves with functions like sleep, CNS stimulation, and metabolism.

When lots of ATP is being consumed and not much being produced, adenosine levels rise. This would most likely occur during exercise or prolonged wakefulness. Adenosine accumulates the longer we’ve been awake, and returns to normal during sleep (2).

Stimulation or antagonism of adenosine receptors indirectly affects other neurotransmitter systems. This is similar to the way nicotine utilizes acetylcholine receptors to induce dopaminergic and serotonergic effects. There are 4 types of adenosine receptors: A1, A2A, A2B, and A3. It appears that normal adenosine levels as well as human caffeine consumption only affect A1 and A2A receptors (1). The A1 receptor when agonized produces a sedative effect through the inhibition of neurotransmitter release. This inhibition is specific, as the A1 receptor will inhibit stimulatory neurotransmitters more than inhibitory ones like GABA (3). A2A receptors are relevant to dopamine function. They are concentrated in dopamine rich regions of the brain and are co-localized with D2 receptors (4), which brings us to our discussion of caffeine and dopamine.