23 August 2013

Caffeine: The science of why we’re all hooked


Until it has been secured, that first cup of coffee is, for many of us, the highest priority of the day. Despite many theories, and many more studies, the exact mechanisms by which caffeine energizes our minds and bodies are still far from understood. With new discoveries in genetics, and new methods to quantify metabolic activity, the incidentals of coffee consumption can now be counted as more than ritual — they have become science.

If your weekend involves taking the GRE exam, a cross-country running competition, and perhaps a prom thrown in for good measure, your caffeination curve may be something you don’t want to leave to serendipity. The situation is becoming even more acute as several competitive sports have even introduced limits to caffeine intake, as measured in the urine despite ambiguity in correlating those levels to consumption. Not long ago, ExtremeTech analyzed an app which estimates the concentration of caffeine in your blood and presumes to help you optimize your caffeine intake. The app is based on the activity of one the cytochrome p450 enzymes, CYP1A2. While the efficiency of this enzyme varies considerably from person to person, companies like 23andMe can now tell you exactly which version of the enzyme you have, and therefore whether you are a fast or slow metabolizer of caffeine.


The full picture of caffeine metabolism is a bit more complex. We all have six different CYP proteins which each serve different functions. In turn, these enzymes are all regulated at control points which can now also be quantified genetically. Several transducer proteins, including dopamine and adenosine receptors, are directly controlled by caffeine, and are at least in part responsible for its effects. Which particular version (called an isoform), you happen to have can be a good predictor of how caffeine and other drugs may affect you physiologically and behaviorally. Individuals who are susceptible to caffeine-induced anxiety have been shown to posses certain unique polymorphisms, or single point variations, in the genes for these particular receptors.

Caffeine eventually gets broken into several metabolites which themselves contribute to many of the downstream effects caused by ingestion of the primary molecule. When uncertainty in concentration of the original source of caffeine (if your source is coffee) is compounded with all the uncertainty in how it is metabolized, you really can’t get a good picture of what is going on other than how you might feel. So what you really want to be able to do is quantify it in the blood.

Caffeine levels in the blood are fairly tough to get a handle on. Measuring these levels in the human brain or muscle are just not practical today. A technique known as microdialysis has been used to directly sample levels in animals, but such studies are only of limited value. In the urine or other liquids like a soft drinks, caffeine concentration can be measured by running samples on a liquid chromatograph, or it can be extracted and subjected to UV spectroscopy.

What makes caffeine unique…

For more caustic liquids, like hot coffee, attempts have been made to create a dipstick that uses, of all things, heat-resistant antibodies raised against caffeine by injecting protein-bound forms of it into camels and llamas. For quantification in a complicated medium like the bloodstream, the immediate prospects are slim. One way to try to do it would be to create an antibody linked to a fluorescent reporter protein that could then be detected in a repurposed glucometer type instrument.

What is so special about caffeine?

All lot of different molecules would give you a buzz of some kind if they got past your blood brain barrier and into your brain. Indeed one of the most striking aspects of the familiar buzz is its similarity regardless of the particular chemical that initially induced it. What we interpret as a buzz might just as well be said to be a transient mismatch in what the brain expects to be feeling based on its recent spiking activity, and what it really is feeling as a result of the chemical alteration. What makes caffeine such a smooth operator is that it exposes three fat-soluble methyl groups on its surface which allow it to slip through cell membranes and quickly access all parts of the body. The CYP1A2 enzymes chop these guys off which not only keeps caffeine out of cells but also marks them for excretion.

Most coffee consumers have unfortunately slipped into a Red Queen’s race where the equilibrium curve for novel experience, so to speak, has been squeezed far too tight. Normal vigor and clarity of purpose arrives only after laboriously saturating the system to the point where the input-output dynamics briefly cease domination of the interesting effects. In other words, when you require more than a few cups of coffee to just to begin to feel a buzz, the drain on your tub has jammed in the open position and the water runs out nearly as fast as you can pipe it in.

What we really could use is a ritualized surrogate, a socially-copacetic methadone, to aid our release us from this devil’s deal every once in a while. While caffeine probably increases the overall need for sleep more than it relieves it, its provisioning for instantaneous, on-demand control of our internal state ensures its continued appeal. It is quite possible that caffeine is about as good as you can get, theoretically or otherwise, as far as a single molecule non-destructively interacting to positive effect at the level of the mind. If that is the case than we should make every effort to get all that we can out of it.

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