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Why your caffeine doesn't always pack the same punch

Posted on January 10 2018

Ben Esgro, MS, RD, CSCS


The pre-workout and energy category of sports nutrition continues to be a top earner, only to be bested by protein supplements.  This is no surprise, because, well, stimulants feel great…That is, when they give you the feeling you expect from them.


This week, we are going to discuss the most common stimulant in your morning joe and pre-workout; caffeine.  Here is what we will cover:


  • How caffeine works.
  • Why it may not always feel the same even if you take the same dose.
  • How can you improve the efficacy of your coffee or pre-workout.




Remember The Magic School Bus?  I sure hope so, because this week we are going to imagine we are shrinking down and taking it through the blood stream.  Hooray for childhood nostalgia mixed with pharmacology!


Now, let’s imagine we can take the shape of any molecule we want with our school bus.  So, we are going to transform it into the structure of caffeine to determine how it interacts with our cells as it travels throughout our body.  For reference, the chemical formula for caffeine is shown below.


Figure 1  Chemical formula of caffeine


Okay, maybe it looks more like an alien space ship than a school bus, but let’s embrace our individuality.  What is most important to us here are the projections coming off the rings of our “bus”.  Those are called functional groups, and, as the name implies, they are very important for the behavior and interaction of compounds.  Just like projections coming off a bus would bump into a lot of things on the highway, the projections off compounds do the same in our internal highways (blood vessels) and cells.  Put simply, for a compound to produce a response you can feel, it must have specific interactions with specific proteins in the body.  To use some examples we know and love, a compound fitting a protein (receptor) is like a baseball being cradled in the netting of a glove, or a key specifically interacting with a lock.  The more specifically they interact, the more distinct the response.


Since they are of vital importance, let’s reiterate those two points.


  1. The specific three-dimensional shape of a compound determines how it will interact once inside the body.
  2. The specific protein (receptor) it interacts with will determine what you feel in response to consuming that compound.


Many natural products like caffeine exert their effects by mimicking the compounds that naturally float around in our blood and influence our conscious states such as feeling tired, energetic, happy, sad, motivated, attentive, anxious, etc…  For the case of caffeine, this mimicry is of the compound adenosine, which naturally floats around in our blood and accumulates in cells throughout the day, producing the sensation of fatigue.


Let’s take the opportunity to connect a few important dots here to highlight the beautiful harmony that is the human body.  If the name adenosine sounds familiar it is for good reason.  Adenosine is an integral part of ATP (Adenosine Triphosphate), commonly referred to as the “fuel of cells”.  When ATP is broken down during the day to fuel cellular activity throughout the body, it also produces some free adenosine.  This adenosine then functions as a signal of fuel reserves in the body, the greater the accumulation the greater the fatigue signal to your brain that rest is needed.


So, using caffeine and adenosine as our examples, we can now give life to the concept of functional groups discussed previously.  The reason caffeine works in the body to produce its anti-fatigue effects is that it’s innate structure and functional groups allow it to interact stronger with the adenosine receptors than adenosine itself.  Caffeine is literally allowing you to play tricks on your brain by preventing adenosine from interacting with its receptors!  In pharmacology this concept is called competitive antagonism.



Figure 2 Through simple geometry, can you note the similarities between adenosine (left) and caffeine (right)?  Now note the subtle differences in projections off the rings.  They are the magic of your “energizing” caffeine!




These are admittedly my favorite part of the formulation Fridays because now that we have gotten through the heavy stuff, we can discuss the practical applications to be smarter supplement users.


We now know that adenosine is constantly accumulating at receptors during wakeful activity throughout the day and this causes fatigue.  We also know caffeine is a compound which can counteract this short term.  But there is a missing piece to the puzzle.  Why don’t we always feel the same kick from caffeine and how does the body deal with accumulated adenosine?  The answer to both questions is tied to one thing, sleep!


While you are sleeping, less ATP is consumed so less adenosine is produced.  This also means more adenosine can be broken down by enzymes and it can be cleared from receptors.  So, what can you do about your problem of erratic response to caffeine?  Make sure you are getting enough sleep!  If you chronically under sleep, you never clear adenosine adequately, so you will always have some lingering fatigue.  Then, even if you take caffeine, it cannot do anything for the adenosine which has already accumulated.  So, through sleep deprivation, you are not allowing caffeine and other stimulants to properly work.


We often rely upon supplements or drugs to magically wake us up when we are sleep deprived, over-worked, or over-stressed.  So, I suppose the lesson here is we may be able to trick the body short term, but we can’t long term.  Aside from the benefit of maintaining a healthy range of caffeine intake, getting enough sleep is something we can all likely benefit more from both in and out of the gym.




  1. Caffeine mimics and competes with the natural neuromodulator adenosine to produce its effects in the body.
  2. Functional groups are essential to drug and supplement action.
  3. If you want your caffeine (and all stimulants) to work best, you need to ensure you are getting adequate sleep!




  1. Council for Responsible Nutrition, The CRN Consumer Survey on Dietary Supplements: 2014. 2014:
  2. Nehlig, A., J.L. Daval, and G. Debry, Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev, 1992. 17(2): p. 139-70.
  3. McGill Publishers, Molecules That Build Up and Make You Sleep, in The Brain From Top to Bottom.


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