Caffeine - An Updated Series (Part II)


   By: Talayna Tremblay

   2015-09-02 04:43 PM

Caffeine - An Updated Series (Part II)

 Key Points:

  • 100% bio-availability
  • Water and fat soluble
  • Consumed either intravenously or orally (foods, drinks, capsules)
  • Antagonizes adenosine receptors in the central nervous system
  • Stimulates the central nervous system and neurotransmitter release
  • High variability in response to caffeine 
    • May depend on genetics, exogenous, or endogenous factors

 Part II

Caffeine Chemistry & Bioavailability

Molecular Structure of Caffeine 

Figure 1. The molecular structure of caffeine and adenosine.


Caffeine chemistry:

  • Chemical formula: 1, 3, 7-trimethylxanthine 5.
  • Molecular formula: C8H10N4O2 (Figure 1) 13.
  • Molecular weight is 194.1906 g/mol
  • Exact mass is 194.08036 g/mol 9.
  • Bioavailability is 100% 1

Caffeine was first isolated by chemist Friedrich Ferdinand Runge in 1819 11. Caffeine, also called methyltheobromine, guaranine, cafeina or koffein 8, is a methylxanthine 14. Caffeine is involved in metabolic reactions which include N-demethylation and oxidation to eventually produce uric acid derivatives 13. Caffeine is an organic, fat and water soluble compound 9, 4.


Methods of Caffeine Intake

Caffeine can be administered orally or through intravenous (IV) 9. As discussed in Part I of this series, there are many dietary sources of caffeine in foods and beverages, as well as isolated caffeine compounds (pills, etc.). Caffeine is absorbed within minutes through the digestive tract without being broken down 5. Peak concentrations occur between 15 and 120 minutes 11. The length of time that caffeine takes to reduce to half of it’s peak concentration in the body (halflife) varies between 3-8 hours 1. Caffeine can cross the blood-brain barrier; the concentration of caffeine in the brain has been predicted to be equivalent to the concentration in the blood 12. One study stated that after four cups of coffee, caffeine concentration in the blood and the brain can reach 60 µg12. After consuming caffeine, even though it’s absorption is nearly 100%, about 85% of caffeine is excreted in urine and does not exert an effect 13. Caffeine is considered a psychoactive drug. Urine or stomach contents can be tested for caffeine levels, but sensitivity of these tests are poor 13.


How does caffeine work and why do effects vary so widely amongst individuals?

Caffeine stimulates the central nervous system (CNS) 14. While most people enjoy greater attentiveness, increased motivation, decreased fatigue and a sense of a greater well-being from caffeine, some individuals experience adverse effects from consuming just a small cup of coffee 1, 7. These adverse effects include anxiousness, jitters/shakiness, sleep disturbances, and quite possibly a panic attack 1, 7.

Caffeine enters the blood stream and eventually the brain via absorption in the digestive tract 5.  An enzyme (protein created for a specific biochemical reaction) in the liver, called cytochrome P-450 1A2 is responsible for metabolizing caffeine 11, 14. Availability of this enzyme determines the rate at which caffeine is broken down, which relates to the variable responses to caffeine 14. The less cytochrome P-450 1A2 an individual has, the more sensitive they will be to caffeine; this translates to a greater risk for adverse effects.

A gene on chromosome 22 is responsible for the availability of cytochrome P-450 1A2, called CYP1A2; this gene varies greatly between individuals 14. Approximately 95% of caffeine demethylation (breakdown) is attributed to the CYP1A2 gene 10. Variations in this gene could be the causal determinant and explanation for the vast variation in response to caffeine. Studies on congenital twins have found correlation values for genetic influence ranging from 0.30 to 0.60; a direct correlation would be 1.0, no relationship would be 0.0 14. Deciphered, there is a moderately strong relationship between genetic factors and sensitivity to caffeine. Genetics pose a logical, valid solution for inter-individual differences in response to caffeine but there is yet to be one universal reason for the variability. There are a number of external factors that can effect an individual’s reaction to caffeine including medications (Eg. Aspirin, Benadryl, Adderall), alcohol, caffeine itself, and smoking 3, 14. Some smoking participants were found to have 1.6 times higher caffeine metabolic rate than that of non-smokers which indicates lesser sensitivity 14. Internal factors that can effect response to caffeine other than genetics included pregnancy and ethnicity 14. Asian and African populations metabolize caffeine slower than Caucasians, making Asians and Africans more sensitive 14. Furthermore, Caucasian subjects have demonstrated a higher prevalence of a certain DNA morphology (single nucleotide morphology; C—>A) which has been related to higher P-450 1A2 enzyme levels 14.

In the body, caffeine is broken down into three dimethylxanthine metabolites, paraxanthine, theobromine, and theophylline 14. Paraxanthines increase fat breakdown, increasing free fatty acid availability in the blood 11. Theobromine is a vasodilator (blood vessel dilator) and diuretic (increases urine output) 1. Theophylline is a potent bronchodilator (airway dilator) which is actually used for treatment of asthma; theophylline and caffeine are used for treatment of infant apnea 8, 11. These dimethylxanthine metabolites can be broken down further into monomethylxanthines and these are the molecules that are excreted in urine 11, 14. It is important to note that not all caffeine is broken down into it’s dimenthylxantines. Depending on the amount of enzyme present, caffeine is mainly broken down into these metabolites to exert their physiological effects, or caffeine will have an accentuated effect on the CNS directly.


What makes caffeine a stimulant?

What Makes Caffeine a Stimulant

Figure 2. Caffeine inhibits adenosine molecules from binding by blocking their target site on adenosine receptors; image provided by AsapSCIENCE.

There are ample amounts of adenosine receptors located throughout the body and brain, most are G-protein-coupled and embedded in membranes 11, 14. Adenosine is a compound composed of adenine and ribose molecules.  Adenosine causes a mild sedative effect and is also associated with control of breathing rhythm, sleeping pattern, cognitive function, and memory 5, 11. Caffeine is an adenosine receptor antagonist that competitively inhibits adenosine from it’s receptor’s binding site (caffeine is able to do this because it’s structure is quite similar to adenosine; Figure 2) 11. Caffeine, therefore, can effect all areas of the brain where these receptors are located 11.

When caffeine interacts with adenosine receptors, it promotes the release of neurotransmitters (glutamate, acetylcholine, dopamine, epinephrine/adrenaline) and calcium 14. Neurotransmitters are released from nerve cells in the brain and either have a positive or negative effect on the subsequent nerve cell. Excess dopamine (positive neurotransmitter) release is the direct cause for increased motor stimulation (greater power output, quicker reflexes, etc.) associated with caffeine intake 14. Adenosine, when its occupying it’s receptors, inhibit dopamine release from nerve cells 14. Dopamine is an important part of caffeine’s stimulant effect, even though caffeine does not directly act upon dopamine receptors, they are stimulated through the nervous system 14. Alterations in adenosine receptors or in associated neurotransmitters can cause differences in response to caffeine and effect tolerance. Alterations in the adenosine receptors could be causal for a negative response in some individuals 14. For example, a person who regularly consumes caffeine will increase the amount of adenosine receptors in their brain, which in turn, effect response to caffeine. Research suggests, the way that adenosine receptors morph, can increase the risk for caffeine induced anxiety and has also been associated with panic disorders 14.


Bottom Line

In summary, caffeine is both water and fat soluble, and can cross the blood-brain barrier. Caffeine is 100% bio-available for the body to use. Caffeine primarily effects neuron transmission in the brain by antagonizing AR’s. Adenosine receptors, when adenosine occupies it’s binding site, mediates neuron activity, controls release of neurotransmitters, and provides a mild sedative effect 5. Therefore, caffeine blocks this sedating effect associated with adenosine and causes an increase in brain activity and alertness 5. This is, fundamentally, what makes caffeine a stimulant 5. This simple explanation also offers logic in describing how withdrawal symptom of extreme fatigue occurs with cessation of habitual caffeine ingestion 5. The secondary effect of caffeine is the release of neurotransmitters. These neurotransmitters are responsible for mood elevation and motor stimulation.

These biochemical effects of caffeine are the mechanics behind the magic of some of the world’s most popular drinks, coffee and tea, so enjoy your AR antagonism and reap the alerting and mood elevating neurotransmitter effects; ’til next time, cheers. 

If you are still feeling confused about how caffeine effects the brain, watch the full caffeine video by AsapScience for clarification:



  1. Dagger, S. R., Layton, M. E., Strauss, W., Richards, T. L., Heide, A., . . . & Posse, S. (1999). Human brain metabolic response to caffeine and the effects of tolerance. The American Journal of Psychiatry, 156(2), 229-237.
  2. Ding, M., Bhupathiraju, S. N., Satija, A., van Dam, R. M., & Hu, F. B. (2014). Long-term coffee consumption and risk of cardiovascular disease. Circulation, 129, 643-659. 
  3. (2015). Caffeine drug interactions. Retrieved from: caffeine.html
  4. Fredholm, B. B.Battig, K., Holmen, J., Nehlig, A., & Zvartau, E. E. (1999). Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews, 51(1), 83-133. Retrieved from:
  5. Frey, R. J. (2012). Caffeine related disorders. The Gale Encyclopedia of Mental Health, 3(2). Detroit: Gale.
  6. Liggins, J. T. P (2009). The roles of dopamine d1 and d2 receptors in working memory function. McGill Science Undergrad Research Journal, 4(1), 39-45.
  7. Meeusen, R., Roelands, B., & Spriet, L. L. (2013). Limits of human endurance: Caffeine, exercise and the brain. Oxford: Nestle Nutrition Institute Workshop Series.
  8. Mueni, E., Opiyo, N., & English, M. (2009). Caffeine for the management of apnea in preterm infants.  International Health, 1(2), 190-195.
  9. National Center for Biotechnology Information (2015). Caffeine. Retrieved from:
  10. Renda, G., Zimarino, M., Antonucci, I., Tatasciore, A., Ruggieri, B., . . . & Caterina, R. (2012). Genetic determinants of blood pressure responses to caffeine drinking. The American Journal of Clinical Nutrition, 95(1), 241-248.
  11. Ribeiro, J. A. & Sebastiao, A. M. (2010). Caffeine and adenosine. Journal of Alzheimer’s Disease, 20, S3-S15.
  12. Vyleta, N. P. & Smith, S. M. (2008). Fast inhibition of glutamate-activated currents by caffeine. Plos One, 3(9), e3155.
  13. World Health Organization (2013). Basic analytical toxicology. Retrieved from:
  14. Yang, A., Palmer, A. A., & Wit, H. (2010). Genetics of caffeine consumption and responses to caffeine. Psychopharmacology, 211, 245-257.

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