Tag Archives: caffeine

Caffeine and the Brain: Part 2

Did you miss Caffeine and the Brain: Part 1? Read it HERE.

In Caffeine and the Brain: Part 1, we looked at how caffeine has become a universal habit and why it can be detrimental to achieving maximal health. We discussed the egregious consumption of a pesticide and stimulant, but how exactly does caffeine work, scientifically, once it gets inside our brain? It acts as a central nervous system stimulant,1 by binding to adenosine receptor sites, blocking adenosine from doing its job.2

Adenosine is an inhibitory neurotransmitter, which normally helps the body relax.3 This explains why caffeine causes sleep issues4 and alertness when sleep-deprived.5 Caffeine molecules are stopping adenosine from doing its job.6

However, your body is smart, and is a big believer in a thing called “homeostasis,” meaning it likes to keep things the same.7 So when you start drinking large amounts of caffeine8 your body makes more of these adenosine receptor sites, and you need more caffeine to block them, since you feel caffeine’s effects via blocking a large majority of these receptors.9, 10

Caffeine is a vasoconstrictor, narrowing blood vessels, and decreases blood flow, and sometimes used in pain relief medications.11 By blocking adenosine from doing its job, caffeine also increases respiratory rate.12 However, caffeine ingestion promotes neurotransmitter release (acetylcholine, monoamines, etc.) which is how it does its job, as a stimulant.13 Meanwhile, dopamine and glutamate are released in the nucleus accumbens (your brain’s pleasure center).14

When following a Paleo Diet and lifestyle, look to the scientific basis behind leaving caffeine out. It’s better to rely on your body’s own natural energy stores. Natural sleep and wake cycles are ideal, and help your body function optimally.15 This isn’t possible when you are drinking lots of caffeine.16

And, as most of you already likely know, caffeine also causes cortisol to be released.17 Your body thinks some kind of emergency is happening, and it wants to prepare you. Humans need extremely huge doses of caffeine in order for it to become toxic.18 However, other animals are not nearly as tolerant (hence its original use as a pesticide).19 Below is the effect seen on a spider, that has ingested caffeine.20

Interestingly, caffeine is legal and unregulated, which is not at all the case for basically every other psychoactive drug in the world.21 In fact, Dr. William Dement, professor from Stanford University, posits if caffeine were introduced today, it would not be made legal.22 The addictive nature and withdrawal effects are well-documented23 among the sleep, stimulant, and biochemical effects.24

Noever, R., J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity. NASA Tech Briefs 19(4):82. Published in New Scientist magazine, 29 April 1995.

Noever, R., J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity. NASA Tech Briefs 19(4):82. Published in New Scientist magazine, 29 April 1995.


Thorn Caroline F, Aklillu Eleni, McDonagh Ellen M, Klein Teri E, Altman Russ B. “PharmGKB summary: caffeine pathway” Pharmacogenetics and genomics (2012).


Genetically, caffeine has a stronger effect on some individuals, compared to others.25 Humans with at least one C variant of CYP1A2, a gene, react less favorably to caffeine, and metabolize it slower.26 This could possibly explain the difference between you, and your friend who goes off the rails on just one cup of espresso.

Besides this scientific evidence, caffeine depletes magnesium stores, causing many effects downstream.27 These effects can be exhibited as: poor sleep, muscle cramps and chronic pain.28 About 50% of people in the United States are deficient in magnesium, whether due to too much caffeine, or not enough magnesium consumption to begin with, though it’s likely both.29

Caffeine, if consumed, is best kept at the ‘therapeutic’ dose, of 100-200mg per day.30 Incorporating caffeine into your Paleo Diet isn’t advisable, however, if you’re looking to maximize its effects. If looking to minimize your pesticide load, organic coffee is more ideal, and green tea offers L-theanine, which has a calming effect on the brain, along with lower amounts of caffeine, compared with coffee.31, 32

Lastly, let us not forget that the most beneficial beverage of all…water! A Paleo Diet should be hydrating, and keep your cells happy! Raise your glass (or bottle) to good health!


1. Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev. 1992;17(2):139-70.

2. Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004;61(7-8):857-72.

3. Ribeiro JA. Purinergic inhibition of neurotransmitter release in the central nervous system. Pharmacol Toxicol. 1995;77(5):299-305.

4. Snel J, Lorist MM. Effects of caffeine on sleep and cognition. Prog Brain Res. 2011;190:105-17.

5. Daniello A, Fievisohn E, Gregory TS. Modeling the effects of caffeine on the sleep/ wake cycle. Biomed Sci Instrum. 2012;48:73-80.

6. Ribeiro JA, Sebastião AM. Caffeine and adenosine. J Alzheimers Dis. 2010;20 Suppl 1:S3-15.

7. Houseknecht KL, Portocarrero CP. Leptin and its receptors: regulators of whole-body energy homeostasis. Domest Anim Endocrinol. 1998;15(6):457-75.

8. Pallarés JG, Fernández-elías VE, Ortega JF, Muñoz G, Muñoz-guerra J, Mora-rodríguez R. Neuromuscular responses to incremental caffeine doses: performance and side effects. Med Sci Sports Exerc. 2013;45(11):2184-92.

9. Kaplan GB, Greenblatt DJ, Ehrenberg BL, et al. Dose-dependent pharmacokinetics and psychomotor effects of caffeine in humans. J Clin Pharmacol. 1997;37(8):693-703.

10. Holtzman SG, Mante S, Minneman KP. Role of adenosine receptors in caffeine tolerance. J Pharmacol Exp Ther. 1991;256(1):62-8.

11. Dager SR, Layton ME, Strauss W, et al. Human brain metabolic response to caffeine and the effects of tolerance. Am J Psychiatry. 1999;156(2):229-37.

12. Barry RJ, Clarke AR, Johnstone SJ, Rushby JA. Timing of caffeine’s impact on autonomic and central nervous system measures: clarification of arousal effects. Biol Psychol. 2008;77(3):304-16.

13. Rossi S, De chiara V, Musella A, et al. Effects of caffeine on striatal neurotransmission: focus on cannabinoid CB1 receptors. Mol Nutr Food Res. 2010;54(4):525-31.

14. Solinas M, Ferré S, You ZB, Karcz-kubicha M, Popoli P, Goldberg SR. Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci. 2002;22(15):6321-4.

15. Krystal AD. How the circadian rhythm affects sleep, wakefulness, and overall health: background for understanding shift work disorder. J Clin Psychiatry. 2012;73(2):e05.

16. Sherman H, Gutman R, Chapnik N, Meylan J, Le coutre J, Froy O. Caffeine alters circadian rhythms and expression of disease and metabolic markers. Int J Biochem Cell Biol. 2011;43(5):829-38.

17. Lovallo WR, Whitsett TL, Al’absi M, Sung BH, Vincent AS, Wilson MF. Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels. Psychosom Med. 2005;67(5):734-9.

18. Kerrigan S, Lindsey T. Fatal caffeine overdose: two case reports. Forensic Sci Int. 2005;153(1):67-9.

19. Bonati M, Jiritano L, Bortolotti A, et al. Caffeine distribution in acute toxic response among inbred mice. Toxicol Lett. 1985;29(1):25-31.

20. Witt PN. Drugs alter web-building of spiders: a review and evaluation. Behav Sci. 1971;16(1):98-113.

21. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks–a growing problem. Drug Alcohol Depend. 2009;99(1-3):1-10.

22. Dement, W. and Vaughan, C. (1999). The promise of sleep. 1st ed. New York: Delacorte Press.

23. Griffiths RR, Chausmer AL. Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement. Nihon Shinkei Seishin Yakurigaku Zasshi. 2000;20(5):223-31.

24. Smith JE, Lawrence AD, Diukova A, Wise RG, Rogers PJ. Storm in a coffee cup: caffeine modifies brain activation to social signals of threat. Soc Cogn Affect Neurosci. 2012;7(7):831-40.

25. Cornelis MC, Byrne EM, Esko T, et al. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Mol Psychiatry. 2014;

26. Available at: //www.pharmgkb.org/pathway/PA165884757. Accessed October 15, 2014.

27. Kynast-gales SA, Massey LK. Effect of caffeine on circadian excretion of urinary calcium and magnesium. J Am Coll Nutr. 1994;13(5):467-72.

28. Johnson S. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses. 2001;56(2):163-70.

29. Al-ghamdi SM, Cameron EC, Sutton RA. Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis. 1994;24(5):737-52.

30. Jenkins NT, Trilk JL, Singhal A, O’connor PJ, Cureton KJ. Ergogenic effects of low doses of caffeine on cycling performance. Int J Sport Nutr Exerc Metab. 2008;18(3):328-42.

31. Cabrera C, Artacho R, Giménez R. Beneficial effects of green tea–a review. J Am Coll Nutr. 2006;25(2):79-99.

32. Chacko SM, Thambi PT, Kuttan R, Nishigaki I. Beneficial effects of green tea: a literature review. Chin Med. 2010;5:13.

Caffeine and the Brain: Part 1

Before switching to a Paleo Diet, many of us drank coffee on a regular basis.1 If not coffee, maybe an energy drink, espresso, or a diet or regular soda.2, 3 All of these beverages have one thing in common: caffeine. Caffeine is the world’s most popular psychoactive drug.4 Though a small amount (about 10%) of humans do not consume any of the stimulant, worldwide consumption is enough to make the average caffeine intake equivalent to about one drink, per person, per day.5, 6 With over 7 billion people in the world – that’s a LOT of caffeine.7

Caffeine is derived from plants, and acts as a pesticide.8, 9, 10 If that’s not disturbing enough, it’s also one of the most heavily sprayed crops, pesticide-wise, in the world.11, 12, 13, 14, 15, However, while pesticides can be destroyed in the roasting process, I would argue that anything sprayed heavily with pesticides, is not something worth consuming. Still feel comfortable nursing that cup next to you? Below, is a pest which burrows into and lays its eggs in coffee berries. It has genetically adapted from bacteria (via lateral gene transfer) which enables it to continue to invade coffee crops.16

Proc Natl Acad Sci U S A. Mar 13, 2012; 109(11): 4197–4202. Published online Feb 27, 2012.

Proc Natl Acad Sci U S A. Mar 13, 2012; 109(11): 4197–4202.
Published online Feb 27, 2012.

Since caffeine is so widely consumed, it is in the public’s interest to know exactly it is doing to your brain.17 Caffeine, chemically, is a member of the xanthine and alkaloid family.18 Other members of these families include cocaine, nicotine, morphine, psilocin, and codeine, to name but a few.19 Starting to second-guess that cup of coffee yet?

Caffeine, unfortunately, is one of the elements of “fast food America,” along with processed foods, added sugar, and television.20 A Paleo Diet is superior to this widespread way of living, in every single category.21 By taking time to savor your food, eating foods which make you healthier, and avoiding stimulants, you’ll maximize your own potential to be healthy.


Caffeine synthase and related methyltransferases in plants. Frontiers In Bioscience, Landmark, 9, 1833-1842, May 1, 2004

Here, we see the biosynthesis of caffeine. What we ultimately must understand from this process, is that theobromine is an important precursor to caffeine.22 Besides caffeine, theobromine itself has been studied to be the other psychopharmacologically active element in another, as-yet unnamed, caffeine-containing substance – chocolate.23 Beyond the psychopharmacological effects of theobromine, it also has been shown to be the main constituent that we come to crave when we eat chocolate.24 The other? Caffeine itself.

Caffeine Figure 3

Nutrients. Jan 2014; 6(1): 319–341.
Published online Jan 10, 2014.

Since we are all composed of different genetic and molecular material, our brains respond to caffeine differently.25, 26 In these diagrams, we see how different regions of the brain are affected and impacted by merely the sight of chocolate, which contains caffeine and theobromine.27 Some will immediately have activity in brain regions such as the pregenual cingulate cortex and medial orbitofrontal cortex.28 Others, will not.

Since chocolate is a multivariate compound, we must look at pure caffeine, to see what its effects are on your brain. Perhaps most alarmingly, caffeine restricts blood flow to the brain, by about 25%.29 This is not good. In the below two images, we can see the effects of reduced blood flow, graphically, in those who drink caffeine, and also the increase in blood flow, in those who are going through caffeine withdrawal.

Caffeine Figure 4

Hum Brain Mapp. Author manuscript; available in PMC Oct 1, 2010. Published in final edited form as:
Hum Brain Mapp. Oct 2009; 30(10): 3102–3114.

 Hum Brain Mapp. Author manuscript; available in PMC Oct 1, 2010. Published in final edited form as: Hum Brain Mapp. Oct 2009; 30(10): 3102–3114.

Hum Brain Mapp. Author manuscript; available in PMC Oct 1, 2010. Published in final edited form as:
Hum Brain Mapp. Oct 2009; 30(10): 3102–3114.

Besides these disturbing effects (cerebral blood flow is most definitely something you want more of, not less of), caffeine disrupts the ends of our DNA, causing aging.30 This process happens via telomeres, which normally protect the chromosome ends from degradation. Another suspect on this list? Alcohol, which shouldn’t be a surprise.31

A Paleo Diet removes these common vices, and instead offers healthy fats, nutrient-rich foods, and choices that help make you healthier. By taking time to savor your food, eating foods which make you healthier, and avoiding stimulants, you can reap the plethora of benefits offered by a Paleo lifestyle!


1. Gilbert RM. Caffeine consumption. Prog Clin Biol Res. 1984;158:185-213.

2. Heckman MA, Weil J, Gonzalez de mejia E. Caffeine (1, 3, 7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci. 2010;75(3):R77-87.

3. Persad LA. Energy drinks and the neurophysiological impact of caffeine. Front Neurosci. 2011;5:116.

4. Daly JW, Holmén J, Fredholm BB. [Is caffeine addictive? The most widely used psychoactive substance in the world affects same parts of the brain as cocaine]. Lakartidningen. 1998;95(51-52):5878-83.

5. Lovett R. Coffee: The demon drink? New Scientist. 2005;24:2518–2522.

6. Available at: //www.washingtontimes.com/news/2012/jan/17/amp-up-america/. Accessed October 15, 2014.

7. Available at: //www.worldometers.info/world-population/. Accessed October 15, 2014.

8. Uefuji H, Tatsumi Y, Morimoto M, Kaothien-nakayama P, Ogita S, Sano H. Caffeine production in tobacco plants by simultaneous expression of three coffee N-methyltrasferases and its potential as a pest repellant. Plant Mol Biol. 2005;59(2):221-7.

9. Nathanson JA. Caffeine and related methylxanthines: possible naturally occurring pesticides. Science. 1984;226(4671):184-7.

10. Hollingsworth RG, Armstrong JW, Campbell E. Caffeine as a repellent for slugs and snails. Nature. 2002;417(6892):915-6.

11. Ngowi AV, Maeda DN, Partanen TJ, Sanga MP, Mbise G. Acute health effects of organophosphorus pesticides on Tanzanian small-scale coffee growers. J Expo Anal Environ Epidemiol. 2001;11(4):335-9.

12. Available at: //www.csmonitor.com/World/Americas/2010/0103/Organic-coffee-Why-Latin-America-s-farmers-are-abandoning-it. Accessed October 15, 2014.

13. Acuña R, Padilla BE, Flórez-ramos CP, et al. Adaptive horizontal transfer of a bacterial gene to an invasive insect pest of coffee. Proc Natl Acad Sci USA. 2012;109(11):4197-202.

14. Sakamoto K, Nishizawa H, Manabe N. Behavior of pesticides in coffee beans during the roasting process. Shokuhin Eiseigaku Zasshi. 2012;53(5):233-6.

15. Cetinkaya M, Von düszeln J, Thiemann W, Silwar R. [Organochlorine pesticide residues in raw and roasted coffee and their degradation during the roasting process]. Z Lebensm Unters Forsch. 1984;179(1):5-8.

16. Ioannidis P, Lu Y, Kumar N, et al. Rapid transcriptome sequencing of an invasive pest, the brown marmorated stink bug Halyomorpha halys. BMC Genomics. 2014;15:738.

17. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. 1999;51(1):83-133.

18. Schimpl FC, Kiyota E, Mayer JL, Gonçalves JF, Da silva JF, Mazzafera P. Molecular and biochemical characterization of caffeine synthase and purine alkaloid concentration in guarana fruit. Phytochemistry. 2014;105:25-36.

19. Available at: //www.britannica.com/EBchecked/topic/15672/alkaloid. Accessed October 15, 2014.

20. Pereira MA, Kartashov AI, Ebbeling CB, et al. Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet. 2005;365(9453):36-42.

21. Mellberg C, Sandberg S, Ryberg M, et al. Long-term effects of a Palaeolithic-type diet in obese postmenopausal women: a 2-year randomized trial. Eur J Clin Nutr. 2014;68(3):350-7.

22. Judelson DA, Preston AG, Miller DL, Muñoz CX, Kellogg MD, Lieberman HR. Effects of theobromine and caffeine on mood and vigilance. J Clin Psychopharmacol. 2013;33(4):499-506.

23. Smit HJ, Gaffan EA, Rogers PJ. Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology (Berl). 2004;176(3-4):412-9.

24. Smit HJ, Blackburn RJ. Reinforcing effects of caffeine and theobromine as found in chocolate. Psychopharmacology (Berl). 2005;181(1):101-6.

25. Dager SR, Layton ME, Strauss W, et al. Human brain metabolic response to caffeine and the effects of tolerance. Am J Psychiatry. 1999;156(2):229-37.

26. Cornelis MC, Byrne EM, Esko T, et al. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Mol Psychiatry. 2014;

27. Asmaro D, Liotti M. High-caloric and chocolate stimuli processing in healthy humans: an integration of functional imaging and electrophysiological findings. Nutrients. 2014;6(1):319-41.

28. Rolls ET, Mccabe C. Enhanced affective brain representations of chocolate in cravers vs. non-cravers. Eur J Neurosci. 2007;26(4):1067-76.

29. Addicott MA, Yang LL, Peiffer AM, et al. The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?. Hum Brain Mapp. 2009;30(10):3102-14.

30. Romano GH, Harari Y, Yehuda T, et al. Environmental stresses disrupt telomere length homeostasis. PLoS Genet. 2013;9(9):e1003721.

31. Strandberg TE, Strandberg AY, Saijonmaa O, Tilvis RS, Pitkälä KH, Fyhrquist F. Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki Businessmen Study. Eur J Epidemiol. 2012;27(10):815-22.

Caffiene | The Paleo Diet

Many people who switch to The Paleo Diet often find themselves questioning their ritual morning cup of coffee. With roughly 90% of the North American population consuming coffee on a daily basis you’re left wondering if coffee is an acceptable drink to include in your Paleo menu.

What is Coffee?

Coffee is created by brewing the roasted seed or “bean” of one of the numerous species of Coffee trees (coffea). The trees tend to thrive in high elevation, tropical climates with fertile soil. Because the tree can often grow up to 30 feet in height, it is typically pruned at much shorter heights to ensure an easy harvest. The majority of the world’s coffee producers originate from countries located near the equator.

What Effect Does Coffee Have on the Human Body?

Caffeine is the main stimulant found in coffee. The consumption stimulates the central nervous system in humans and tends to ward off drowsiness. It also tends to act as a diuretic. Many heavy coffee drinkers report that their morning cup of Joe no longer gives them the same burst of energy that they experienced when they first developed their habit. In fact, many habitual coffee drinkers report suffering from sleep disturbances, headaches, and general “sluggish” behavior. This is often due to the fact that long term consumption has an exhaustion effect on the adrenal glands. It also hinders insulin sensitivity, which can lead to fatigue and headaches.

Should Coffee be a Part of a The Paleo Diet?

Coffee should be excluded by anyone seeking to achieve the most out of their Paleo lifestyle. The Paleo Diet focuses on eating nutrient dense, naturally occurring, anti-inflammatory foods that promote overall wellness and sustained levels of energy. Many people who switch to The Paleo Diet discover that their morning cup of black gold becomes a habit of the past. If you find yourself having a hard time quitting the coffee ritual, it might be helpful to incorporate moderate amounts of green tea which is slightly higher in antioxidants, and contains lower levels of caffeine.


Loren Cordain, Ph.D., Professor Emeritus

Affiliates and Credentials