Currently, I’m normal. I know what you’re thinking, John…you’re far from normal, you only have 5 pairs of shirts, you wake up at 4:30 am, and read research for fun…nerd alert! Well, I’m at least normal when it comes to caffeine consumption, at the moment. I consume ~3 cups of coffee a day, ~200 mg of caffeine a day, the American average. However, I alter my caffeine intake a lot and discuss it constantly, especially with my wife. I discuss it so much, I had it in my wedding vowels, appreciating her ear during times of self-debate on the topic! This self-debate results in me altering my consumption a lot, sometimes completely removing it and sometimes taking caffeine pills…I know sounds crazy, Mad Mullen alert!
Enough about me, now to caffeine, the most consumed drug in the world. This long piece will discuss the sources of caffeine, the differences in caffeine between various types of caffeinated beverages, the effects of caffeine and what is the result of caffeine withdrawal?
Sources of Caffeine
Natural Sources (FDA)
- Cocoa (Theobroma cacao), a major ingredient in chocolate products, contains a small amount of caffeine. Cocoa’s weak stimulant effect may also be due to a combination of the theobromine and theophylline it contains, as well as caffeine. The amounts of these compounds contained in chocolate products are too small for typical servings to create effects equal to those of coffee. Chocolate bars (in a typical 28-g serving) contain from 11 to 115 mg of caffeine.
- Coffee beans (Coffea sp.) from which coffee are brewed constitute the primary source of caffeine. The caffeine content in coffee varies widely, depending on the type of coffee bean and the method of preparation; even beans from a given coffee bush can vary in their caffeine concentration. Roasted coffee beans contain 0.8–2.5% caffeine. Generally, dark-roast coffee has less caffeine than lighter roasts because the roasting process reduces the bean’s caffeine content. Arabica coffee normally contains less caffeine than the Robusta variety. In general, one serving of coffee ranges from 64 mg for a single cup (30 ml) of espresso to about 145 mg for an 8-oz. ounce cup (237 ml) of automatic drip coffee.
- Guarana (Paullina cupana), grown in South America, typically contains more caffeine than coffee beans (2-4.5% vs. 5%). In addition, guarana contains other stimulants such as theobromine and theophylline.
- Kola nuts or Cola (Cola nitida) from trees in African rainforests also contains caffeine. Kola was once used in making cola soft drinks, but artificial flavorings are now generally used. Caffeine content ranges between 2 to 3.5%; also contains theobromine at 1.)-2.5% concentration. Some new energy drinks contain Kola nut extract (see the discussion below).
- Tea (Camellia sinensis) fresh leaves contain about 4% caffeine. Tea beverages typically contain about 20 to 80 mg of caffeine per cup—about half the caffeine per serving of coffee. Black tea’s caffeine content is higher than that of most other teas. Preparation affects brewed tea’s caffeine content, although the color of brewed tea is not a good indicator of the amount of caffeine in the tea; for example, the Japanese green tea Gyokuro, a pale tea, contains much more caffeine than do dark teas like Lapsang Souchong, which has very little.
- Taurine a functional food ingredient added to many energy drinks and energy products as a caffeine adjuvant. Caffeine and taurine are dissimilar. Whereas caffeine is a stimulant, taurine is an amino acid produced naturally by the body. Taurine supports neurological development and helps regulate blood constituents; it may also be an antioxidant.
- Yerba maté (Ilex paraguariensis) contains xanthenes—stimulants in the same family as caffeine, theophylline, and theobromine, all of which found in coffee and chocolate. Yerba maté’s caffeine content ranges from 0.3wt% to 1.7wt% dry. In addition it contains theobromine at 0.3-0.9% level. Although yerba maté products are sometimes marketed as “caffeine-free” alternatives to coffee and tea, such claims are based on assuming that “mateine”—the primary active xanthine in maté —is a caffeine stereoisomer. That is a chemical impossibility, however; in fact, chemical databases treat “mateine” as a caffeine synonym.
- Caffeine is commonly added to soft drinks—typically, from 30 to 40 mg of caffeine per 12 oz. (355 ml) serving. The caffeine in these drinks originates either from the ingredients used or is an additive derived from the decaffeination of coffee or from chemical synthesis.
- Energy drinks, with added caffeine, vitamins, taurine, guarana, kola nut, Yerba maté and herbal supplements, are sold to improve drinkers’ performance and alertness. The additional ingredients may act in synergy to provide a stimulant effect greater than
that provided by caffeine without them. In contrast to typical soft drinks, some contain as much as 200 mg of caffeine per 12 fl. oz. (355 ml) serving. In addition many energy drink brands are sold in larger serving size containers (16-20 fl. oz. – 474-592 ml).
- Energy shots are a specialized kind of energy drink. Whereas most energy drinks are generally sold in 12 to 16 fluid oz. cans or bottles, energy shots are usually sold in 2 fluid oz. plastic bottles. Energy shots normally contain the same amount of caffeine, or other functional ingredients per container as their larger counterpart, and therefore they may be considered concentrated forms of energy drinks accounting for 11 percent of the energy drink market. As of June 2009, there are approximately 250 energy shot brands in the US, with Chaser 5-Hour Energy owning 78% of the market share. Energy shots are the fastest-growing part of the energy drink category and are stealing the momentum from their bigger – in package size – rivals. A niche is emerging within the energy shot space called micro shots. These are shots with 1-5 teaspoons of liquid.
- Caffeinated alcoholic beverages are energy drink mixes with alcohol. Prior to 2008 over 40 products were marketed in the U.S. Various consumer groups complained that caffeine a stimulant reduced the drinkers’ sense of intoxication and were marketed to young drinkers who were already more likely to have risky behavior in driving and other activities. In November 2009 The Food and Drug Administration notified manufacturers of caffeinated alcoholic beverages that they would have 30 days to prove “clear evidence of safety,” or this product line would have to be taken off the market. At the time of preparation of this report it is unknown how many of these products are still sold. However, the leading brands Miller/Coors’ Sparks and Anhaeuser Busch’s Tilt that previously contained caffeine and guarana presently sold without any caffeinated ingredient.
Volume of Caffeine in Products
Caffeine Effects and Withdrawal
Caffeine has a half life of around 4-6 hours in the human body. Withdrawal symptoms typically begin around 12-24 hours after abrupt caffeine abstinence. Caffeine withdrawal symptoms have been shown to reach peak intensity between 20 and 51 hours after abstinence and tend to last between 2 to 9 days. However, the possibility of withdrawal headaches have been suggested to occur up to 21 days after abstinence.
Individuals experiencing significant symptoms following cessation of caffeine intake consume more than 129 mg caffeine daily. A typical withdrawal period begins within the first 6 to 24 hours since the last dose. This varies primarily depending upon how dependent the user is. The withdrawal peaks in symptoms at approximately 36 hours and last several days in total. Notable residual withdrawal may last up to a week, depending on the level of chronic usage. This indicates that the neurochemical pathways of interest (particularly the receptors) likely reset to a basal level within a week post-withdrawal.
Interestingly, those people who are not tolerant to caffeine tend to experience negative side effects upon consuming caffeine:
Caffeine tolerance is especially rapid in animals and made more rapid with intake of other methyxanthines. The typical result is an increased dosage over time to compensate. Locomotor function has been shown to return to normal by the third day following the last administration, though the mechanism is not certain.
Caffeine and Neurotransmitters (NT)
Getting at the molecular biology, though, there’s a few things going on.
Actual NT levels can vary quite quickly. The transport, synthesis, and degradation of common NTs is on the order of microseconds (e.g. NT release) to minutes and hours. When you cease caffeine intake, though, you’re not going to have a large effect on NT levels at all; rather, these effects will come from the receptors.
Caffeine is an adenosine receptor antagonist. In terms of receptor activity, caffeine will make it seem like there is less adenosine in your system. Over time, your body compensates for this by upregulating adenosine receptor levels. When you stop taking caffeine, you have more receptors than you need and the effects of normal adenosine levels are much greater. Recovering from this compensation will take as long as it takes your receptor levels to go back to normal. This involves cycling the receptors between places in the cell where they are and are not active, but also in the actual synthesis and degradation of the receptors.
The regulatory response depends on the specific genes involved, but generally they proceed by positive and negative feedback loops. E.g. adenosine receptor signaling can act to downregulate adenosine receptor levels (negative-feedback). For a basic idea of how long this might take, I found this paper talking about acetylcholine receptors:
In studies using repeated imaging of identified neuromuscular junctions in living adult mice, the half-time of synaptic AChRs was estimated to be approximately 14 days. Blockade of neurotransmission rapidly (within 2 h) decreased the half-time 25-fold, to less than 1 day. The decrease in half-time appeared to reflect a combination of increased lateral dispersal of synaptic nAChRs and increased internalization. More recent studies using repeated in vivo imaging have provided evidence that nAChRs that are internalized at neuromuscular junctions can be recycled to the cell surface and reincorporated at the synapse; this recycling apparently requires synaptic activity. It is interesting to note that recycled nAChRs are subsequently removed from the synapse more quickly than newly inserted nAChRs that were not (yet) recycled37, suggesting that recycled receptors are somehow tagged or in some way differ from “naive” receptors in their interactions with other proteins.
Clearly there’s a pretty cool regulatory network in charge of this, and shows how responsive receptor levels can be. The rate of degradation is strongly regulated in this case, and that’s likely the key aspect of caffeine withdrawal. If nothing else, this tells us that we probably can’t make assumptions about how adenosine receptors are regulated.
Generally speaking, caffeine addition and withdrawal are going to vary by how much caffeine you consume and your own particular physiology. Individual responses occur with effects as well, so some may find caffeine quite helpful for mental capacity and alertness, while others find it minimally beneficial.
If addicted, somewhere in that 2-9 day time frame your adenosine receptor levels go back to normal and the withdrawal ends, this is approximately how long caffeine addiction takes, if you want to be atypical and remove the caffeine from your life.
- Juliano LM, Griffiths RR.A critical review of caffeine withdrawal: empirical validation of symptoms and signs,incidence, severity, and associated features. Psychopharmacology (Berl). 2004 Oct;176(1):1-29. Epub 2004 Sep 21. Review.
- St John PA. Cellular trafficking of nicotinic acetylcholine receptors.Acta Pharmacol Sin. 2009 Jun;30(6):656-62. doi: 10.1038/aps.2009.76. Review.
- Nehlig A: Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev 23: 563, 1999. PubMed: 10073894