Introduction: A Basic Description of Caffeine

Coffee. Chocolate. A can of soda. A cup of tea. What do all of these have in common? Aside from being largely consumed products worldwide on a daily basis, they all contain a compound known as caffeine. Caffeine is a stimulant found primarily in coffee beans, the seeds of the plant Coffea arabica, as well as tea leaves, in which its bitterness serves the purpose of discouraging consumption by pests. It is consumed orally via the products in which it is present, in which it acts as the primary psychoactive ingredient.

Caffeine use is legal, and it is an easy to obtain and socially acceptable to consume substance, which makes it one of the most used drugs in the world. It is estimated that in the United States almost 75% of children under  18 years of age consume caffeine on any given day, and coffee is the most consumed beverage in the world after water. Approximately 90% of adults report regular caffeine use (Temple, 2009). The morning coffee to start the day is a tradition followed by many around. However, are there any risks accompanying this chronic consumption? Can caffeine be considered an addictive substance? Does it present other benefits aside from this extra burst of energy to get us through the day? These are all questions we seek to answer. 

Products that contain caffeine eaten on a daily basis:

Chocolate:	Average:
Cocoa beverage (6 oz)	4 mg
Chocolate flavored syrup (2 tbs)	5 mg
Chocolate milk (8 oz)	8 mg
Milk chocolate (1 oz)	7 mg
Semi-sweet chocolate (1 oz)	18 mg
Unsweetened chocolate (1 oz)	25 mg
Coffee:*
Brewed (6 oz)	100 mg
Instant (1 rounded tsp)	57 mg
Brewed decaffeinated (6 oz cup)	3 mg
Instant decaffeinated (1 rounded tsp)	2 mg
Cappuccino (4 oz)	100 mg
Espresso (2 oz)	100 mg
Latte (single)	50 mg
Mocha (single)	55 mg
Other Beverages (12-oz servings):
Coca-Cola, Diet Coke	46 mg
Dr. Pepper (regular & sugar-free)	40 mg
Mello Yello	52 mg
Mountain Dew	54 mg
Pepsi-Cola, Diet Pepsi	38 mg
Red Bull (8.2 oz)	80 mg
5-Hour Energy	138 mg
Monster Energy	160 mg
Tea (5-oz cup):
Brewed, green or black, U.S. brands (3 minutes)	40 mg
Brewed, imported brands	60 mg
Instant (1 tsp)	30 mg
Iced (8 oz)	25 mg
Decaffeinated	5 mg
Non-Prescription Drugs:**
Caffeine Tablets:
No-Doz	100 mg
Vivarin	200 mg
Pain Relievers (per tablet):
Anacin	32 mg
Excedrin	65 mg
Midol (maximum strength)	60 mg

*Caffeine content of coffee varies depending on type of bean, quantity used, how finely beans are ground and brewing time

Caffeine Pharmacology

Caffeine is a naturally ocurring substance in many plants like guarana, cacao beans, cola nut but can be artificially manufactured. To understand how this substance reacts its, important to note the chemical aspects of the compound; chemically, it is a methylzantine which means that it's structure is derived from guanine, hypoxanthine and xanthosine by different methods. These analogs derived from these compounds are commonly used as psycho-stimulants because of their diferent effects on the body, and as it could be noted these could be used to oppose the actions of adenosine (what makes you sleepy) by increasing alertness in the central nervous system. Those groups that are methylated (like caffeine, for instance) stimulate the heart rate and force of contraction. Now for a little science on how they do it, these cause the release of cathecolamines stimulating adenosine receptors (A1 and A2a) and block inhibitory neurotransmitter adenosine (an inhibitor) by inhibiting phosphodiesterase resulting in increased intracelular cyclic adenosine monophosphate (cAMP). (Pohler, 2010) The following image shows the pathway:

Image extracted from http://www.sivabio.50webs.com/amp.htm; this shows adenosine interaction whith a receptor protein, blocking the production of cAMP.

A1 and A2a receptors are G coupled proteins. Their properties are rather dissimliar, A1 receptors once active lead to the inhibition of adenylyl cyclase and some types of Ca2+ sensitive channels which cause the inactivation of celular activity (or depolarization of action potentials). A2a receptors once active production of adenylyl cyclase. The distribution are diverse; since A1 are found in crainial areas that are in the hippocampus, cerebral cortex, and certain thalamic nuclei and A2a receptors are found in some glial cells, nucleus accumbens and globulus pallidus. A1 are co localized with D1 (dopamine) receptors, A2a receptors are localized with D2 (dopamine) receptors that interact with the release of GABA (an inhibitory neurotransmitter) that blocks the release of GABA in the globus pallidus. (Pohler, 2010)

Figure 2: Structural resemblance between adenosine and caffeine. It can be observed that because their similarities they would compete for the same receptor.

Caffeine contains the properties to become 100% bioavaiable by oral administration. It's later metabolized by the liver. cAMP is known as a messenger that is associated to several biochemical processes. This secondary messenger is know for it's regulation of glycogen, sugar and lipids. It activates protein kinase A (PKA) which in turn phophorylates substrate proteins. These phosphorylations are like a switch which turn "on" other functions like enzymes that convert glycogen into glucose, enzymes that increase smooth muscle contraction (like your heart) and transcription factors that regulate gene expressions.(Al-Saleh, 2010)

 To sumarize what you just read, caffeine acts as a non-selective "brake" for adenosine. This means that there will be more cAMP available to "activate" or "switch on" your body.

Now, how does this compound affect other functions? Let's evaluate it's effects on a hormonal level; in other words, the pituitary gland. The pituitary gland is a small gland found at the base of the skull made of endocrine tissue. The pituitary is known to regulate several physiological processes like stress, reproduction and even growth. Since your brain on caffeine is activated similar to the way than you would if you were scared, the anterior pituitary springs to action, releasing the adrenocorticotropic hormone (ACTH). ACTH acts on various portions of the pituitary which produces and secretes the hormone epinephrine (also called adrenaline). Adrenaline acts on the body in different manners, if you think about it, once you consume too much caffeine, or had that 3rd cup you don't usually have, you begin to feel jittery, restles and anxious.An other effect that this has on the pituitary would be the release of dopamine certain portions of the brain (to be specific, the nucleus accumbens). (Costenla, 2010)

Risks and Addictive Potential

When dealing with a psychoactive substance such as caffeine careful observations regarding the risks of consuming said substance. How much is enough to produce an effect? Are there health risks? Is there a possibility of developing tolerance, or becoming dependent?

Caffeine intake acts primarily as a Central Nervous System stimulant, but it also presents certain peripheral effects. Caffeine has been shown increase blood pressure and cause panic attacks (ref). This is especially true of energy drinks. However, caffeine is not considered a severe drug, as it has a very high lethal dose, making an overdose very difficult.

The effects of caffeine on pregnancy have also been studied. The U.S Food and Drug Administration advises pregnant women to limit their caffeine intake to 400 mg per day. To put this into perspective, 6 oz of brewed coffee contains 100 mg. This is more a precautionary measure, as a concrete relationship has not been established. Several studies have been performed, linking caffeine to spontaneous abortion and developmental malformations. However, studies have also been performed that show no relationship between caffeine and pregnancy success. (Al-Saleh et al., 2010)  

Another concern of caffeine intake is its place in the daily diet, especially of children. Caffeine by itself has not been linked to an effect on weight (ref), but it is important to consider the manner in which it is consumed. In adults, caffeine consumption is mainly via coffee, but children consume products such as chocolate, soda and other sweetened beverages. Caffeine use, in particular in the form of sugar-sweetened carbonated beverages, is associated with higher incidence of overweight in children, and studies show that children who consume more servings of soda per week also consume fewer servings of milk, fruits, and vegetables. (Temple, 2009)

Is caffeine addictive? Addiction is a difficult concept to define, with substance dependence being the more utilized term. Substance dependence is characterized by the presence of tolerance and withdrawal. In a survey conducted in 2013 to different organizations that specialize in addiction, the majority of addiction professionals believe that caffeine withdrawals and dependence are clinically important. (Budney et al., 2013) However, although caffeine can cause dopamine liberation, it does not cause dopamine liberation in the nucleus accumbens, which is the key structure in the brain for reward and addiction.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is the primary diagnostic tool of the American Psychiatric Association, lists caffeine intoxication and caffeine withdrawal as substance abuse disorders, and lists caffeine dependence as needing more research. Thus we can see that caffeine is recognized in the medical community as a substance that can be abused, however it lacks reward mechanism characteristic of other drugs.

Withdrawal Symptoms

Withdrawal (or discontinuation syndrome) takes by definition the unpleasant physical reaction that accompanies not taking a drug or stimulant. It is mostly characterized by the inverse of certain effects that the drug in question has in the body since the central nervous system has adapted to certain conditions (a process called “neuro-adaptation”). After prolonged exposure, a total of five categories of withdrawal symptoms due to intake caffeine are mainly characterized by headache, fatigue or drowsiness, dysphoric or depressed mood, difficulty concentrating and flu like somatic symptoms (that include tremor, nausea, vomiting).

The time course after administration usually occurs 12 to 24 hours after terminating caffeine intake; but of course, this is relative; since dosing parameters vary between individuals; but the minimal dose to feel certain withdrawal symptoms occurs after abstinence from a dose of 100 mg/day. Withdrawal symptoms can be avoided or suppressed by taking even more of a substance containing the compound.

Drug tolerance implies the response to repeated constant dose of the drug or the need to increase doses to maintain a constant response. Caffeine remains an interesting subject since drinkers usually develop tolerance to the secondary effects of the drug. Prolonged exposure of the drug shows a tolerance to the jitteriness, anxiety and edginess that result from first-time users.

(Information extracted from the American Journal of Drug and Alcohol Abuse)

Behavioral Effects

Caffeine has several effects on mood and anxiety that depend on the dosage being consumed. Interestingly, caffeine acts as a central and peripheral nervous system stimulant in animals (yes, that includes humans). This could be because of enhanced memory consolidation; but, how much should you drink? Even though this is determined by a number of factors, like genetic polymorphisms that deal with the enzymatic breakdown of caffeine or adenosine, a general list has been developed by various researchers dealing with caffeine’s' side effects. (Temple, 2009)

It is known that low doses are known to influence positively on mood; subjects that had 20 to 200 mg of caffeine reported feeling energetic, efficient and able to concentrate more during a task. This has to do with the stimulation of the locus coeruleus and the serotoninergic median and dorsal raphe nuclei involved in regulation of wakefulness, mood and well being. Caffeine releases serotonin in limbic areas and dopamine in the cortex which is a similar effect that antidepressants have on the human body. (Temple, 2009)

Moderate doses of caffeine, raging from 200mg to 350mg decrease heart rate and increases blood pressure. Moderate doses are associated with enhanced cognitive performance, auditory vigilance, and reaction time. (Brunya, 2010)

High doses of caffeine or low doses on people who have not usually consume as much caffeine may have a more adverse effect, subjects that administered 400 mg of caffeine had feelings of anxiety, nausea, jitteriness, and nervousness.  People who do not consume caffeine regularly are more sensitive to caffeine's anxiogenic and psycho stimulant effects. It is also not recommended for people with naturally anxious individuals or those that suffer from panic attacks. This is a result of the increase in functional activity in the amygdala, a structure in the brain that deals with fear and anxiety. (Brunya, 2010)

Figure extracted from "Acute caffenine consumption enhances the executive control of visual attention in habitual consumers" by Tad T. Brunyé; this shows a graph that shows varius adiminstrations of caffeine on the ANT (attention network based on alerting, orienting, and excecutive control) performace test which sought to numerically measure the "alerting" which maintains vigilance and alertness during the performance of a continuous task. "Orienting" defers to allow individuals to use cues to selectively orient attention to particular regions of space, and "executive control" implies individuals to reduce performace degradation with visual-incompatible information.

Therapeutic Effects and Possible Medical Applications

Aside from its widely known stimulating effects, caffeine has been shown to possess a variety of beneficial health applications. It is present as an ingredient added to common pain-relieving medicines which are available without prescription, such as paracetamol, ibuprofen and aspirin (Derry et al., 2012). Caffeine functions as an adjuvant, which is a substance added to a medicine to make it work better. Studies have found that adding caffeine at a dose equivalent to a mug of coffee to a standard dose of common analgesics increases the number of people with acute pain who will experience a good level of pain relief by 5% to 10%. (Figure 1)

Figure 1. L’Abbé plot showing the consistent effect of added caffeine (all doses in all conditions) irrespective of pain relief from analgesic alone. The position of the circles above the lines indicate that the treatment (analgesic + caffeine) is more effective than the control (analgesic alone).

Caffeine can also function as a bronchodilator, which widens the airways. Studies involving people suffering from mild to moderate asthma have found that caffeine, even at low doses (less than 5 mg/kg of body weight), appears to improve lung function for up to two hours after consumption. (Welsh et al., 2011)

Aside from these clinical trials in humans, caffeine is being studied for possible medical applications in the future. One of these cases is the study of Alzheimer’s disease. Studies in mice have demonstrated that caffeine treatment can improve working memory. (Arendasha et al., 2009) Further studies need to be performed to find possible applications in humans for this and other diseases. 

Conclusion and References

         Caffeine, as an independent substance, poses some beneficial effects and also exhibits tolerance and some withdrawal symptoms. However, these are relatively mild in comparison to other drugs. As for the pharmacology of the substance, caffeine acts as a non-selective "brake" against adenosine acting on it’s receptors. We can conclude that the major risk of caffeine consumption is actually the combination of its reinforcing effects with the products in which it can be found, such as energy drinks, soda and other generally unhealthy items.

References:

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 Al-Saleh, I., Coskun S., El-Doush, I., Grisellhi, B. (2010) The effect of caffeine consumption on the success rate of pregnancy as well various performance parameters of in-vitro fertilization treatment.  Med Sci Monit, 16(12): CR598-605

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 Bara, A., Barley, E., Cates C., Welsh, E. (2011) Caffeine for asthma (Review). The Cochrane Library(10)

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 Budney, A., Brown, P., Griffiths, R., Hughes, J., Juliano, L. (2013) Caffeine Withdrawal and Dependence: A Convenience Survey Among Addiction Professionals.  Journal of Caffeine Research, 3(2): 67-71

Brunya, T., Giles, G., Lieberman, H., Mahoney, C., Taylor, H. (2010). Acute caffeine consumption enhances the executive control of visual attention in habitual consumers. Brain and Cognition, 74(3), 186-192

Chu, Y., Joseph, J., Lyle, B., Miller, M., Shukitt, B. (2013). Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging. Age, 35(6), 2183-2192.

 Costenla, A., Cunhab, R., de Mendonca, A. (2010) Caffeine, Adenosine  Receptors, and Synaptic Plasticity. Journal of Alzheimer’s Disease, 20: S25–S34

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