Caffeine is the most-widely consumed psychoactive substance by human beings throughout the world (Reid, 2005).
This report will detail its natural origins, chemical structure (as well as those of similar substances), and the methods and dosages in which it is rendered into its usable form. Additionally, this report will detail caffeine's various biological pathways within the human body, including access to the brain and various neurotransmitter pathways.

Caffeine is a chemical that occurs naturally in over 100 plant species throughout the world (Steffen, 2000). Perhaps the most widely recognized of these plants is the coffee tree, whose small seed (commonly referred to as a "bean") is roasted and then crushed into a fine powder (Weinberg and Bealer,
2001). Caffeine also occurs naturally in cocoa beans, tea leaves, kola nuts, and gurana seeds, and mate. Some of these plants, such as tea, actually bear a distinct, but similar chemical to caffeine (i.e. theophylline); these chemicals will be discussed further in the chemistry section (Steffen, 2000).

Caffeine is chemically known by two names. The first is
1,3,7 -trimethylxanthine; the second is 3,7,-Dihydro-1,3,7- trimethyl-1H-purine-2,6-dione. Historically, caffeine has also gone by the name of methyltheobromine, as well as thein
(Weinberg and Bealer, 2001). The chemical formula of caffeine is C8 H10 N4 O2. The molecular weight for this chemical is
194.19 atomic units. Its composition is as follows: 49.5 percent carbon, 5.2 percent hydrogen, 28.9 percent nitrogen, and 16.5 percent oxygen. Caffeine melts from a solid hexagonal crystal at 238 degrees Celsius (Karch, 1993).

Caffeine is a methylated purine derivative and is classified as an alkaloid. An alkaloid is a class of organic compounds composed of carbon, hydrogen, and nitrogen; oxygen is usually found amongst these compounds. The term "alkaloid" refers to compounds that can be extracted from plants, and whose salts can be crystallized. Other alkaloids include cocaine, serotonin, and the hallucinogenic compound, LSD. A purine is a base compound, consisting of a six-membered and five-membered nitrogen containing ring fused together; other examples of purines include adenine and guanine, two bases found in human DNA (Angstadt, 1997). The term "methylated" refers to the fact that hydrogen atoms upon the compound have been replaced with a methyl (CH3) compound (Methylation,
2005).[See figure 3]

Caffeine is often served within hot beverages, such as coffee or tea. In the case of the latter, the coffee bean is ground up into a coarse powder, which is used as a filtrate for hot water (Weinberg and Bealer, 2001). Hot water can also be passed through tea leaves. At hot temperatures, such as those found within serving temperatures of coffee and tea, provide for the complete solubility (Weinberg and Bealer,
2001). Caffeine can also be found in solid food substances such as chocolate and gurana fudge (Steffen, 2000).Certain soft drinks and so-called "energy" drinks also contain caffeine additives (Reid, 2005). All of the above substances are ingested orally. The percentage of caffeine in the above substances varies. In coffee, for example, caffeine composes
1.34% of the drink by weight; in tea, this number is 3.24%
(Weinberg and Bealer, 2001). Chemical extraction of caffeine from roasted coffee beans yields between 8 and 20 milligrams
(mg) of caffeine per gram (g) of coffee beans (Karch, 1993).

Human consumption varies across demographic characteristics, especially nationality. In the Scandinavian countries, such as Norway and Denmark, the average daily consumption of caffeine for a 60-70 kilogram (kg) subject 7.0 milligrams (mg) per kilogram of body mass; in American and
United Kingdom subjects, this daily average is between 2.4 mg/kg and 4.0 mg/kg of body mass. In Denmark, the mean daily intake for children under the age of 18 years is 2.5 mg/kg of body mass, and in the United States, this number is 1.0 mg/kg.
(Nehlig, 2000)

There is considerable variation amongst persons in terms of bodily concentrations of caffeine (Weinberger and
Bealer, 2001). In an experiment in which the participants each consumed 568 milliliters (ml) of coffee, peak blood levels of caffeine were reached between 15 and 45 minutes after ingestion; the amount of caffeine present per liter of blood was 5.3 micrograms (Marks and Kelly, 1973, as cited in Karch,
1993). The half-life of caffeine in the body varies as well: in healthy adults, the half-life of caffeine is 3.5 hours on average, in pregnant women, the half life of caffeine up to 18 hours, and in term infants, the half life of caffeine is 82 hours. Additionally, other substance use factors, such as the ingestion of alcohol or tobacco products can significantly impact the half-life of caffeine within human blood. (Weinberg and Bealer, 2001). Eventually, the caffeine is metabolized by the liver, where, according to Weinberg and Bealer (2001), it is either "demethylated" into dimethylxanthine and monoethylxanthine, or oxidized and converted into uric acid, and eventually excreted in the urine.

NEUROLOGICAL PATHWAYS OF CAFFEINE:

Caffeine acts upon the human central nervous system (Spiller, 1998). The central nervous system encompasses the brain and the spinal cord (Kalat, 2001). Caffeine is designated as a stimulant drug; according to Kalat, stimulants produce "…excitement, alertness, elevated mood, decreased fatigue, and sometimes increased motor activity (2001, p.
70)." Indeed, many people report using caffeine, often in the form of coffee or other beverages, as a means of staying alert during activities requiring intense concentration (Reid,
2005). Additionally, caffeine also works as a vasoconstrictor within the brain, causing the blood vascular to constrict whilst increasing the overall heart rate (Kalat, 2001). The subsequent vasodilation occurring upon withdraw of caffeine from the brain may be responsible for the severe headaches endured by habitual users (Spiller, 1998)

The following sections will detail the effects of caffeine upon the neurotransmitters adenosine, dopamine, and serotonin, respectively:

CAFFEINE AND ADENOSINE:

Over the years, there have been competing reports of the action of caffeine upon brain physiology (in example, see Weinberg and Bealer, 2001). Theories included caffeine as means of increasing calcium secretion of neurons, as calcium is a necessary agent for nervous impulse transmission (Myers,
Johnson, and McVey, 1999). Another theory posited that phosphodiesterase became inhibited by caffeine (Spiller,
1999). At the present time, both of these theories have been more or less abandoned, mainly along the lines that the dosages required of caffeine to activate these systems are so large that ingestion would most likely yield lethal effects
(Weinberg and Bealer, 2001; see also Nehlig, 2000).
Researchers now look to the neuromodulator adenosine as the molecule that plays a direct role in the neurological effects associated with caffeine (Weinberg and Bealer, 2001).

Caffeine works directly upon the neuromodulator adenosine as an antagonist (Daly et al, 1999). An antagonist is a chemical that blocks the effect of a neurotransmitter
(Kalat, 2001). During metabolic activity, adenosine monophosphate breaks down into adenosine. Adenosine inhibits the brain's arousal system by binding to receptors in the basal forebrain, an area responsible for wakefulness. As a person goes about the day, adenosine accumulates; at high enough levels, the adenosine inhibits the arousal centers and induces sleepiness. (Kalat, 2001)

Caffeine binds with presynaptic adenosine receptors
(Daly et al, 1999). The primary molecular sites for the action of caffeine are A1 and A2a receptors; these are high affinity and low affinity receptor, respectively (Myers, Johnson, and
McVey, 1999). Adenosine mediates the release inhibition of various neurotransmitters, including serotonin, dopamine, glutamate, GABA, and acetylcholine. These neurotransmitters are instrumental themselves in mediating alertness, sleep cycles, attention, and memory, to name a few (Weinberg and
Bealer, 2001). The next two sections will briefly discuss the inhibition of adenosine upon the neurotransmission of serotonergic and dopaminergic pathways.

CAFFEINE AND THE DOPAMINERGIC PATHWAYS

Dopamine is a catecholamine neurotransmitter, meaning that it is composed of a catechol and an amine group compound (Kalat, 2001). Dopamine is often found in reinforcement and reward pathways, hence its designation as a
"pleasure" molecule (Kalat, 2001). In a study involving rats, caffeine was administered to two different dopaminergic pathways (Nehlig, 2000). Regarding the first of these pathways, the nigrostriatal dopaminergic system, caffeine was found to activate a structure known as the caudate nucleus, inducing dopamine release by modifying the spontaneous electrical activity of the neurons within this structure.
Dopamine release in the nigrostriatal system accounts for the stimulant effects of caffeine on locomotor activity (Nehlig,
2000).

The second dopaminergic pathway in the Nehlig study, the mesolimbic dopaminergic system, has been studied as a possible site for the formation of a physical dependency on caffeine; it should be noted, though, that the issue of caffeine and dependence is somewhat controversial (2001; see also Weinberg and Bealer, 2001, and Spiller, 1999). This system originates in the ventral tegmental area of the midbrain, "…projects into the nucleus accumbens, and terminates in the medial prefrontal cortex ( Nehlig, 2000,
p.50)." The nucleus accumbens is divided into a core and a shell unit. The medioventral shell is thought to be a key component of emotional, motivational, and reward functions; the laterodorsal core regulates somatomotor functions. Other stimulants, such as nicotine and cocaine, selectively activate dopamine release within the shell; caffeine, however, does not display any similar stimulation of dopamine release at a normal dosing level of 0.5 to 5 mg/kg. In fact, activation of the nucleus accumbens occurs only at high doses
(i.e 10 mg/kg), an amount 4 to 5 times greater than the average adult American's daily consumption. (Nehlig, 2000)

CAFFEINE AND SEROTONERGIC PATHWAYS

Serotonin is a 5-HT indoleamine neurotransmitter; amongst other attributes, serotonin is known for its influence upon arousal and sleep activity (Kalat, 2001). Serotonergic neuron cell groupings play a part in the regulation of sleep, mood, and general well being (Nehlig, 2000). At low-to-medium doses, caffeine stimulates electrical activity in reticular formation neurons, as well as lowering electrical activity in the thalamus, a site known to be connected with caffeine- induced arousal (Nehlig, 2000). Serotonin availability is also reduced by medium levels of caffeine, which in turns reduces the sedative effects of the neurotransmitter at the postsynaptic level (Myers, Johnson, and McVey, 1999). This can lead to an interference of the sleep cycle, as well as changes in motor function (Nehlig, 2000). Additionally, caffeine has been shown to induce serotonin release in the cerebellum and cerebral cortex (Spiller, 1998).

CONCLUSION:

Caffeine and its methylxanthine relatives compose the most widely used psychoactive substances in the world.
This widely available drug can be found in beverages such as coffee and tea, and in foods like chocolate. Much research exists describing its chemical and molecular properties, as well as its human dosing information. Caffeine works directly upon the neuromodulator adenosine; this effect subsequently influences the neurotransmission of hormones and neurotransmitters, such as dopamine and serotonin. As more research unfolds regarding neurological physiology and chemistry, the scientific community will no doubt discover many more facets of the workings of caffeine.

WORKS CITED

Angstadt, C. (1997). Purines and pyrimidine metabolism.
Retrieved March 6, 2005 from Net Biochem website:http://wwwmedlib.med.utah.edu/NetBiochem/pupyr/pp.htm. Daly, J., Shi, D., Nikodijevic, O., and Jacobson, K. (1999).
The role of adenosine receptors in the central action of caffeine. In B. Gupta and U. Gupta (Eds.), Caffeine and behavior: Current views and research trends (p.1-16). New
York: CRC Press.

Kalat, J. (2001). Biological psychology,7th ed.. Belmont:
Wadsworth-Thompson.

Karch, S. (1993). The pathology of drug abuse. Boca Raton: CRC
Press.

Methylation (2005). Retrieved March 6, 2005 from Wikipedia, the Free Encyclopedia website: http://en.wikipedia.org/wiki/Methylation. Myers, P., Johnson, D., and McVey, D. (1999). Caffeine in the modulation of brain function. In B. Gupta and U. Gupta (Eds.),
Caffeine and behavior: Current views and research trends
(p.17-30). New York: CRC Press.

Nehlig, A. (2000). Caffeine effects on the brain and behavior: a metabolic approach. In H. Parliament, C.Ho, and P.Schieberle
(Eds.), Caffeinated beverages: Health benefits, physiological effects, and chemistry (p.46-53). Washington, D.C: American
Chemical Society.

Spiller, G. (1998). Basic metabolism and physiological effects of the methylxanthines. In G. Spiller (Ed.), Caffeine (p.225-
231). New York: CRC Press.

Steffen, D.(2000). Chemistry and health benefits of caffeinated beverages: symposium overview. In H. Parliament,
C.Ho, and P.Schieberle (Eds.), Caffeinated beverages: Health benefits, physiological effects, and chemistry (p.2-8).
Washington, D.C: American Chemical Society.

Reid, T. (2005). Caffeine: What's the buzz? Why we love caffeine. National Geographic, 207, 1, p.2-33.

Weinberg, B., and Bealer, B. (2001). The world of caffeine:
The science and culture of the world's most popular drug. New
York: Routledge.