Everything about Caffeine totally explained
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Like
alcohol,
nicotine, and
antidepressants, caffeine readily crosses the
blood brain barrier. Once in the brain, the principal mode of action of caffeine is as an
antagonist of
adenosine receptors found in the brain. The caffeine molecule is structurally similar to
adenosine, and binds to adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a
competitive inhibitor. Caffeine being a competitive inhibitor of adenosine, an understanding of adenosine’s role in the central nervous system is crucial. One of the roles of adenosine is as a signal that one neuron can use to tell another to stop releasing neurotransmitter because it can’t handle the stimulation. Explained: one of adenosine’s mechanisms is as a retrograde neurotransmitter (a neurotransmitter that's released by the post-synaptic cell and received by the pre-synaptic cell in the direction opposite to most neurotransmitters) . Adenosine is the final breakdown product of
adenosine triphosphate (ATP), which is the cellular currency of energy. When cells have used the energy of adenosine triphosphate it breaks into
adenosine diphosphate, which is then used for energy and broken down into
adenosine monophosphate. Finally, the last phosphate bond is broken for energy in the cell’s last attempt to squeeze molecular power from this molecule: adenosine monophosphate is broken down into simple
adenosine. At this point, the neuron has very little energy left for the successful firing of an
action potential. Adenosine from this process is then released from the postsynaptic cell and binds to receptors on the presynaptic cell. If the release of adenosine is great enough, this release has an inhibitory effect on the release of neurotransmitter from the presynaptic neuron’s axon terminal. This triggers a mechanism that inhibits the further secretion of excitatory neurotransmitters into the
synapse. It is as if the postsynaptic neuron is telling the presynaptic neuron that its resources are scarce and it needs time to recover before further stimulation by neurotransmitters. Thus, adenosine works to inhibit activity of the central nervous system. Caffeine being a competitive inhibitor of adenosine, it binds to the adenosine receptor, but doesn't trigger the chemical cascade that inhibits neurotransmitter release and blocks the site so adenosine can't bind and get its message across the synapse. By inhibiting adenosine, caffeine excites the central nervous system and allows for continued stimulation of neurons that otherwise wouldn't fire or wouldn't release neurotransmitter into the synapse.
The reduction in adenosine activity results in increased activity of the
neurotransmitter dopamine, largely accounting for its stimulatory effects. This inhibition of adenosine is the only known biochemical effect that caffeine has in humans at the concentrations achieved during normal human consumption of the drug. Caffeine also increases levels of
epinephrine/adrenaline, possibly via a different mechanism. Acute usage of caffeine also increases levels of
serotonin, causing positive changes in mood.
Caffeine is also a known competitive inhibitor of the enzyme
cAMP-phosphodiesterase (cAMP-PDE), which converts
cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in activation of
Protein Kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal caffeine intensifies and prolongs the effects of
epinephrine and epinephrine-like drugs such as
amphetamine,
methamphetamine, or
methylphenidate. Increased concentrations of cAMP in
parietal cells causes an increased activation of
protein kinase A (PKA) which in turn increases activation of
H+/K+ ATPase, resulting finally in increased
gastric acid secretion by the cell.
Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the
endoplasmic reticulum(ER). This release is only partially blocked by Ryanodine receptor blockade with
ryanodine,
dantrolene,
ruthenium red, and
procaine (thus may involve
ryanodine receptor and probably some additional calcium channels), but completely abolished after calcium depletion of ER by
SERCA inhibitors like
Thapsigargin (TG) or
cyclopiazonic acid (CPA). The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate. This mode of action of caffeine is probably due to mimicking the action of the physiologic metabolite of NAD called cADPR (
cyclic ADP ribose) which has a similar potentiating action on
Ryanodine receptors.
Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons.
The metabolites of caffeine contribute to caffeine's effects. Theobromine is a
vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth
muscle relaxant that chiefly affects
bronchioles and acts as a
chronotrope and
inotrope that increases heart rate and efficiency. The third metabolic derivative, paraxanthine, is responsible for an increase in the
lipolysis process, which releases
glycerol and
fatty acids into the blood to be used as a source of fuel by the muscles.
Effects when taken in moderation
The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours. Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight. The extensive boost shown in the runners isn't an isolated case; additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high intensity circuits.
Caffeine citrate has proven to be of short and long term benefit in treating the breathing disorders of
apnea of prematurity and bronchopulmonary displasia in
premature infants.
citrated caffeine, the only short term risk associated with caffeine citate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.
While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more significant effect on
spiders, for example, than most other drugs do.
Caffeine relaxes the
internal anal sphincter muscles and thus should be avoided by those with
fecal incontinence.
Tolerance and withdrawal
| Product |
Serving size |
Caffeine per serving (mg) |
Caffeine per litre (mg) |
| Caffeine tablet (regular strength) |
1 tablet |
100 |
— |
| Caffeine tablet (extra strength) |
1 tablet |
200 |
— |
| Excedrin tablet |
1 tablet |
65 |
— |
| Chocolate, Dark (Hershey's Special Dark) |
|
31 |
— |
| Chocolate, Milk (Hershey Bar) |
|
10 |
— |
| Coffee, brewed |
|
80-135 |
386-652 |
| Coffee, drip |
|
115-175 |
555-845 |
| Coffee, decaffeinated |
|
5 |
24 |
| Coffee, espresso |
|
100 |
1691-2254 |
| Tea, leaf or bag |
|
50 |
281 |
| Tea, green |
|
30 |
169 |
| Soft drink, Coca-Cola Classic |
|
34 |
96 |
| Soft drink, Mountain Dew |
|
54.5 |
154 |
| Soft drink, Jolt Cola |
|
150 |
216 |
| Red Bull |
|
80 |
320 |
| Wired X344 |
|
344 |
727 |
| Buckfast Tonic Wine |
|
281 |
375 |
Because caffeine is primarily an
antagonist of the central nervous system's receptors for the
neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of
adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences. First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a
tolerance adaptation. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.
Caffeine tolerance develops very quickly, especially among heavy coffee and energy drink consumers. Complete tolerance to sleep disruption effects of caffeine develops after consuming 400 mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300 mg 3 times per day for 18 days, and possibly even earlier. In another experiment, complete tolerance of caffeine was observed when subject consumed 750-1200 mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine.
Because adenosine, in part, serves to regulate blood pressure by causing
vasodilation, the increased effects of adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a
headache and
nausea. Reduced
catecholamine activity may cause feelings of
fatigue and drowsiness. A reduction in
serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild
depression. Together, these effects have come to be known as a "crash".
Withdrawal symptoms—possibly including headache, irritability, an inability to concentrate, and stomach aches—may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption.
Analgesics, such as
aspirin, can relieve the pain symptoms, as can a small dose of caffeine. Most effective is a combination of both an analgesic and a small amount of caffeine.
This isn't the only case where caffeine increases the effectiveness of a drug. Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief. For this reason, many over-the-counter headache drugs include caffeine in their formula. It is also used with
ergotamine in the treatment of
migraine and
cluster headaches as well as to overcome the drowsiness caused by
antihistamines.
Overuse
In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as
caffeinism. Caffeinism usually combines caffeine
dependency with a wide range of unpleasant physical and mental conditions including
nervousness,
irritability,
anxiety,
tremulousness,
muscle twitching (
hyperreflexia),
insomnia,
headaches,
respiratory alkalosis and
heart palpitations. Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to
peptic ulcers, erosive
esophagitis, and
gastroesophageal reflux disease.
There are four caffeine-induced psychiatric disorders recognized by the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: caffeine intoxication, caffeine-induced anxiety disorder,
caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS).
Caffeine intoxication
An acute overdose of caffeine, usually in excess of about 300 milligrams, dependent on body weight and level of caffeine tolerance, can result in a state of central nervous system over-stimulation called
caffeine intoxication. The symptoms of caffeine intoxication are not unlike overdoses of other
stimulants. It may include restlessness,
nervousness, excitement, insomnia, flushing of the face,
increased urination,
gastrointestinal disturbance,
muscle twitching, a rambling flow of thought and speech, irritability,
irregular or
rapid heart beat, and
psychomotor agitation.
In cases of extreme overdose, death can result. The median lethal dose (
LD50) given orally, is 192 milligrams per kilogram in rats. The LD
50 of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult taken within a limited time frame that's dependent on
half-life. Though achieving lethal dose with caffeine would be exceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine. Death typically occurs due to
ventricular fibrillation brought about by effects of caffeine on the
cardiovascular system.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then
peritoneal dialysis,
hemodialysis, or
hemofiltration may be required.
Anxiety and sleep disorders
Two infrequently diagnosed caffeine-induced disorders that are recognized by the
American Psychiatric Association (APA) are
caffeine-induced sleep disorder and
caffeine-induced anxiety disorder, which can result from long-term excessive caffeine intake.
In the case of caffeine-induced
sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. A study in the
British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population. The mechanism by which caffeine affects PD remains a mystery. In animal models, researchers have shown that caffeine can prevent the loss of dopamine-producing nerve cells seen in Parkinson's Disease, but researchers still don't know how this occurs.
Effects on memory and learning
An array of studies found that caffeine could have
nootropic effects, inducing certain changes in memory and learning. However, it's still not definitely clear whether the effect is negative or positive.
Researchers have found that long-term consumption of low dose caffeine slowed
hippocampus-dependent learning and impaired long-term memory. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls during the experiment. The conclusion was that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.
In one study, caffeine was added to rat neurons
in vitro. The
dendritic spines (a part of the brain cell used in forming connections between neurons) taken from the
hippocampus (a part of the brain associated with memory), grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.
Another study showed that subjects—after receiving 100 milligrams of caffeine—had increased activity in brain regions located in the frontal lobe, where a part of the working memory network is located, and the
anterior cingulum, a part of the brain that controls attention. The caffeinated subjects also performed better on the memory tasks.
However, a different study showed that caffeine could impair short term memory and increase the likelihood of the
tip of the tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-term memory when the information to be recalled is related to the current
train of thought, but also to hypothesize that caffeine hinders short-term memory when the train of thought is unrelated. In essence, focused thought coupled with caffeine consumption increases mental performance.
Effects on the heart
Caffeine increases the levels of cAMP in the heart cells, mimicking the effects of
epinephrine. cAMP diffuses through the cell and acts as a "secondary messenger," activating protein kinase A (PKA;
cAMP-dependent protein kinase). According to one study, caffeine, in the form of coffee, significantly reduces the risk of
heart disease in epidemiological studies. However, the protective effect was found only in participants who were not severely
hypertensive (for example patients that are not suffering from a very high blood pressure). Furthermore, no significant protective effect was found in participants aged less than 65 years or in
cerebrovascular disease mortality for those aged equal or more than 65 years.
Effects on children
There is no scientific evidence for the mistaken but common belief that caffeine consumption causes stunted growth in children. However, as with adults, nausea, urinary urgency, nervousness, or other effects from an elevated caffeine intake via chocolate milk, sodas, cold medicines, iced tea, coffee and other products that are widely used, may be reasons to limit the amount of caffeine that's consumed each day.
Caffeine intake during pregnancy
The
Food Standards Agency has recommended that pregnant women should limit their caffeine intake to less than 300 mg of caffeine a day – the equivalent of four cups of coffee a day. A higher intake may be associated with miscarriage.
Dr De-Kun Li of Kaiser Permanente Division of Research, which appears in the American Journal of Obstetrics and Gynecology, concludes that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage". However, Dr. David Savitz, a professor in community and preventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on the subject published in the January issue of Epidemiology, found no link between miscarriage and caffeine consumption. If desired, it may be synthesized from
dimethyl urea and
malonic acid.
Decaffeination
Pure caffeine is a white powder, and can be extracted from a variety of natural sources. Caffeine extraction is an important industrial process and can be performed using a number of different solvents.
Benzene,
chloroform,
trichloroethylene and
dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they've been superseded by the following main methods:
Water extraction
Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute to the flavor of coffee, is then passed through
activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter
caffeine tablets.
Supercritical carbon dioxide extraction
Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO
2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73
atm. Under these conditions, CO
2 is in a "
supercritical"
state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97–99% of the caffeine. The caffeine-laden CO
2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by
charcoal adsorption (as above) or by
distillation,
recrystallization, or
reverse osmosis. don't consume caffeine. Followers of both religions believe that God wishes them to be free of any addiction.
The Church of Jesus Christ of Latter-day Saints has no official position on this matter, but advise against any harmful, habit forming, drinks.
see Word of WisdomFurther Information
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