• Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
• Theobromine (12%): Dilates blood vessels and increases urine volume.^ Caffeine increases the level of circulating fatty acids.
  • Coffee and Caffeine FAQ 15 September 2009 6:10 UTC www.nootropics.com [Source type: FILTERED WITH BAYES]
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  ^ Theobromine, paraxanthine and the combined effects of methylxanthines.
  • Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]
  
  ^ Effects of black and green tea consumption on blood glucose levels in non-obese elderly men and women from Mediterranean Islands (MEDIS epidemiological study).
  • CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]
  
  .Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.
• Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma.^ Theophylline: Sources: Tea Effects: Cariac stimulant, smooth muscle relaxant, diuretic, vasodilator Theobromine: Sources: Principle alkaloid of the cocoa bean (1.5-3%) Cola nuts and tea Effects: Diuretic, smooth muscle relaxant, cardiac stimulant, vasodilator.
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  ^ The crop contained 20 g of what appeared to be dark chocolate; a conservative estimate of the dose of methylxanthines ingested by the bird was 250 mg/kg theobromine, 20 mg/kg caffeine and 3 mg/kg theophylline.
  • CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]
  
  ^ Tea also contains two other alkaloids, theobromine and theophylline.
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  The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

Mechanism of action

Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain.

1. competitive nonselective phosphodiesterase inhibitor ^[61] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha ^[62][63] and leukotriene ^[64] synthesis, and reduces inflammation and innate immunity ^[64].^ When caffeine was added together with NCS to the culture of HeLa-S3 cells, NCS-induced inhibition of DNA synthesis and of mitosis was markedly reduced in the presence of caffeine.
   • Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]
   
   ^ Background: Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (CAMP) levels.
   • CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]
   
   ^ Caffeine 1,3,7-trimethylxanthine Theophylline 1,3-dimethylxanthine Theobromine 3,7-dimethylxanthine Coffee and tea contain caffeine and theophylline, respectively, which are methylated purine derivatives that inhibit cAMP phosphodiesterase.
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   .Caffeine is also added to agar, which partially inhibits the growth of Saccharomyces cerevisiae by inhibiting cyclic AMP phosphodiesterase.^ When caffeine was added together with NCS to the culture of HeLa-S3 cells, NCS-induced inhibition of DNA synthesis and of mitosis was markedly reduced in the presence of caffeine.
   • Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]
   
   ^ Background: Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (CAMP) levels.
   • CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]
   
   ^ Sublethal effects measured for caffeine exposure included impaired C. dubia reproduction (IC50 = 44 mg/L) and inhibited P. promelas growth (IC50 = 71 mg/L).
   • CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]
   
   ^[65]
2. nonselective adenosine receptor antagonist ^[56] (see above).

.Phosphodiesterase inhibitors inhibit cAMP-phosphodiesterase (cAMP-PDE) enzymes, which convert cyclic AMP (cAMP) in cells to its noncyclic form, thus allowing cAMP to build up in cells.^ Background: Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (CAMP) levels.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ On the other hand, when the level of l -homocysteine is raised, it can trap adenosine formed via AMP breakdown as S -adenosylhomocysteine inside the cell.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ CrossRef Medline ↵ Smellie FW , Davis CW , Daly JW , Wells JN ( 1979 ) Alkylxanthines: Inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phosphodiesterase activity.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Cyclic AMP participates in activation of protein kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis.^ Because caffeine fools the body into using enzymes to break it down instead, the cyclic AMP supply remains higher for longer.* I bet you always wanted to know that.

• Bodybuilding.com - Caffeine Information and Product Listing! Caffeine FAQ! 15 September 2009 6:10 UTC www.bodybuilding.com [Source type: FILTERED WITH BAYES]

^ It is further assumed that the rate of cyclic AMP production is importantly controlled by adenosine, acting on A 2A receptors to stimulate adenylyl cyclase, and by dopamine, acting on D 2 receptors to inhibit the enzyme.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Cyclic AMP response element-binding protein (CREB) is a likely candidate.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.By blocking its removal, caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, and methylphenidate.^ In some studies, the effects of caffeine are even weaker in this regard than those of nicotine, which is notoriously unreliable as a reinforcing drug.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ However, also a dose of caffeine taken in the morning can have such effects the following night ( Landolt et al., 1995b ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Finally, we will briefly comment upon the similarities and dissimilarities between caffeine and known addictive drugs such as cocaine, morphine, and nicotine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.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.^ We turn now to the question of whether there are adenosine receptors that are activated not only by the high adenosine levels seen in ischemia, but also by the low (high nanomolar concentrations) physiological levels.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Caffeine causes a concentration-dependent increase in c- fos expression, which is confined to the striatum ( Johansson et al., 1994 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Because activation of adenosine A 1 receptors is known to cause a decrease in cAMP formation, it is conceivable that this may also be a mechanism of decreased transmitter release—at least under some circumstances.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Cyclic AMP also increases the activity of the funny current, which directly increases heart rate.^ Background: Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (CAMP) levels.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Significantly greater increases in forearm blood flow and heart rate during mental arithmetic on the caffeine day suggested a potentiation of sympathetic, beta-adrenergic activity.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Results: Nicotine increased heart rate and subjective ratings indicative of aversive effects, and decreased reaction times.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.Caffeine is also a structural analogue of strychnine and, like it (though much less potent), a competitive antagonist at ionotropic glycine receptors.^ CrossRef Medline ↵ Holtzman SG ( 1996 ) Discriminative effects of CGS 15943, a competitive adenosine receptor antagonist, in monkeys: Comparison to methylxanthines.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ There is indeed ample evidence that caffeine (and other adenosine receptor antagonists) can increase behaviors related to dopamine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ This effect of caffeine could be partly mimicked by DPCPX, an adenosine A 1 receptor antagonist, but not by the A 2A receptor antagonist SCH 58261.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[66]

.Metabolites of caffeine also contribute to caffeine's effects.^ Effects of caffeine on the vasculature may contribute to the relief of some headaches and in postprandial hypotension.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The effect of caffeine is shared by some other xanthines, including its metabolites theophylline and paraxanthine ( Fredholm et al., 1976 ; Garrett and Holtzman, 1995 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.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.^ DATA SYNTHESIS: Caffeine appears to affect blood pressure through adenosine receptor inhibition and an increased release of select neurotransmitters.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ CONCLUSIONS: Blood pressure and plasma glucose increased post-exercise with DS use, which could be detrimental in some people.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Caffeine increases the level of circulating fatty acids.

• Coffee and Caffeine FAQ 15 September 2009 6:10 UTC www.nootropics.com [Source type: FILTERED WITH BAYES]
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.Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles.^ However, these changes are moderate and the decrease in blood flow could be compensated for by an increase in oxygen and glucose extraction, because the consumption of moderate amounts of caffeine has positive effects on alertness.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency.^ Theophylline: Sources: Tea Effects: Cariac stimulant, smooth muscle relaxant, diuretic, vasodilator Theobromine: Sources: Principle alkaloid of the cocoa bean (1.5-3%) Cola nuts and tea Effects: Diuretic, smooth muscle relaxant, cardiac stimulant, vasodilator.

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^ On humans caffeine acts particularly on the brain and skeletal muscles while theophylline targets heart, bronchia, and kidneys.

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^ Results: Nicotine increased heart rate and subjective ratings indicative of aversive effects, and decreased reaction times.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[67]

Caffeine has a significant effect on spiders, which is reflected in the construction of their webs.

Effects when taken in moderation

.

Overview of the more common side-effects of caffeine, possibly appearing even at levels below overdose.^ Studies on the side-effects of caffeine.

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^ Few side effects associated with taking caffeine during exercise were reported.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ It was found that researchers have generally failed to take account of the fact that habitual use of caffeine, even at moderate levels, leads to physical dependence evidenced by physiological, behavioural and subjective withdrawal effects during periods of abstinence.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[68]

.The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine.^ This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The effects of caffeine and smoking on cognitive performance, subjective variables, heart rate, and EEG were assessed in two sessions.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours.^ Indeed, not less than 14% of all erstwhile consumers in Vermont had stopped the intake of all caffeine-containing beverages largely for this reason ( Hughes and Oliveto, 1997 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ We found reduced saccadic interruptions as a result of caffeine ingestion compared with placebo (p less than .05).

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Children reported feeling significantly less "sluggish" after caffeine ingestion than after placebo ingestion.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[28] .Consumption of caffeine does not eliminate the need for sleep, it only temporarily reduces the sensation of being tired throughout the day.^ Influence of alcohol and caffeine consumption on caffeine elimination.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Regular caffeine consumption reduces sensitivity to caffeine.

• Coffee and Caffeine's Frequently Asked Questions 19 January 2010 8:49 UTC www.faqs.org [Source type: FILTERED WITH BAYES]
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^ Secondary analyses of data collected after a day of normal caffeine consumption were also carried out to examine some alternative explanations of their results which showed effects of caffeine after a day of normal caffeine consumption.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.In general, 25 to 50 milligrams of caffeine is sufficient for most people to report increased alertness and arousal as well as subjectively lower levels of fatigue.^ Influence of caffeine on selective attention in well-rested and fatigued subjects.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Caffeine increases anxiety in people with anxiety disorders.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ After adjusting for various confounders, tea intake was associated with lower blood glucose levels in non-obese (P for trend < 0.001), but not in obese people (P = 0.24).

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[69]

.With these effects, caffeine is an ergogenic, increasing a person's capability for mental or physical labor.^ Caffeine induced alerting effects in various tests and differed from triazolam in some (digit substitution, drowsiness, calmness, mental slowness) but not all variables measured.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Increased anxiogenic effects of caffeine in panic disorders.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ These data support prior reports that panic patients have increased sensitivity to caffeine; some depressed patients may also have increased sensitivity.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects that consumed caffeine compared to control subjects.^ In another study ( Lane, 1996 ) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Recent references are Pastore and Savitz, Case-control study of caffeinated beverages and preterm delivery.

• Coffee and Caffeine FAQ 15 September 2009 6:10 UTC www.nootropics.com [Source type: FILTERED WITH BAYES]
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^ The effects of caffeine and smoking on cognitive performance, subjective variables, heart rate, and EEG were assessed in two sessions.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[70] .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.^ It seems to show much more relevant results.

• Official Google Webmaster Central Blog: Help test some next-generation infrastructure 19 January 2010 8:49 UTC googlewebmastercentral.blogspot.com [Source type: General]

^ One final note: this would probably be even better with iced espresso, because the espresso is so much more powerful and loses its taste less when it's cold.

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^ The sensitivity analysis which means removing one study at a time confirmed the stability of our results.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[71] .Additional studies have reported similar effects.^ In addition, this self-report survey suggested that patients with panic disorder had an increased sensitivity to the effects of one cup of coffee.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The effect was similar to that of acetaminophen, which is frequently combined with caffeine, and showed no relation to the effects on mood or to self-reported coffee drinking.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high-intensity circuits.^ Caffeine can affect velocity in the middle cerebral artery during hyperventilation, hypoventilation, and thinking: A transcranial doppler study.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ In another study ( Lane, 1996 ) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ We found reduced saccadic interruptions as a result of caffeine ingestion compared with placebo (p less than .05).

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[72]

.Caffeine citrate has proven to be of short- and long-term benefit in treating the breathing disorders of apnea of prematurity and bronchopulmonary dysplasia in premature infants.^ Normal caffeine use in humans is long-term, oral use, whereas the experiments in rodents used single parenteral administrations.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ The adaptive changes to long-term caffeine are very dramatic, being not only quantitatively different from but often opposite to the acute effects of caffeine in normal and pathological conditions.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ A fourth infant (premature) attained a high plasma caffeine concentration, but this infant's symptoms were altered by intraventricular hemorrhage.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[68] .The only short-term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy,^[73] and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.^ This initial screening was followed by an 18-day treatment period for which the subjects were split into a placebo and a caffeine group, balanced for caffeine choosers and nonchoosers.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ The adaptive changes to long-term caffeine are very dramatic, being not only quantitatively different from but often opposite to the acute effects of caffeine in normal and pathological conditions.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ A fourth infant (premature) attained a high plasma caffeine concentration, but this infant's symptoms were altered by intraventricular hemorrhage.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[74][75]

.Caffeine relaxes the internal anal sphincter muscles and thus should be avoided by those with fecal incontinence.^ Those who easily become anxious should avoid caffeine.

• Bulk Nutrition - Caffeine Description by David Tolson 19 January 2010 8:49 UTC www.bulknutrition.com [Source type: Academic]

^ Opposite actions of caffeine and creatine on muscle relaxation time in humans .

• Bulk Nutrition - Caffeine Description by David Tolson 19 January 2010 8:49 UTC www.bulknutrition.com [Source type: Academic]

^ Therefore, it should be emphasized that individuals suffering from epilepsy should avoid, or at least reduce consumption of coffee and other caffeine-containing beverages.

• Coffee and Caffeine FAQ 15 September 2009 6:10 UTC www.nootropics.com [Source type: FILTERED WITH BAYES]
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^[76]

.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.^ It has been suggested that the subjects most sensitive to the effects of coffee on sleep might metabolize caffeine more slowly than the others ( Levy and Zylber-Katz, 1983 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In that study, caffeine dose-dependently increased ratings of positive mood, and the higher doses of caffeine were more frequently identified with other stimulant drugs like amphetamine and cocaine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Although not significantly different, the flurazepam, 30 mg, group demonstrated a trend toward poorer performance and a more negative mood than all other groups.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.Caffeine has also a pronounced effect on mollusks and various insects as well as spiders.^ The effects of caffeine and smoking on cognitive performance, subjective variables, heart rate, and EEG were assessed in two sessions.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine induced alerting effects in various tests and differed from triazolam in some (digit substitution, drowsiness, calmness, mental slowness) but not all variables measured.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Rationale The effects of caffeine on mood and performance are well established.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[77]

Further information: Effect of psychoactive drugs on animals

Tolerance and withdrawal

.Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals that regularly consume caffeine adapt to the continuous presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system.^ The role of adenosine receptors in the central action of caffeine.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Adenosine, adenosine receptors and the actions of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Caffeine is the most widely consumed central-nervous-system stimulant.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences.^ There is indeed ample evidence that caffeine (and other adenosine receptor antagonists) can increase behaviors related to dopamine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Blockade of methylxanthine-sensitive adenosine receptors is the currently accepted mechanism of action of caffeine.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ It is therefore important to consider where these two adenosine receptors are located.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[78] .First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation.^ Caffeine increased resting electrodermal activity (EDA) and increased the SC orienting response to the first non-signal tone, but reduced the increase in tonic EDA due to task performance.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.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.^ In line with these effects, caffeine intake has been associated with increased risk of heart attack 1 .

• Bulk Nutrition - Caffeine Description by David Tolson 19 January 2010 8:49 UTC www.bulknutrition.com [Source type: Academic]

^ However, increased sensitivity to caffeine in these patients has been suggested as contributing to their symptoms.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Physiological responses to caffeine during endurance running in habitual caffeine users.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^[78]

.Other research questions the idea that up-regulation of adenosine receptors is responsible for tolerance to the locomotor stimulant effects of caffeine, noting, among other things, that this tolerance is insurmountable by higher doses of caffeine (it should be surmountable if tolerance were due to an increase in receptors), and that the increase in adenosine receptor number is modest and does not explain the large tolerance that develops to caffeine.^ Tolerance to caffeine-induced stimulation of locomotor activity in rats.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ The methylxanthine induces dose-response increases in locomotor activity in animals.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Thus, cerebral energy metabolism does not seem to develop tolerance to the stimulant effects of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[79]

.Caffeine tolerance develops very quickly, especially among heavy coffee and energy drink consumers.^ CrossRef Medline ↵ Colton T , Gosselin RE , Smith RP ( 1968 ) The tolerance of coffee drinkers to caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In addition, it is well known that smokers are particularly liable to smoke when drinking coffee, whereas, on the other hand, coffee is consumed more in the morning and alcohol in the evening.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Complete tolerance to sleep disruption effects of caffeine develops after consuming 400 mg of caffeine 3 times a day for 7 days.^ Tolerance develops to some caffeine effects but not to others.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Secondary analyses of data collected after a day of normal caffeine consumption were also carried out to examine some alternative explanations of their results which showed effects of caffeine after a day of normal caffeine consumption.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Okuma T, Matsuoka H, Matsue Y, Toyomura K Experimental sleep disturbances (model insomnia) were produced by the administration of methylphenidate (MPD) 10 mg and caffeine (CAF) 150 mg.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.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.^ Tolerance develops to some caffeine effects but not to others.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Subsequently, subjects received either caffeine (300 mg t.i.d.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ However, virtually complete tolerance to the increase of locomotor activity was observed in rats consuming approximately 40 mg/kg caffeine per day via their drinking water ( Finn and Holtzman, 1986 ), and this was accompanied by a downward displacement and flattening of the dose-response curve.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[80] .In another experiment, complete tolerance of caffeine was observed when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine.^ However, virtually complete tolerance to the increase of locomotor activity was observed in rats consuming approximately 40 mg/kg caffeine per day via their drinking water ( Finn and Holtzman, 1986 ), and this was accompanied by a downward displacement and flattening of the dose-response curve.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In another study ( Lane, 1996 ) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In one session, subjects received caffeine (2.5 mg/kg bodyweight), while in the other they received placebo.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[81]

.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.^ Caffeine, blood pressure, and serum lipids.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ In response to this oversensitiveness, blood pressure drops dramatically, causing an excess of blood in the head (though not necessarily on the brain), leading to a headache.

• Coffee and Caffeine's Frequently Asked Questions 19 January 2010 8:49 UTC www.faqs.org [Source type: FILTERED WITH BAYES]
• Frequently Asked Questions about Coffee and Caffeine 19 January 2010 8:49 UTC www.indwes.edu [Source type: FILTERED WITH BAYES]

^ Caffeine raises blood pressure at work.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

.Reduced catecholamine activity may cause feelings of fatigue and drowsiness.^ Caffeine has long been suspect of causing mal-formations in fetus, and that it may reduce fertility rates.

• Frequently Asked Questions about Coffee and Caffeine 19 January 2010 8:49 UTC www.indwes.edu [Source type: FILTERED WITH BAYES]

^ Moreover, this effect may be related to antagonism of a tonic inhibitory activity of adenosine A 1 receptors that reduce cholinergic transmission (cf.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Carbohydrate and fluid intake before, during, and after a workout may help to reduce fatigue and enhance performance.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.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.^ Symptoms of depression and anxiety were related to caffeine use.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ High correlation has been obtained between the kynurenine concentration and initial values of personal and reactive anxiety.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ CrossRef Medline ↵ Hicks RA , Hicks GJ , Reyes JR , Cheers Y ( 1983 ) Daily caffeine use and the sleep of college students.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Together, these effects have come to be known as a "crash".^[82]

.Withdrawal symptoms — possibly including headache, irritability, an inability to concentrate, drowsiness, insomnia and pain in the stomach, upper body, and joints^[83] — 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.^ Withdrawal of caffeine, even from moderate intake levels, can produce symptoms such as headache, fatigue and anxiety.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ When caffeine intake is reduced, the body becomes oversensitive to adenosine.

• Coffee and Caffeine's Frequently Asked Questions 19 January 2010 8:49 UTC www.faqs.org [Source type: FILTERED WITH BAYES]

^ Adenosine, adenosine receptors and the actions of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.^ This may be the first evidence for direct neurochemical changes induced by such low, clearly stimulant doses of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ However, also a dose of caffeine taken in the morning can have such effects the following night ( Landolt et al., 1995b ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Withdrawal of caffeine, even from moderate intake levels, can produce symptoms such as headache, fatigue and anxiety.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[84] .Most effective is a combination of both an analgesic and a small amount of caffeine.^ Caffeine is used therapeutically in combination with ergotamine for migraine headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic formulations.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine, in addition to being a food constituent, is also a common analgesic adjuvant that is used in combination with aspirin in certain over-the-counter preparations.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ We conclude that caffeine ingestion is likely to produce small but significant gains in 5-km running performance for both well-trained and recreational runners.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.This is not the only case in which caffeine increases the effectiveness of a drug.^ Mikkelsen EJ Two cases are described in which markedly increased consumption of caffeine led to an exacerbation of a schizophrenic process.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In that study, caffeine dose-dependently increased ratings of positive mood, and the higher doses of caffeine were more frequently identified with other stimulant drugs like amphetamine and cocaine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ This was taken as evidence that adenosine receptor antagonism may not be the only mechanism by which caffeine causes an increased rotation behavior ( Garrett and Holtzman, 1994b ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief.^ More subjects reported unauthorized use of medications during the placebo period (13 percent) than during the caffeine period (2 percent, P = 0.017).

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Mothers who consumed more caffeine also smoked more often, were younger, were less educated, reported less sleep effectiveness and more obstetric complications.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ In their pioneering study on caffeine withdrawal, Dreisbach and Pfeiffer (1943) observed that caffeine was highly efficient in relieving withdrawal headache.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[85] .For this reason, many over-the-counter headache drugs include caffeine in their formula.^ However few behavioral studies have examined this substance's acute effects when administered in a range of doses that include the low doses typically found in foods and over-the-counter drugs.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine is used therapeutically in combination with ergotamine for migraine headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic formulations.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Conclusion(s): The expectation of receiving caffeine under alcohol is sufficient to counter-act the impairing effects of the drug.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.It is also used with ergotamine in the treatment of migraine and cluster headaches as well as to overcome the drowsiness caused by antihistamines.^ Caffeine is used therapeutically in combination with ergotamine for migraine headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic formulations.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

Overuse

.In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as caffeinism.^[86][87] 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.^ The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500-mg dose exceeded those of the 250-mg dose.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The present study examined cardiovascular responses to the combination of caffeine (250mg) and mental arithmetic, cold pressor, and static exercise stressors in 48 healthy males.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11 Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[88][89] .Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease.^ These results suggest that even a single, albeit high, dose of caffeine can induce changes in gene expression that could lead to adaptive changes in the brain.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ It appears that anxiety disorder patients have increased caffeine sensitivity which leads to decreased consumption.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ These results suggest that previous reports of subjective caffeine effects are also suspect because of their failure to control for the increased probability of Type I error.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[90]

.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).^ Furthermore, there was no relationship to the intake of caffeine in patients with anxiety.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ American Psychiatric Association ( 1994 ) Diagnostic and Statistical Manual of Mental Disorders ( American Psychiatric Association , Washington, DC. ) Revised 4th ed.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ American Psychiatric Association ( 1987 ) Diagnostic and Statistical Manual of Mental Disorders ( American Psychiatric Association , Washington, DC. ) Revised 3rd ed.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Caffeine intoxication

Main symptoms of caffeine intoxication.^[68]

.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 (DSM-IV 305.90),^[91] or colloquially the "caffeine jitters". The symptoms of caffeine intoxication are not unlike overdoses of other stimulants.^ The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine is the most widely consumed central-nervous-system stimulant.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine commonly causes symptoms of an acute overdose and withdrawal symptoms.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.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.^ The short term consumption of caffeine may result in increased urination, gastrointestinal distress, tremors, decreased sleep, and anxiety symptoms in certain individuals.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine may produce symptoms of anxiety-nervousness without increasing central norepinephrine turnover.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[89] In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, and psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.^[92][93]

In cases of extreme overdose, death can result. .The median lethal dose (LD₅₀) given orally, is 192 milligrams per kilogram in rats.^ Malformations have been demonstrated in mice at 50-75 mg/kg of caffeine, whereas the lowest dose usually needed to induce malformations is 80 mg/kg in rats.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Indeed, the effect seen at the lowest dose was almost 75% of that maximally observed, suggesting that the threshold effect may be on the order of a few milligrams per kilogram.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Caffeine given as an acute dose of 10 mg/kg increases the rates of cerebral energy metabolism in the rat.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[2] .The LD₅₀ 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 is dependent on half-life.^ Abstract / FREE Full Text ↵ Stern KN , Chait LD , Johanson CE ( 1989 ) Reinforcing and subjective effects of caffeine in normal human volunteers.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In addition, this self-report survey suggested that patients with panic disorder had an increased sensitivity to the effects of one cup of coffee.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Malformations have been demonstrated in mice at 50-75 mg/kg of caffeine, whereas the lowest dose usually needed to induce malformations is 80 mg/kg in rats.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.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.^ There are also several reports on caffeine abstinence and postoperative headaches ( Fennelly et al., 1991 ; Weber et al., 1993 ; Nikolajsen et al., 1994 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ However, as discussed below (Section IX) such constant and regular intake has not been possible to achieve with caffeine in animals and hence there are no reliable animal data relating to this point.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ A review of 86 studies of nicotine withdrawal, caffeine withdrawal, and caffeine toxicity suggests that the symptoms are similar enough to be confused, and that reported nicotine withdrawal symptoms may be a mixture of nicotine withdrawal and caffeine toxicity.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.An exception to this would be taking a drug such as fluvoxamine, which blocks the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine dramatically at 5-fold.^ Caffeine increases maximal anaerobic power and blood lactate concentration.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Caffeine restriction: Effect on blood pressure.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Moderation in all caffeine containing products is the basic rule of thumb for the positive attributes without the undesireable effects of taking too much.

• Bodybuilding.com - Caffeine Information and Product Listing! Caffeine FAQ! 15 September 2009 6:10 UTC www.bodybuilding.com [Source type: FILTERED WITH BAYES]

.It is not contraindicated, but highly advisable to minimize the intake of caffeinated beverages, as drinking one cup of coffee will have the same effect as drinking five under normal conditions.^ Astorino TA; Rohmann RL; Firth K. Effect of caffeine ingestion on one-repetition maximum muscular strength.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ One month later the effect of caffeine alone was tested.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Indeed, not less than 14% of all erstwhile consumers in Vermont had stopped the intake of all caffeine-containing beverages largely for this reason ( Hughes and Oliveto, 1997 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^{[94][95][96][97]} .Death typically occurs due to ventricular fibrillation brought about by effects of caffeine on the cardiovascular system.^ Cardiovascular effects of caffeine.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Given that many caffeine-containing drinks are typically consumed in social settings, surprisingly little is known about the possible effects of caffeine on social behavior (see Bättig and Welzl, 1993 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.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.^ Serum caffeine levels confirmed compliance.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Thus, the levels of caffeine may be at least as high.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Patients with high anxiety scores due to depression do not appear to be supersensitive to caffeine ( Boulenger et al., 1984 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Detection in biological fluids

.Caffeine may be quantitated in blood, plasma or serum to monitor therapy in neonates, confirm a diagnosis of poisoning in hospitalized patients or assist in a medicolegal death investigation.^ An alternative approach to blood pressure monitoring would be to ask the patient about recent caffeine consumption and interpret the blood pressure reading based on this information.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ These data support prior reports that panic patients have increased sensitivity to caffeine; some depressed patients may also have increased sensitivity.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.Urine caffeine concentrations are frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.^ Caffeine pharmacokinetics were assessed by measurement of saliva caffeine concentrations.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Peak plasma caffeine concentration is reached between 15 and 120 min after oral ingestion in humans and equals 8 to 10 mg/l for doses of 5 to 8 mg/kg ( Arnaud and Welsch, 1982 ; Bonati et al., 1982 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Sublethal effects measured for caffeine exposure included impaired C. dubia reproduction (IC50 = 44 mg/L) and inhibited P. promelas growth (IC50 = 71 mg/L).

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[98]

Anxiety and sleep disorders

.Two infrequently diagnosed caffeine-induced disorders that are recognized by the American Psychological Association (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder, which can result from long-term excessive caffeine intake.^ Similar associations were observed for caffeine intake.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Copyright 2008, American Psychological Association .

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Caffeine increases anxiety in people with anxiety disorders.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.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.^ Okuma T, Matsuoka H, Matsue Y, Toyomura K Experimental sleep disturbances (model insomnia) were produced by the administration of methylphenidate (MPD) 10 mg and caffeine (CAF) 150 mg.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ This may be the first evidence for direct neurochemical changes induced by such low, clearly stimulant doses of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Sleep disorders constitute a major predictor for depression ( Chang et al., 1997 ), and caffeine is known to affect sleep.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[91]

.In some individuals, the large amounts of caffeine can induce anxiety severe enough to necessitate clinical attention.^ The physiological effects are partially similar to the effects seen in clinical anxiety states, and they are also consistent with the physiological concomitants of good sustained attention.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Anxiety disorder patients do not consume toxic amounts of caffeine.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The short term consumption of caffeine may result in increased urination, gastrointestinal distress, tremors, decreased sleep, and anxiety symptoms in certain individuals.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.This caffeine-induced anxiety disorder can take many forms, from generalized anxiety to panic attacks, obsessive-compulsive symptoms, or even phobic symptoms.^ Caffeine increases anxiety in people with anxiety disorders.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine is believed to induce anxiety in normal people and anxiety disorder patients and panic attacks in panic disorder patients.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Anxiety disorder patients do not consume toxic amounts of caffeine.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[91] .Because this condition can mimic organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, or even schizophrenia, a number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced psychosis would simply be to stop further caffeine intake.^ Caffeine toxicity remains a rarely reported condition, which may mimic anxiety disorders.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine increases anxiety in people with anxiety disorders.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine is believed to induce anxiety in normal people and anxiety disorder patients and panic attacks in panic disorder patients.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[99] .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.^ Although no impact is observed on dementia incidence, further studies are required to ascertain whether caffeine may nonetheless be of potential use in prolonging the period of mild cognitive impairment in women prior to a diagnosis of dementia.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ We analyzed the association of personality traits with both caffeine intake and smoking, controlling the possible confounding effects of sex, age and each substance with the other one.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ It is suggested that caffeine use is one of the important factors, in researching psychological health among the general population.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[87] .Co administration of theanine was shown to greatly reduce this caffeine-induced anxiety.^ When caffeine was added together with NCS to the culture of HeLa-S3 cells, NCS-induced inhibition of DNA synthesis and of mitosis was markedly reduced in the presence of caffeine.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Although depressed patients did not differ from control subjects in caffeine intake or most symptoms, more depressed patients reported that caffeine induced anxiety.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Acute exercise reduces caffeine-induced anxiogenesis.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^[100]

Effects on memory and learning

Anhydrous caffeine

.An array of studies found that caffeine could have nootropic effects, inducing certain changes in memory and learning.^ Effect of caffeine and nicotine on avoidance learning in mice: Lack of interaction.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In some studies, the effects of caffeine are even weaker in this regard than those of nicotine, which is notoriously unreliable as a reinforcing drug.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Researchers have found that long-term consumption of low dose caffeine slowed hippocampus-dependent learning and impaired long-term memory in mice.^ Low-dose caffeine physical dependence in humans.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ This may be the first evidence for direct neurochemical changes induced by such low, clearly stimulant doses of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Maternal consumption of caffeine affects brain composition, especially in case of a low-protein diet and also seems to interfere with zinc fixation in brain.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls during the experiment.^ We found reduced saccadic interruptions as a result of caffeine ingestion compared with placebo (p less than .05).

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ For example, it must be kept in mind that in most experiments on rodents, one single high dose of caffeine is administered, whereas human consumption of coffee is divided up during the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Caffeine consumption did not reduce dementia risk over 4 years.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.The conclusion was that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.^ The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In a double-blind crossover study of 26 long-stay schizophrenic patients, no correlation was found between caffeine consumption and levels of anxiety and depression.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Normal caffeine use in humans is long-term, oral use, whereas the experiments in rodents used single parenteral administrations.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[101].

.In another study, caffeine was added to rat neurons in vitro.^ Another study from the same laboratory ( Silverman et al., 1994 ) revealed that situational conditions might have a substantial effect on caffeine reinforcement.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Abstract / FREE Full Text ↵ Calabresi P , Lacey MG , North RA ( 1989 ) Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Essentially similar results were obtained in a rat study where rats self-administering cocaine were treated with caffeine either as an i.p.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.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.^ This association is highly variable between preparations and methods used.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ There is a weak association between caffeine and alcohol consumption, which is stronger if the drugs are used heavily ( Istvan and Matarazzo, 1984 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In these regions of the brain there is a marked discrepancy between the distribution of the receptor and the corresponding mRNA. This suggests that many of the adenosine A 1 receptors in the area of the DA cell bodies are located not on the dopaminergic neurons, but on the terminals of the input neurons.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

After an hour or two, however, these cells returned to their original shape.^[102]

.Another study showed that human 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 cingulate cortex, a part of the brain that controls attention.^ The effects of caffeine on mood have been studied in human subjects.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ At week 2, the other 6 subjects received caffeine.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ These results suggest that caffeine modulates neuronal activity as evidenced by fMRI signal changes in a network of brain areas associated with executive and attentional functions during working memory processes.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.The caffeinated subjects also performed better on the memory tasks.^ The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine increased resting electrodermal activity (EDA) and increased the SC orienting response to the first non-signal tone, but reduced the increase in tonic EDA due to task performance.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The effects of caffeine and smoking on cognitive performance, subjective variables, heart rate, and EEG were assessed in two sessions.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[103]

.However, a different study showed that caffeine could impair short-term memory and increase the likelihood of the tip of the tongue phenomenon.^ [K]o, however, caffeine could increase the upstroke of slow response and the force.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In that study, caffeine dose-dependently increased ratings of positive mood, and the higher doses of caffeine were more frequently identified with other stimulant drugs like amphetamine and cocaine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ The adaptive changes to long-term caffeine are very dramatic, being not only quantitatively different from but often opposite to the acute effects of caffeine in normal and pathological conditions.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.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.^ The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The purpose of this study was to investigate if caffeine ingestion improves 5-km time-trial performance in well-trained and recreational runners.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ These results suggest that even a single, albeit high, dose of caffeine can induce changes in gene expression that could lead to adaptive changes in the brain.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[104] .In essence, caffeine consumption increases mental performance related to focused thought while it may decrease broad-range thinking abilities.^ The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Caffeine increased resting electrodermal activity (EDA) and increased the SC orienting response to the first non-signal tone, but reduced the increase in tonic EDA due to task performance.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ There is indeed ample evidence that caffeine (and other adenosine receptor antagonists) can increase behaviors related to dopamine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Effects on the heart

.Caffeine binds to receptors on the surface of heart muscle cells, which leads to an increase in the level of cAMP inside the cells (by blocking the enzyme that degrades cAMP), mimicking the effects of epinephrine (which binds to receptors on the cell that activate cAMP production).^ There is indeed ample evidence that caffeine (and other adenosine receptor antagonists) can increase behaviors related to dopamine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Background: Clopidogrel inhibits the platelet P2Y12 receptor, leading to increased intracellular cyclic AMP (CAMP) levels.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Holtzman (1996) also found that the adenosine analog CGS 21680 blocked the effect of CGS 15943, indicating a role of A 2A receptors.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

cAMP acts as a ."second messenger," and activates a large number of protein kinase A (PKA; cAMP-dependent protein kinase).^ A second factor that limits its usefulness as a radioligand is that it is an agonist and that its affinity consequently depends on the association of the receptor with G-proteins.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Indeed, there is evidence that cAMP-dependent protein kinase is very important in the acquisition of cocaine self-administration and also in relapse into cocaine-seeking behavior ( Self et al., 1998 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.This has the overall effect of increasing the rate of glycolysis and increases the amount of ATP available for muscle contraction and relaxation.^ Results: Nicotine increased heart rate and subjective ratings indicative of aversive effects, and decreased reaction times.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Abstract / FREE Full Text ↵ Myers DE , Shaikh Z , Zullo TG ( 1997 ) Hypoalgesic effect of caffeine in experimental ischemic muscle contraction pain.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Pairing with quinine increased the rated bitterness of the tea odour, and reduced the rated sweetness of the tea flavour, post-training, independent of effects of caffeine.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.According to one study, caffeine in the form of coffee, significantly reduces the risk of heart disease in epidemiological studies.^ Caffeine consumption did not reduce dementia risk over 4 years.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ A lower risk of coronary heart disease among moderate coffee drinkers might be due to antioxidants found coffee.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Results: Coffee and caffeine consumption at all 3 time points were unrelated to total miscarriage risk and the risk of loss after the interview.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.However, the protective effect was found only in participants who were not severely hypertensive (i.e., patients that are not suffering from a very high blood pressure).^ Effect of coffee on ambulatory blood pressure in patients with hypertension.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Caffeine restriction: Effect on blood pressure.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ The effects of caffeine on ambulatory blood pressure, heart rate, and mood in coffee drinkers.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

.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.^ We found reduced saccadic interruptions as a result of caffeine ingestion compared with placebo (p less than .05).

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ A significant interaction between age and condition (IRR = 2.27 95% Cl, 1.28-4.16 P < 0.01) showed that napping led to fewer inappropriate line crossings in younger participants than in middle-aged participants.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ MEASUREMENTS--Gestational age was determined from ultrasound and maternal dates; preterm birth was defined as less than 37 completed weeks.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[105]

Effects on children

.It is a common myth that excessive intake of caffeine results in stunted growth within children, particularly younger children and teenagers.^ Because caffeine is so widely available and frequently consumed by children, these results are important and need replication.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Since caffeine plasma levels were indistinguishable between suppressors and nonsuppressors we reject that excessive caffeine intake accounts for DST nonsuppression among individuals with schizophrenia.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ To determine whether caffeine intake influenced DST results in depression, we retrospectively studied the relationship between regular daily caffeine consumption and pretreatment DST status in major depressives.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[106] - recently, scientific studies have disproved the notion. .Children are found to experience the same effects from caffeine as adults.^ The reinforcing and subjective effects of caffeine (100 and 300 mg, PO) were determined in a group of 18 normal, healthy adults.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ This double-blind cross-over pilot study evaluated the effect of ibuprofen and caffeine compared with ibuprofen and placebo in 12 children with headaches.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Another study from the same laboratory ( Silverman et al., 1994 ) revealed that situational conditions might have a substantial effect on caffeine reinforcement.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.However, subsidiary beverages that contain caffeine, such as energy drinks, most of which contain high amounts of caffeine, have been banned in many schools throughout the world, due to other adverse effects having been observed in prolonged consumption of caffeine.^ Effects of caffeine consumption on delayed conception.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Objective: To describe benefits and adverse effects associated with the consumption of energy drinks.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Caffeine is consumed in many beverages and foods throughout the world.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^[107] .Furthermore, in one study, caffeinated Cola has been linked to hyperactivity in children.^ This double-blind cross-over pilot study evaluated the effect of ibuprofen and caffeine compared with ibuprofen and placebo in 12 children with headaches.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ In one study it was shown that subjects involved in a discrimination study were able to make an accurate choice of caffeine or placebo ( Silverman et al., 1994 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ There is some evidence for a causal link between caffeine and ethanol use from animal studies, and this relates to effects of ethanol on adenosine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[108]

Caffeine intake during pregnancy

.Despite its widespread use and the conventional view that it is a safe substance, a 2008 study suggested that pregnant women who consume 200 milligrams or more of caffeine per day have about twice the miscarriage risk as women who consume none.^ In another study ( Lane, 1996 ) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Three capsules were given per day, the caffeine capsules containing increasing amounts of caffeine with 100 mg at the start and 300 mg at the end of the treatment phase.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Although no impact is observed on dementia incidence, further studies are required to ascertain whether caffeine may nonetheless be of potential use in prolonging the period of mild cognitive impairment in women prior to a diagnosis of dementia.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.However, another 2008 study found no correlation between miscarriage and caffeine consumption.^ However, there was no relationship between caffeine consumption and depressive symptoms.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In a double-blind crossover study of 26 long-stay schizophrenic patients, no correlation was found between caffeine consumption and levels of anxiety and depression.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ In another study ( Lane, 1996 ) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[109] .The UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake to less than 200 mg of caffeine a day—the equivalent of two cups of instant coffee or a half to two cups of fresh coffee.^ Therefore, pregnant mothers should be advised to limit their coffee and caffeine intake to 300 mg caffeine/day (i.e.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ It is thus recommended that all patients should be questioned on their caffeine intake.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Indeed, not less than 14% of all erstwhile consumers in Vermont had stopped the intake of all caffeine-containing beverages largely for this reason ( Hughes and Oliveto, 1997 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^[110][111] .The FSA noted that the design of the studies made it impossible to be certain that the differences were due to caffeine per se, instead of other lifestyle differences possibly associated with high levels of caffeine consumption, but judged the advice to be prudent.^ Differences in fertility associated with caffeinated beverage consumption.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Patients with high anxiety scores due to depression do not appear to be supersensitive to caffeine ( Boulenger et al., 1984 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Effects of black and green tea consumption on blood glucose levels in non-obese elderly men and women from Mediterranean Islands (MEDIS epidemiological study).

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

Dr De-Kun Li of Kaiser Permanente Division of Research, writing in the American Journal of Obstetrics and Gynecology, concluded that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage".^[112] However, Dr. David A. 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.^[109]

Genetics and caffeine metabolism

A 2006 study by Dr. Ahmed El-Sohemy at the University of Toronto discovered a link between a gene affecting caffeine metabolism and the effects of coffee on health.^[113] .Some people metabolize caffeine more slowly than the general population due to variations in a specific cytochrome P450 gene^[114], and there is evidence people with this gene may be at a higher risk of myocardial infarction when consuming large amounts of coffee.^ Metabolism of caffeine and other components of coffee.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ There were generally more complaints in the afternoons than in the mornings.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Indeed, not less than 14% of all erstwhile consumers in Vermont had stopped the intake of all caffeine-containing beverages largely for this reason ( Hughes and Oliveto, 1997 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.For rapid metabolizers, however, coffee seemed to have a preventative effect.^ It has been suggested that the subjects most sensitive to the effects of coffee on sleep might metabolize caffeine more slowly than the others ( Levy and Zylber-Katz, 1983 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Thus, cerebral energy metabolism does not seem to develop tolerance to the stimulant effects of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Slow and fast metabolizers are comparably common in the general population, and this has been blamed for the wide variation in studies of the health effects of caffeine.^ The studies concerning caffeine reinforcement in animals have generally examined the effect of i.v.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Also in studies with oral intake, the reinforcing effect of caffeine varies with the dose.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In some studies, the effects of caffeine are even weaker in this regard than those of nicotine, which is notoriously unreliable as a reinforcing drug.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Intraocular Pressure and caffeine

.Recent data has suggested that caffeine consumption can raise intraocular pressure.^ Caffeine raises blood pressure at work.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Secondary analyses of data collected after a day of normal caffeine consumption were also carried out to examine some alternative explanations of their results which showed effects of caffeine after a day of normal caffeine consumption.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ An alternative approach to blood pressure monitoring would be to ask the patient about recent caffeine consumption and interpret the blood pressure reading based on this information.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^[115] This may be a significant consideration for those with open angle glaucoma.^[116]

Decaffeination

Main article: Decaffeination

.Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an important industrial process and can be performed using a number of different solvents.^ The majority of caffeine is produced in decaffeinating coffee.

• Bodybuilding.com - Caffeine Information and Product Listing! Caffeine FAQ! 15 September 2009 6:10 UTC www.bodybuilding.com [Source type: FILTERED WITH BAYES]

^ Associations between maternal decaffeinated and caffeinated coffee consumption and fetal growth and gestational duration.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ The responses of the patient groups regarding caffeine and carbohydrate use did not differ from each other, but all differed significantly from the responses of normal volunteers.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods:

Water extraction

Coffee beans are soaked in water. .The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine.^ Metabolism of caffeine and other components of coffee.

• Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations 19 January 2010 8:49 UTC www.nap.edu [Source type: Academic]

^ Caffeine is an alkaloid; of which there are numerous compounds such as the methylxanthines, with three distinguished compounds: caffeine, theophylline, and theobromine, found in guarana, kola nuts, coffee, tea, cocoa beans, mate and other plants.

• Bodybuilding.com - Caffeine Information and Product Listing! Caffeine FAQ! 15 September 2009 6:10 UTC www.bodybuilding.com [Source type: FILTERED WITH BAYES]

^ In addition, it is well known that smokers are particularly liable to smoke when drinking coffee, whereas, on the other hand, coffee is consumed more in the morning and alcohol in the evening.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor.^[117] .Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.^ Nobody really needs caffeine, but I once read an article that said if all of America were to stop drinking coffee or caffeine-containing soft drinks/beverages, productivity would fall by 70%.

• Bodybuilding.com - Caffeine Information and Product Listing! Caffeine FAQ! 15 September 2009 6:10 UTC www.bodybuilding.com [Source type: FILTERED WITH BAYES]

^ Rationale: Although both contain behaviourally significant concentrations of caffeine, tea is commonly perceived to be a less stimulating drink than coffee.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ CrossRef Medline ↵ Griffiths RR , Bigelow GE , Liebson IA ( 1986a ) Human coffee drinking: Reinforcing and physical dependence producing effects of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Supercritical carbon dioxide extraction

.Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used.^ More subjects reported unauthorized use of medications during the placebo period (13 percent) than during the caffeine period (2 percent, P = 0.017).

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ Therefore the induction of IEG expression might reflect behavioral depression rather than the behavioral stimulation that is the basis for the widespread human use of caffeine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ This could indicate that the decrease in caloric intake noted above (Section IVF) might be an effect of acute rather than long-term caffeine use.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

The extraction process is simple: CO₂ is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. .Under these conditions, CO₂ is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine.^ I would like to simply do a copy-and-paste of these pre-saved searches into Google's front page search screen.

• Official Google Webmaster Central Blog: Help test some next-generation infrastructure 19 January 2010 8:49 UTC googlewebmastercentral.blogspot.com [Source type: General]

^ It cannot be excluded that caffeine might have analgesic properties for specific types of pain, which may be the case for headache ( Ward et al., 1991 ), which is significantly and dose-dependently reduced by caffeine under double-blind conditions.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Conversely, liking for the taste and aroma of coffee might be acquired through the process of classical conditioning, involving association of these orosensory cues with the psychopharmacological consequences of caffeine ingestion.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.The caffeine-laden CO₂ is then sprayed with high pressure water to remove the caffeine.^ A regression analysis on maternal depression suggested that 28% of the variance was explained by low support scale scores, not co-sleeping with their infant and high caffeine intake.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.^[117]

Extraction by organic solvents

.Organic solvents such as ethyl acetate present much less health and environmental hazard than previously used chlorinated and aromatic solvents.^ Accordingly, the overall activity of the nucleus accumbens is much less affected by caffeine than by cocaine, nicotine, and amphetamine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ Exsmokers use more coffee than nonsmokers but somewhat less than smokers.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The reinforcing properties of caffeine are, however, very much weaker and less consistent than those of cocaine and amphetamine.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.Another method is to use triglyceride oils obtained from spent coffee grounds.^ Methods: Data on oral contraceptive use, habitual coffee consumption and smoking habits were obtained from 100 Serbian and 149 Swedish healthy volunteers using a detailed questionnaire.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Using this method, the reward values of cigarettes and coffee were compared ( Bickel et al., 1992 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

Religion

.Some Latter-day Saints (Mormons), Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists^[118] do not consume caffeine.^ Secondary analyses of data collected after a day of normal caffeine consumption were also carried out to examine some alternative explanations of their results which showed effects of caffeine after a day of normal caffeine consumption.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ The odds ratio for patients to develop postoperative headache amounted to 5.0 for those consuming more than 400 mg/day caffeine and to 3.7 for those operated after noon on the following day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.A few followers from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive.^ Participants rated legal sanctions against pregnant women who used one of these substances and risk potential for developing children.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ Caffeine is one of the most widely consumed psychoactive substances in the world and is ingested in a variety of favorites, such as coffee, tea, cola and so on.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: “With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful drugs under circumstances that would result in acquiring the habit.^ Indeed, not less than 14% of all erstwhile consumers in Vermont had stopped the intake of all caffeine-containing beverages largely for this reason ( Hughes and Oliveto, 1997 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ In another study ( Lane, 1996 ) it was found that the rate of smoking was higher during such periods of the day when caffeine-containing beverages were consumed than during other parts of the day.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ The results indicated that the expectation of receiving caffeine was sufficient to counteract the impairment of intentional control seen under alcohol.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

.Any beverage that contains ingredients harmful to the body should be avoided.” (Priesthood Bulletin, Feb.^ Objective: To test whether consumption of a beverage containing active ingredients will increase 24-hour energy metabolism in healthy, young, lean individuals.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

1972, p. 4.) See also Word of Wisdom.

.Gaudiya Vaishnava Hindus generally also abstain from caffeine, as it is alleged to cloud the mind and over-stimulate the senses.^ As already noted, psychomotor stimulants do not readily generalize to caffeine ( Chait and Johanson, 1988 ).

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

.To be initiated under a guru, one must have had no caffeine (along with alcohol, nicotine and other drugs) for at least a year.^ The results indicated that the expectation of receiving caffeine was sufficient to counteract the impairment of intentional control seen under alcohol.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

^ In one session, subjects received caffeine (2.5 mg/kg bodyweight), while in the other they received placebo.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ The patients (N = 94) were assessed for their intake of alcohol, nicotine, and caffeine, and then treated openly for 8 weeks with 20 mg/day of fluoxetine.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

.In Islam the main rule on caffeine is that it is permissible, however it is worth noting that it should not be overused and can cause severe harm to one's body.^ However, not everyone agrees that such a correction based on the metabolic body weight should be applied.

• Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]

^ The caffeine-caused reduction of cell cycle effects was also observed in several other cancer chemotherapeutic agents, including bleomycin and Adriamycin.

• Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]

^ However, caffeine and sugar are present in amounts known to cause a variety of adverse health effects.

• CORK Bibliography: Caffeine 15 September 2009 6:10 UTC www.projectcork.org [Source type: Academic]

With regard to the caffeine in coffee, Imam Shihab al-Din said: 'it is halal (lawful) to drink, because all things are halal (lawful) except that which God has made haraam (unlawful)'.^[119]

See also

Pharmacy and Pharmacology portal

• Coffee substitute

References

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External links

.

• How Stuff Works: "How Caffeine Works"
• Erowid Caffeine Vaults
• Highly Caffeinated: The Caffeine Information Archive"
• National Geographic January 2005: Caffeine
• Caffeine Zone: Social and Medical info on caffeine and its effects.
• Naked Scientists Online: Why do plants make caffeine?
• The Physician and Sportsmedicine: Caffeine: A User's Guide
• The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
• Coffee: A Little Really Does Go a Long Way, NPR, September 28, 2006
• Does coffee really give you a buzz?^ In some studies, the effects of caffeine are even weaker in this regard than those of nicotine, which is notoriously unreliable as a reinforcing drug.
  • Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]
  
  ^ C. Effects of Caffeine in the Cortex and Hippocampus—Information Processing and Performance .
  • Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use — Pharmacological Reviews 19 January 2010 8:49 UTC pharmrev.aspetjournals.org [Source type: Academic]
  
  ^ The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
  • Psychopharmacology of Caffeine. 15 September 2009 6:10 UTC www.psycom.net [Source type: Academic]
  
  by John Triggs in the Daily Express April 17 2007
• Caffeine: ChemSub Online
• How much caffeine is in your daily habit? (Caffeine content in common foods and drinks) by Mayo Clinic Staff October 2007
• How to determine caffeine in decaffeinated coffee by NIR spectroscopy

News

• Alcohol and Drugs History Society: Caffeine news page
• National Post: Caffeine linked to psychiatric disorders
• Caffeine Withdrawal Recognized as a Disorder

Health

• Is Caffeine a Health Hazard?
• eMedicine Caffeine-Related Psychiatric Disorders
• Protects brain from Alzheimer's?

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Stimulants Adamantanes Adaphenoxate • Adapromine • Amantadine • Bromantane • Chlodantane • Gludantane • Memantine • Midantane Arylcyclohexylamines Benocyclidine • Dieticyclidine • Esketamine • Eticyclidine • Gacyclidine • Ketamine • Phencyclamine • Phencyclidine • Rolicyclidine • Tenocyclidine • Tiletamine • Benzazepines 6-Br-APB • SKF-81297 • SKF-82958 Cholinergics A-84543 • A-366,833 • ABT-202 • ABT-418 • AR-R17779 • Altinicline • Anabasine • Arecoline • Cotinine • Cytisine • Dianicline • Epibatidine • Epiboxidine • GTS-21 • Ispronicline • Nicotine • PHA-543,613 • PNU-120,596 • PNU-282,987 • Pozanicline • Rivanicline • Sazetidine A • SIB-1553A • SSR-180,711 • TC-1698 • TC-1827 • TC-2216 • TC-5619 • Tebanicline • UB-165 • Varenicline Convulsants Anatoxin-a • Bicuculline • DMCM • Flurothyl • Gabazine • Pentetrazol • Picrotoxin • Strychnine • Thujone Eugeroics Adrafinil • Armodafinil • CRL-40941 • Modafinil Oxazolines 4-Methylaminorex • Aminorex • Clominorex • Cyclazodone • Fenozolone • Fluminorex • Pemoline • Thozalinone Phenethylamines 2-Fluoroamphetamine • 2-Fluoromethamphetamine • 2-OH-PEA • 2-Phenyl-3-aminobutane • 2-Phenyl-3-methylaminobutane • 2,3-MDA • 3-Fluoroamphetamine • 3-Fluoromethcathinone • 3-Methoxyamphetamine • 3-Methylamphetamine • 4-BMC • 4-Ethylamphetamine • 4-FA • 4-FMA • 4-MA • 4-MMA • 4-MTA • 6-FNE • Alfetamine • α-Ethylphenethylamine • Amfecloral • Amfepentorex • Amfepramone • Amidephrine • Amphetamine (Dextroamphetamine, Levoamphetamine) • Amphetaminil • Arbutamine • Atomoxetine (Tomoxetine) • β-Methylphenethylamine • Benfluorex • Benzphetamine • BDB (J) • BOH (Hydroxy-J) • BPAP • Buphedrone • Bupropion (Amfebutamone) • Butylone • Cathine • Cathinone • Chlorphentermine • Clenbuterol • Clobenzorex • Clortermine • D-Deprenyl • Denopamine • Dimethoxyamphetamine • Dimethylamphetamine • Dimethylcathinone (Dimethylpropion, Metamfepramone) • Dobutamine • DOPA (Dextrodopa, Levodopa) • Dopamine • Dopexamine • Droxidopa • EBDB (Ethyl-J) • Ephedrine • Epinephrine (Adrenaline) • Epinine (Deoxyepinephrine) • Etafedrine • Ethcathinone (Ethylpropion) • Ethylamphetamine (Etilamfetamine) • Ethylnorepinephrine (Butanefrine) • Ethylone • Etilefrine • Fenbutrazate • Fencamine • Fencamfamine • Fenethylline • Fenfluramine (Dexfenfluramine) • Fenproporex • Flephedrone • Fludorex • Furfenorex • Gepefrine • HMMA • Hordenine • Ibopamine • Indanorex • IMP • Indanylamphetamine • Isoetarine • Isoprenaline (Isoproterenol) • L-Deprenyl (Selegiline) • Lefetamine • Lisdexamfetamine • Lophophine (Homomyristicylamine) • Manifaxine • MBDB (Methyl-J; "Eden") • MDA (Tenamfetamine) • MDBU • MDEA ("Eve") • MDMA ("Ecstasy", "Adam") • MDMPEA (Homarylamine) • MDOH • MDPR • MDPEA (Homopiperonylamine) • Mefenorex • Mephedrone • Mephentermine • Metanephrine • Metaraminol • Methamphetamine (Desoxyephedrine, Methedrine; Dextromethamphetamine, Levomethamphetamine) • Methoxamine • Methoxyphenamine • MMA • Methcathinone (Methylpropion) • Methedrone • Methoxyphenamine • Methylone • MMDA • MMDMA • MMMA • Naphthylamphetamine • Nisoxetine • Norepinephrine (Noradrenaline) • Norfenefrine • Norfenfluramine • Normetanephrine • Octopamine • Orciprenaline • Ortetamine • Oxilofrine • Paredrine (Norpholedrine, Oxamphetamine, Mycadrine) • PBA • PCA • PHA • Pargyline • Pentylone • Phendimetrazine • Phenmetrazine • Phenpentermine • Phenpromethamine • Phentermine • Phenylalanine • Phenylephrine (Neosynephrine) • Phenylpropanolamine • Pholedrine • PIA • PMA • PMEA • PMMA • PPAP • Prenylamine • Propylamphetamine • Pseudoephedrine • Radafaxine • Ropinirole • Salbutamol (Albuterol; Levosalbutamol) • Sibutramine • Synephrine (Oxedrine) • Theodrenaline • Tiflorex (Flutiorex) • Tranylcypromine • Tyramine • Tyrosine • Xamoterol • Xylopropamine • Zylofuramine Piperazines 2C-B-BZP • BZP • DBL-583 • GBR-12783 • GBR-12935 • GBR-13069 • GBR-13098 • GBR-13119 • MeOPP • MBZP • Vanoxerine Piperidines 2-Benzylpiperidine • 4-Benzylpiperidine • Desoxypipradrol • Diphemethoxidine • Ethylphenidate • Methylnaphthidate • Methylphenidate (Dexmethylphenidate) • Nocaine • Phacetoperane • Pipradrol • SCH-5472 Pyrrolidines α-PPP • α-PBP • α-PVP • MDPPP • MDPBP • MDPV • MPBP • MPHP • MPPP • MOPPP • Naphyrone • Prolintane • Pyrovalerone Tropanes 3α-Bis-(4-fluorophenyl)methoxytropane • 3-CPMT • 3-Pseudotropyl-4-fluorobenzoate • Altropane (IACFT) • Brasofensine • CFT (WIN 35,428) • β-CIT (RTI-55) • Cocaethylene • Cocaine • Dichloropane (RTI-111) • Difluoropine • FE-β-CPPIT • FP-β-CPPIT • Ioflupane (123I) • Norcocaine • PIT • PTT • RTI-31 • RTI-32 • RTI-51 • RTI-105 • RTI-112 • RTI-113 • RTI-117 • RTI-121 (IPCIT) • RTI-126 • RTI-150 • RTI-154 • RTI-171 • RTI-177 • RTI-183 • RTI-194 • RTI-202 • RTI-229 • RTI-241 • RTI-336 • RTI-354 • RTI-371 • RTI-386 • Salicylmethylecgonine • Tesofensine • Troparil (β-CPT, WIN 35,065-2) • Tropoxane • WF-23 • WF-33 • WF-60 Xanthines Aminophylline • Caffeine • Dimethazan • Paraxanthine • Theobromine • Theophylline Others 1-(Thiophen-2-yl)-2-aminopropane • 2-Amino-1,2-dihydronaphthalene • 2-Aminoindane • 2-Aminotetralin • 2-Diphenylmethylpyrrolidine • 2-MDP • 5-(2-Aminopropyl)indole • AL-1095 • Amfonelic acid • Amineptine • Amiphenazole • Atipamezole • Bemegride • Benzydamine • BTQ • BTS 74,398 • Carphedon • Ciclazindol • Cilobamine • Clofenciclan • Cropropamide • Crotetamide • Diclofensine • Dimethocaine • Diphenylprolinol • Efaroxan • Etamivan • Fenpentadiol • Feprosidnine • Gamfexine • Gilutensin • GYKI-52895 • Hexacyclonate • Idazoxan • Indatraline • JNJ-7925476 • JZ-IV-10 • Lazabemide • Leptacline • LR-5182 • Mazindol • Meclofexonate • Medifoxamine • Mefexamide • Mesocarb • Nefopam • Nikethamide • Nomifensine • O-2172 • Oxaprotiline • Phthalimidopropiophenone • Propylhexedrine • PRC200-SS • Rasagiline • Rauwolscine • Rubidium chloride • Tametraline • Tandamine • UH-232 • Yohimbine • See also Sympathomimetic amines

Psychostimulants, Agents Used for ADHD, and Nootropics (N06B) Centrally acting sympathomimetics Amphetamine • Amphetaminil • Atomoxetine • Dextroamphetamine • Dextromethamphetamine • Fencamfamine • Fenozolone • Fenethylline • Lisdexamfetamine • Methylphenidate • Mesocarb • Pemoline • Pipradrol • Prolintane Xanthine derivatives Caffeine • Propentofylline • Fenethylline Glutamate receptor Racetams Aniracetam • Nefiracetam • Noopept • Oxiracetam • Phenylpiracetam • Piracetam • Pramiracetam Ampakines CX-516 • CX-546 • CX-614 • CX-691 • CX-717 • IDRA-21 • LY-404,187 • LY-503,430 • PEPA • Sunifiram • Unifiram Eugeroics / Benzhydryl compounds Adrafinil • Armodafinil • Modafinil Histamine H3 receptor antagonists A-349,821 • ABT-239 • Ciproxifan • GSK-189,254 GABAA α5 inverse agonists α5IA • L-655,708 • PWZ-029 • Suritozole • TB-21007 • ZK-93426 Dopamine D1 receptor agonists A-77636 • Dihydrexidine • Dinapsoline • Doxanthrine • SKF-81297 • 6-Br-APB α7 nicotinic agonists / PAMs AR-R17779 • PNU-282,987 • SSR-180,711 Prolyl endopeptidase inhibitors S-17092 Other psychostimulants and nootropics Acetylcarnitine • Adafenoxate • Bifemelane • Carbenoxolone • Citicoline • Cyprodenate • Ensaculin • Idebenone • Ispronicline • Deanol • Dimebon • Fipexide • Leteprinim • Linopirdine • Meclofenoxate • Nizofenone • Pirisudanol • Pyritinol • Rubidium • Sulbutiamine • Taltirelin • Tricyanoaminopropene • Vinpocetine

Adenosinergics Receptor Ligands A1 Agonists: 2'-MeCCPA • CCPA • GR 79236 • N6-Cyclopentyladenosine • SDZ WAG 994 Antagonists: 8-Phenyl-1,3-dipropylxanthine • Acefylline • Bamifylline • Caffeine • CPX • Chlorotheophylline • Cyclopentyltheophylline‎ • DPCPX • Paraxanthine • PSB 36 • Rolofylline • Theophylline A2 A2A Agonists: ATL-146e • CGS-21680 • Regadenoson Antagonists: Acefylline • Caffeine • Istradefylline • Paraxanthine • Preladenant • SCH-442,416 • SCH-58261 • Theophylline • ZM-241,385 A2B Agonists: 5'-N-ethylcarboxamidoadenosine • BAY 60–6583 • LUF-5835 • LUF-5845 Antagonists: Acefylline • Chlorotheophylline • CVT-6883 • MRS-1706 • MRS-1754 • PSB-603 • PSB-788 • PSB-1115 • Theophylline A3 Agonist: 2-(1-Hexynyl)-N-methyladenosine • 2-Cl-IB-MECA • CF-101 (IB-MECA) • CP-532,903 • MRS-3558 Antagonist: Acefylline • Chlorotheophylline • KF-26777 • MRE3008F20 • MRS-1191 • MRS-1220 • MRS-1334 • MRS-1523 • MRS-3777 • PSB-10 • PSB-11 • Theophylline • VUF-5574 Reuptake Inhibitors Plasmalemmal ENT Inhibitors Dilazep • Dipyridamole • Hexobendine • Pentoxifylline • Propentofylline Vesicular VNT Inhibitors ..... Enzyme Inhibitors Anabolism ..... ..... Catabolism ..... ..... Others Precursors ..... Cofactors ..... Others .....

Categories: Caffeine | Coffee | Xanthines | Anxiogenics | Bitter compounds | IARC Group 3 carcinogens | Phosphodiesterase inhibitors | Plant toxin insecticides

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