Caffeine

Caffeine is a stimulatory anti-sleep compound extracted from coffee beans. Habitual caffeine use leads to tolerance, which dulls several of caffeine’s effects.

This page features 409 unique references to scientific papers.


Confused about what actually Works?
MUST GET: Supplement Stack Guides - Saving You Money & Time

   

In Progress

This page on Caffeine is currently marked as in-progress. We are still compiling research.

You can help contribute by:



Caffeine comes from coffee beans, but it can also be synthesized in a laboratory. It has the same structure whether it’s in Coffee, Energy Drinks, Tea or pills.

Caffeine is a powerful stimulant, and it can be used to improve physical strength and endurance. It is classified as a Nootropic because it sensitizes neurons and provides mental stimulation.

Habitual caffeine use is also associated with a reduced risk of Alzeimer's, cirrhosis, and liver cancer.

Caffeine’s main mechanism concerns antagonizing adenosine receptors. Adenosine causes sedation and relaxation when it acts upon its receptors, located in the brain. Caffeine prevents this action and causes alertness and wakefulness. This inhibition of adenosine can influence the dopamine, serotonin, acetylcholine, and adrenaline systems.

Habitual caffeine use leads to tolerance. This means the effects of caffeine will be diminished, often to the point where the only benefit a user experiences is caffeine’s anti-sleep effect. This is an ‘insurmountable’ tolerance, which means more caffeine will not overcome it. A month-long break from caffeine will reduce tolerance.

Follow this Page for updates

Confused about Supplements?
Get the Stack Guides

Also Known As

Coffee extract, Tea extract, 1,3,7-Trimethylxanthine, Liquid crack


Do Not Confuse With

Caffeic acid


Things to Note

  • Caffeine is a potent stimulant and typically used as a standard due to its social renown.
  • Metabolic effects of caffeine may vary depending on whether one is 'naive' to caffeine (infrequent user) or 'accustomed' to caffeine (daily user)
  • Metabolic effects may also vary due to genetics, specifically a polymorphism on the CYP1A1/2 enzyme[1]
  • One review notes that, after looking at the differences in metabolism between humans and rats, that a 10mg/kg bodyweight dose in rats is roughly bioequivalent to 250mg in a 70kg person.[2]
  • Caffeine can be affected by some prescription medications such as Fluvoxamine and aromatase inhibitors like Anastrozole

Is a Form of


Goes Well With


Stacks Part Of increased usefulness


Does Not Go Well With

  • Methamphetamine (Street name 'Meth'); increases side effects drastically
  • Propranolol and other beta-blockers

Caution Notice

Caffeine is highly stimulatory and a systemic vasoconstrictor. Caution should be exerted if one is either not used to caffeine ingestion or currently has high blood pressure.

Caffeine should not be used as a supplement in those with cardiac impairments without prior consultation of one's doctor.

Caffeine can also have an effect on ones quality of sleep; while you may be able to fall asleep, it will be of inferior quality.

Examine.com Medical Disclaimer

Caffeine dosages should be tailored to individuals. If you are new to caffeine supplements, start with a 100mg dose. Typically, 200mg of caffeine is used for fat-burning supplementation, while acute strength increases occur at higher doses, 500mg and above. Researchers tend to use a dosage range of 4-6mg/kg bodyweight.

Caffeine can be supplemented through popular beverages, like Coffee, Tea and Energy Drinks, but it can also be taken in a pill form.

Many of caffeine’s effects, including fat burning, strength benefits, and euphoria, are subject to tolerance, and may not occur in people used to caffeine, no matter how large the dose is.


It's hard to come up with any conclusive statements about caffeine; it is an incredibly well researched topic, but the immense social usage of it and creeping biases make it hard to pick a side on things outside of non-applied biochemistry.

All I can say is to review the FAQ page on when to cycle caffeine, if needed at all and work from there. The dosages tend to fluctuate around a certain range, but with the high inter-individual variation seen with the Aromatase enzyme (see the 'Metabolism' section of 'Pharmacology') and thus systemic levels of caffeine and its metabolites I would find it a bit futile to try to find the absolute best dosage.

Choose your caffeine dose (zero, low, medium, or high) and pick your poison for method of consumption (energy drink, pre-workout supplement, coffee, tea, No-Doz pills, etc.) and see how it works for you.


Kurtis Frank

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Caffeine has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
BLactate Production

Minor

Seems to increase lactate production during exercise when caffeine is acutely preloaded

BHeart Rate

Minor

An increase in heart rate is noted, but not wholly consistent. It appears to affect those with lower caffeine tolerance or high overdoses of caffeine

BAnaerobic Running Capacity

Notable

Appears to benefit anaerobic cardiovascular exercise, perhaps due to combination antifatigue effects and increasing power output

BPower Output

Notable

There appears to be a reliable and significant increase in power output (both weight lifting as well as cycle ergometer measurements) in both trained and sedentary persons... show

BAerobic Exercise

Minor

An increase in aerobic exercise capacity is noted with caffeine, possibly secondary to increased free fatty acids and adrenaline

BBlood Pressure

Minor

Tends to increase blood pressure more than it doesn't, which is in part due to caffeine tolerance (naive users experiencing increases in blood pressure at higher rates)... show

BRate of Perceived Exertion

Minor

Although the effects are somewhat unreliable, there appears to be a reduction in the rate of perceived exertion associated with caffeine ingestion

BTraining Volume

Minor

There appears to be an increase in training volume (overall work performed during a workout) associated with caffeine ingestion relative to placebo, extending to both weightlifting... show

BTestosterone

Minor

A very small (usually 12%) increase is noted in trained athletes consuming caffeine above 250mg prior to exercise, this may be dependent on exercise as studies without... show

BCortisol

Minor

In general, cortisol appears to be increased at high doses of caffeine; lower doses may not have an effect.

BInsulin Sensitivity

Minor

A decrease in insulin sensitivity is noted acutely when caffeine is taken alongside carbohydrates, thought to be secondary to reducing glucose deposition.

BBlood Glucose

Minor

There may be an acute increase in blood glucose when caffeine is paired with a carbohydrate containing meal, but long term ingestion of caffeine does not appear to adversely... show

BReaction Time

Minor

Although the overall effect is unreliable and context dependent, caffeine appears to increase reaction time and attention (possibly at the cost of accuracy)

BMemory

Overall, highly mixed effects effects of caffeine on memory. It appears to increase spatial/perceptual memory and reduce working memory (perhaps secondary to overstimulation)

BAdrenaline

Minor

Serum catecholamines (adrenaline, noradrenaline) are increased in naive users of caffeine following acute ingestion

BFat Oxidation

Minor

An increase in fat oxidation appears to be apparent (assessed via increased serum glycerol and free fatty acids) which is thought to be secondary to increases in adrenaline

CVO2 Max

No significant influence on VO2 max ratings

COxygen Uptake

Minor

Appears to be an increase in oxygen uptake with caffeine consumption, may be related to the increase in metabolic rate

CSubjective Well-Being

Minor

May increase subjective well being and mood state, possibly secondary to reducing fatigue or from catecholamines

CAnxiety

Minor

It is possible for caffeine to be anxiogenic, but requires genetic susceptability to it

CFatigue

Minor

Decrease in fatigue have been noted during exercise and during low strenuous physical exercise

CVisual Acuity

No significant influence on visual acuity has been noted with caffeine on hand-eye or target-based visual tasks

CMetabolic Rate

Minor

Mixed effects on metabolic rate following acute doses of caffeine

CHDL-C

No significant influences on HDL cholesterol noted

CLDL-C

No significant influences on LDL cholesterol noted

CTriglycerides

No significant influence on triglyceride levels

CInsulin

No significant influences on fasting insulin (not postprandial) are noted with caffeine

CThermogenesis

Minor

Increases in heat production following caffeine consumption have been noted

CWakefulness

Notable

Caffeine is reliable and effective in increasing the state of wakefulness and suppressing sedation

CBlood Flow

Minor

An increase in blood flow (Flow mediated vasodilation) has been noted with caffeine.

CAppetite

In elderly men, there does not appear to be a significant suppressive effect of caffeine on appetite.


Studies Excluded from Consideration

  • Confounded with other Energy Drink constitiuents[3]

Disagree? Join the Caffeine Discussion

Table of Contents:

  1. Sources and Structure
    1. Sources
    2. Structure and Properties
    3. Formulations and Variants
  2. Pharmacology
    1. Oral Interactions
    2. Gastric (Stomach)
    3. Intestines and Absorption
    4. Metabolism
    5. Distribution
    6. Individual differences in pharmacology
    7. Changes in Pharmacology with Lifestyle
    8. Differences in humans and animals
  3. Longevity and Life Extension
    1. Mechanisms
  4. Neurology
    1. Adenosinergic Neurotransmission
    2. Serotonergic Neurotransmission
    3. Adrenergic Neurotransmission
    4. Glutaminergic Neurotransmission
    5. Cholinergic Neurotransmission
    6. Dopaminergic Neurotransmission
    7. GABAergic Neurotransmission
    8. Opioidergic Neurotransmission
    9. Memory and Learning
    10. Stimulation
    11. Mood
    12. Cerebral Blood Flow
    13. Neuroprotection
    14. Anxiety
    15. Stress
    16. Parkinson's Disease
    17. Addiction
    18. Circadian Rhythm
  5. Cardiovascular Health
    1. Absorption
    2. Blood Pressure
    3. Blood flow and clotting
    4. Risk for Heart Disease
  6. Interaction with Glucose Metabolism
    1. Blood Glucose and Insulin Sensitivity
    2. Glycogen
    3. Diabetes
  7. Obesity and Fat Mass
    1. Metabolic Rate and Weight Loss
    2. Food intake
    3. Substrate Cycles (Mechanism)
    4. Phosphodiesterases (Mechanism)
  8. Skeletal Muscle and Physical Performance
    1. Power Output
    2. Anaerobic Cardiovascular Exercise
    3. Aerobic Exercise
    4. Muscle Soreness
    5. Interactions with Sleep
  9. Interactions with Hormones
    1. Testosterone
    2. Sex Hormone Binding Globulin (SHBG)
    3. Cortisol
  10. Interactions with Cancer
    1. Skin Carcinoma
    2. Colon Cancer
  11. Interactions with Various Organ Systems
    1. Eyes
  12. Tolerance, Dependence and Withdrawal
    1. Metabolic differences between Naive and Tolerant users
    2. Withdrawal Symptoms
    3. Withdrawal Mechanisms
    4. Tolerance Symptoms
    5. Mechanisms of Tolerance
    6. Dependence
  13. Nutrient-Nutrient Interactions
    1. L-Theanine
    2. Taurine
    3. Ephedrine
    4. Methamphetamine (Meth)
    5. Alcohol
    6. Green tea catechins
    7. Propanolol
    8. Danshen
    9. Genistein
  14. Safety and Toxicity
    1. General Toxicology
    2. Caffeine and pregnancy


Edit1. Sources and Structure

1.1. Sources

Caffeine is commonly found in:

Its main sources in society are coffee or tea, which constitute upwards of 90% of standard intake in society with the remaining 10% coming from cocoa products; these numbers were before the advent of energy drinks and mainstream supplementation, however.[7][8] More recent data (2005 published, collected in the 90s) show that coffee + tea dropped to 83% to accomodate the rise of soda to 12% of intake in the United States.[9]

It is seen as the worlds most popular drug, and 92-98% of persons in North America (1984 data) consume some form of caffeine.[7] More recent data (2005) using data throughout the 90s suggest that 87% of Americans consume caffeine, and in the users of caffeine the average intake was 193mg or 1.2mg/kg bodyweight. Children consume less caffeine, at around 36-56% with Americans consuming more than Canadians on average.[10] On a world-wide scale (1995 data) Norway, Netherlands, Denmark, Germany and Sweden appear to top caffeine intake from coffee at over 300mg/person/day.[2] The general trends should be noted, although exact numbers are bound to be inaccurate. Due to variability in caffeine content of sources (to be discussed) and reverse-calculating caffeine from the sources there will be inconsistencies based on whatever standard is used; variability has been noted for caffeine intake in the US given similar data (196-423mg daily) and the UK (359-621mg daily).[11]

As for main sources of caffeine, the exact caffeine content is variable. Coffee in general can have 40-180mg caffeine per 150mL and tea 24-50mg per 150mL.[8] Soda tends to be 15-29mg per 180mL. This variability tends to undermine the accuracy of society-wide estimates mentioned previously.[2]

Cocoa powder tends to have around 0.21% caffeine by weight and finished chocolate products around 0.017-0.125% caffeine by weight; commerical hot chocolates may contain 4-5mg caffeine per serving.[12]

People love their coffee and their caffeine; there is definite basis for calling this compound the world's favorite drug. Scandinavian countries and Germany consume the most, followed by North American countries and Western Europe. Stereotypical trends of coffee in Scandinavia, tea in Western Europe, and a higher soda percentage in the Americas persist.

1.2. Structure and Properties

Caffeine's chemical name is 1,3,7-trimethylxanthine. It is a xanthine compound with three methyl (CH3) groups attached at the 1,3, and 7 carbons on the xanthine backbone.[13]

If it loses a methyl group, it can be converted into similar metabolites like paraxanthine (demethylation at the 3 carbon) theobromine (1 carbon) or theophylline (7 carbon). Further demethylation yeilds either 1, 3 or 7-methylxanthine, and full demethylation yields the basic xanthine molecule.[13]

Most of the metabolism of caffeine goes towards paraxanthine, via the CYP1A1/2 enzyme. Direct conversions to theobromine and theophylline are possible but less prevalent.

Caffeine is a bitter compound, and is sometimes used in sensory research as a standard for bitter. Its perception of bitter may be in part genetically influenced, as assessed by on 0.3 heritability (1 being fully heritable) in some studies.[14]

1.3. Formulations and Variants

Inorganic sources of caffeine can be detected via stable isotope analysis and specifically the δ13C, as products that are synthesized in the lab (usually the original carbon source is coal) tend to have differences in values when measured via stable isotope analysis than those that are created in plants via a photosynthetic pathway; this applies to caffeine,[15][16] Taurine,[17] sugar (for honey products),[18] and Alcohol products[19] amongst others. This detection is mostly just for regulations since FDA regulations say that synthetic, but not naturally occurring caffeine, much be present on the label[15] and there are no known differences in the bioactivity of caffeine depending on source.

Caffeine can be made synthetically or naturally (via plants), and while they treat the body similarly when ingested there are some labelling laws that apply to synthetic but not natural products; laboratory analysis can detect the difference between the two

Caffeine is, by far and large, the most popular ingredient in over-the-counter fat burning supplements and proprietary blends.[20][21]


Edit2. Pharmacology

2.1. Oral Interactions

Caffeine's pharmacokinetic parameters can be fairly reliably measured with a saliva reading of caffeine content, given that the saliva is approximately 80% of the serum value of caffeine at any given time and the correlation is fairly high.[22][23][24]

Caffeine can possibly be measured in saliva, as it can accumulate in bodily fluids

Caffeine can be absorbed through the buccal mucosa, a term for oral absorption without needing to swallow.[25][26] This leads to chewing gum infused with caffeine having a quicker absorption of caffeine relative to coffee as it does not need to pass the stomach and intestines to get into the blood.[27]

It is possible caffeine can be absorbed through the mouth and into the blood when consumed via a chewing gum

2.2. Gastric (Stomach)

Caffeine is able to increase secretion of gastric acid (HCl) per se, but is one of multiple components of Coffee able to do so,[28] but at a weaker potency than these other components (evidenced by decaffeinated coffee causing significantly more gastric acid release than isolated caffeine).[29] The increase of gastrin induced by coffee is not due to caffeine.[30]|published=1976 Mar 19|authors=Börger HW, Schafmayer A, Arnold R, Becker HD, Creutzfeldt W|journal=Dtsch Med Wochenschr]

Appears to increase gastric acid secretion; which may be good for digestion in the stomach yet negative for symptoms of GERD

2.3. Intestines and Absorption

When ingested, it has near perfect intestinal uptake of around 99-100%[31][32] up to acute dosages of 10mg/kg bodyweight, the highest studied in humans.[33] This absorption tends to occur almost completely within 45 minutes of ingestion.[34][32][24]

Most caffeine is taken up from the gut 45 minutes after oral ingestion[32] and reaches peak values in the blood between 15 and 120 minutes dependent on individual physiology and vehicle (liquid, capsule, gum, etc.).[33] A slightly more precise estimate may be 30-60 minutes post oral ingestion,[35][36] and 45-60 minutes until 'peak' serum levels tends to be a relatively accurate estimate used frequently.

There does not appear to be a significant splanchic first pass metabolism in regards to caffeine.[34]

Caffeine absorption is slightly delayed from soda and chocolate relative to coffee,[37][38][39] and capsules have faster absorption than does coffee.[38] Caffeine in a chewing gum format is absorbed faster than capsules, as caffeine can be absorbed through the buccal muscoa (mouth).[27]

Caffeine, when in the stomach, can act upon gastric myenteric and submucous nerves to induce gastric emptying.[40][34] The influx of digestive metabolites into the small intestines may stimulate the gastrocolic reflex[41] and be a possible mechanism behind caffeine causing the need to defecate shortly after consumption. The ultimate result of this reflex mediated by caffeine is an increased anal sphincter contraction power and less neural input needed to induce contraction (decreased sensory threshold).[42] due to these reasons, caffeine is sometimes referred to as a 'cathartic' agent, alongside prunes. Interestingly, Chlorogenic Acid has been implicated in aiding the laxatative effect of prunes,[43] and is an active component of Coffee.[44]

Taken up nearly completely and in under 45 minutes for almost all forms of caffeine and dosages; a slight variance is seen with different vehicles of caffeine such as chewing gum, coffee or chocolate.

2.4. Metabolism

As mentioned previously with the graphic, caffeine can be metabolizes into dimethylxanthine derivatives (paraxanthine, theobromine, and theophylline) and further metabolized into monoxanthine derivatives and then finally a xanthine molecule. Other metabolic byproducts of caffeine include di and trimethylallantion, mono and dimethyluric acids, and various uracil derivatives.[2]

Caffeine per se appears to be metabolized mostly by the P450 enzyme system in the body, and specifically the CYP1A enzymes (CYP1A1, 1A2). The metabolism by CYP1A of caffeine follows first-order kinetics and is the rate-limiting step of plasma clearance.[45][46] This enzyme, being a rate limiting step and subject to genetic variance, is one of the loci for genetic variance in caffeine. These will be discussed further in the 'Individual differences' section, but they may account for up to 40% variance in caffeine pharmacokinetics.[47][48]

Approximately 84% of ingested caffeine is initially demethylated by CYP1A into Paraxanthine by acting on the 3-carbon.[49] 10% of this Paraxanthine can be further metabolized into 1-methylxanthine by CYP1A, but most tends to be subject to other enzymes (NAT1 can create 5-acetylamino-6-formylamino- 3-methyluracil, a uracil derivative; the rest (up to 90%) is subject to CYP2A6 and converted to 1,7-dimethylurate)[49][50]

Xanthine oxidase can convert the metabolite 1-methylxanthine into 1-methylurate.[50]

In an attempt to give approximate values to bridge oral ingestion and serum values, one study suggested that since ingestion of a single cup of coffee provides a dose of 0.4 to 2.5 mg/kg, it can be estimated that this gives a peak concentration of 0.25 to 2 mg/l or approximately 1 to 10 μM.[2]

The half-life of caffeine varies widely, due to aforementioned variations in CYP1A. One study noted a range of 2.7-9.9 hours[32] with highly similar ranges in another group of persons by the same researchers.[31]

Most metabolism of the caffeine molecule (up to 84%) occurs through the CYP1A1/2 (Aromatase) enzyme, and other enzymes (Xanthine Oxidase, CYP2A6, NAT2) are involved in the entire metabolic cascade or quite briefly on caffeine itself. Variations in CYP1A1/2, either genetic or through supplements, can greatly affect caffeine pharmacokinetics.

2.5. Distribution

Caffeine is hydrophobic enough to tranverse most barriers in the body and is readily distributed to all organs.[51] A steady state volume of distribution appears to occur at 500-800mL/kg with dosages below 250mg.[52][53][54] Doses above 250mg start to increase this amount[54][34] and habitual users of caffeine are associated with greater distribution.[55]

Caffeine appears to be readily distributed between serum and extra-cellular fluid, and then the cell. This appears in the mouse[56] and isolated rat cultures[57] with nearly perfect correlation, although the correlation is likely to be less in humans.[58]

The circulating levels of caffeine in the Extra-Cellular tissue of adipose (fat mass) is not significantly different than that circulating in plasma.[58] This suggests that circulating levels of caffeine correlate well with the levels exposed to fat cells, and the approximate estimate of 1mg/kg bodyweight oral ingestion inducing 5-10uM increases in serum concentration reliable when assessing in vitro studies.

2.6. Individual differences in pharmacology

One review has noted that the degree of genetic inheritability for caffeine appears to be in the range of 0.36-0.58 for varying populations (with 1 being completely inheritable) by assessing twin studies, most studies conducted in Caucasians of American or European descent.[59] When looking at heavy caffeine intake (more than 625mg daily) inheritability spikes to 0.77.[60] Studies that assess both genders individually note no significant differences in heritability.[61][62] These differences appear to rise during adolescence, however, and then stabilize; prior to adolescence there is less of a heritable influence on caffeine.[63]

Genetic variations in the CYP1A (aromatase) enzyme that degrades caffeine can alter its ergogenic (performance increasing) effects, with the AA homozygotes outperforming the C allele carriers during endurance exercise.[1]

The AA genotype, in a sample of Caucasians, affects about 46% of persons. The C allele carriers can be either 44% (heterozygous, AC) or 10% (homozygous, CC).[64] AA Genotype is known as a 'fast caffeine metabolizer' and has a higher inducability rate, and degrades caffeine at a faster rate than AC or CC.[64] A higher 'Aromatase activity' tends to be either a genotype of AA, or lifestyle factors that increase CYP1A content.

Swedish persons have higher CYP1A activity than do Korean persons when lifestyle is controlled for,[64]

Activity of the enzyme can be upregulated by smoking, increasing caffeine metabolic rate.[65][64] Heavy coffee drinking may also increase CYP1A activity[66] although perhaps only for the AA genotype.[67]

Some differences exist with other enzymes in caffeine's metabolic pathway, although CYP1A is of most importance. Xanthine Oxidase appears to be slightly higher in Swedish women relative to men and contributed to sex rather than confounding variables, yet shows no differences when comparing ethnicities, in this study Swedes against Koreans.[68] This difference between genders is not overly potent, and some studies fail to find such a significant difference.[69][70]

Four populations have been identified as having a certain percentage of persons as 'slow' Xanthine Oxidisers, with drastically reduced Xanthine Oxidase activity. In particular; Ethiopians (4% of population[71]), Japanese (11%[72]), Caucasian (20%[73]), and Spanish (4%[74]). Even without consideration to demographics, a 2-4 fold difference can be found among tested women.[48]

NAT (N-Acetyl Transferase) appears to work faster in Koreans than it does in Swedes, on average.[68]

2.7. Changes in Pharmacology with Lifestyle

In regards to caffeine itself, a 24 hour absence from caffeine does not seem to significantly alter CYP1A2 activity and its subsequent pharmacokinetic profile[75] and intake of coffee is correlated with increased aromatase activity at an extra 1.45-fold increase per 1L of coffee consumed.[76]

Exercise does not tend to influence caffeine pharmacokinetics,[77] although one study did note that a higher Cmax was seen with exercise relative to sedentary persons.[55]

Many nutraceuticals commonly found in foods, such as the Bioflavonoids class of nutrients and select ones such as Quercetin or Genistein can influence Aromatase function and thus metabolism of caffeine. Some other commonly consumed compound such as Alcohol (drinking ethanol) or Green tea can influence caffeine's pharmacokinetics. For more information, visit the nutrient-nutrient interactions section or respective pages of the above compounds.

Smoking tobacco appears to upregulate the aromatase enzyme, insofar that smokers tend to have 50-70% less circulating caffeine after ingestion.[78][79][80][81]

Age does not influence Aromatase activity or variability.[82] Gender doesn't influence aromatase activity as it pertains to caffeine for the most part,[83][77] but at least some studies suggest women may have less active aromatase.[84][85]

2.8. Differences in humans and animals

The half life of caffeine in rats is typically 0.7-1.2 hours whereas in humans it tends to fluctuate between 2.5-4.5 hours.[86][2] Metabolites also differ, with trimethyl derivatives accounting for 40% of total derivatives in rats but only 6% of total derivatives in man.[87][2]

According to one review, it is generally assumed that 10 mg/kg in a rat represents about 250 mg of caffeine in a human weighing 70 kg (3.5 mg/kg), and that this would correspond to about 2 to 3 cups of coffee.[2] This is with consideration to the differences in metabolic half-life.


Edit3. Longevity and Life Extension

3.1. Mechanisms

Caffeine has been noted to induce nuclear activity of DAF-16 in C. Elegans (nematodes) and promote lifespan by 52%, and inhibiting either DAF-16 or Creb-binding protein 1 (CBP-1; involved in a high level of lifespan variance in mice[88]) abolished these benefits; tannic acid and Baicalein (from Scutellaria baicalensis) also proved to increase lifespan via DAF-16 translocation.[89]

Caffeine has also been noted to inhibit TORC1 activation to a greater degree than TORC2 (IC50 of 0.22mM; Rapamycin as reference drug with an IC50 of 5.2nM),[90] which via Sch9 (mammalian ortholog S6K[91]) phosphorylates PKA and prevents nuclear actions of Rim15[92] (mammalian ortholog LATS[93]) which normally mediates oxidant defense and stress response genes;[94][95] bypassing TORC1 abolishes the longevity promoting effects of caffeine,[90] and the authors hypothesized this may be relevant to humans (one cup of coffee reaches plasma levels of 1-10µM which may result in 4-8% inhibition of mTORc1, with only 3% being required in yeast to promote longevity[90]).

There appears to be dependence on both mTOR inhibition and DAF-16 nuclear accumulation (usually not co-dependent) associated with the longevity promoting effects of caffeine


Edit4. Neurology

4.1. Adenosinergic Neurotransmission

Caffeine is most well known for being an adenosine receptor antagonist. It is a competitive inhibitor of adenosine, and fits into the adenosine receptor without activating it and preventing adenosine from acting.[96] As adenosine mediates the perception of drowsiness, preventing its actions results in alertness.[97][98][99] It is non-selective (hits all isomers of adenosine receptors) although it shows slightly more affinity for the A1 receptor,[100] and has been quantified at occupying 7-44% of A1 receptors at varying IV doses of 0.5-4.3mg/kg after short abstinence in caffeine consumers; a concentration of 67uM (in serum) is needed to occupy half of the receptors.[101] There are four isomers of adenosine receptors heterogeneously expressed across the brain, the A1, A2A, A2B and A3 subsets. All subsets are G-protein coupled receptors.

The A1 subset, when activated, promotes sleep and drowsiness by attenuating brain activation and excitation.[102][103] Thus antagonism (preventing activation) serves to promote wakefulness and excitation by preventing their decline. A1 is a G-protein coupled receptor, and is coupled to Gi-1, Gi-2, Gi-3, Go1, and Go2, the pertussin toxin sensitive proteins.[2] Through these G-proteins, activation of A1 causes inhibition of Adenyl Cyclase, some voltage-sensitive calcium channels (N, Q) and activate K+ channels while activating Phospholipase C and D.[104][105]

The A2A subset, when activated, actually promotes wakefulness rather than induces sleepiness.[106] As a G-protein coupled receptor, A2A is coupled to the Gs proteins, which cause activation of Adenyl Cyclase rather than inhibition. These effects, in part, oppose the actions of A1.

A2B does not appear to be activated at circulating normal levels of adenosine (between 30uM and 300uM estimate), although it can be activated at higher concentrations.[2] This may implicate A2B at pathological levels of adenosine but may not be relevant to normal human levels.

The A3 subset also contributes to sedative effects in a similar fashion to A1, although weaker.[107] A3 has a KD approaching 80uM[104][2] and thus isn't likely to be of much practical significance relative to caffeine usage due to its low activity.

Adenosine receptors are upregulated by 20% in response to chronic caffeine intake,[108] although binding efficacy and the post-translational effects of adenosine antagonism are not altered in chronic vs. naive mice subject to caffeine.[109] The receptors may also become sensitive to adenosine agonism, as assessed by human platelet A2A.[110] Following this, adenosine levels circulating in the body may also increase following chronic caffeine ingestion in rats.[111]

The 'primary', or at least most popular, mechanism of action due to the wakefulness effect. Its effects also induce changes in Acetylcholine and Dopamine systems, and interact with the Serotonergic system. The actual effects of adenosine blockade do not disappear with tolerance, but may be diminished by opposing reactions through adenosine and new receptors.

4.2. Serotonergic Neurotransmission

The protein content of corticol 5HT1 and 5HT2 receptors (responsive to serotonin) are increased by 26-30% in response to chronic caffeine intake.[108] Additionally, brain levels of serotonin itself may increase.[112] One study in rats fed 30mg/kg bodyweight caffeine, for acute tolerance, noted increased brain levels of 5-HTP (serotonin precursor) and 5-HIAA (serotonin metabolite)[113] and that the increase in serotonin may be more significant in obese mice relative to lean, despite occurring in both.[114] Tryptophan levels are also increased in the brain during caffeine usage.[112]

Serotonin appears to be increased with caffeine ingestion via adenosine receptor antagonism.[115] This is seen since caffeine is a non-selective antagonist, as selective antagonism of A2 subsets reduce serotonin levels.[115][116]

The serotonergic system may interact with the analgesic (painkilling) effects of caffeine, which primarily works via caffeine's adenosine antagonism.[117]

Cessation of caffeine is associated with a transient decline in brain serotonin levels, which is associated with temporary memory impairment.[113] This decrease in brain serotonin may be through adaptations in neurons to reduce serotonin synthesis, as cessation of caffeine is associated with reduced serotonin but not reduced tryptophan.[112] As tryptophan was not reduced but 5-HTP was, the intermediate enzyme (tryptophan hydroxylase) appears to be downregulated; this can theoretically be bypassed with 5-HTP supplementation.

Serotonin (5-HT) and its related compounds (5-HTP, 5-HIAA) all seem to be elevated during chronic caffeine usage, and a short deficiency exists after caffeine cessation due to (plausible) downregulation of tryptophan hydroxylase.

4.3. Adrenergic Neurotransmission

Increases in adrenaline appear to be independent of the adenosine receptors, and instead are mediated by adrenergic receptors.[118]

Acutely, caffeine ingestion increases adrenaline and noradrenaline levels in the body of persons who consume it. This increase seems to be fairly dose dependent.[119]

Chronic caffeine ingestion is able to downregulate (reduce) the amount of beta-adrenergic receptors in the brain by up to 25% in some areas.[108] This effect in independent of adenosine antagonism.[120] Caffeine, chronically, has also been shown to decrease circulating catecholamine levels and prevent against diet-induced insulin resistance in rats[121] and prolonged caffeine usage at the same dose causes a lessening of adrenergic (adrenaline-mediated) effects in humans, not just those induced by caffeine.[122]

Seemingly opposite effects with acute and chronic caffeine usage, possibly mediated through changing receptor content.

4.4. Glutaminergic Neurotransmission

Caffeine has been implicated in increasing glutamate release in the shell of the nuclear accumbens in naive rats,[123] theoretically downstream of adenosine A1 receptor antagonism and via NMDA receptors.[124]

NMDA activation does not appear to be a factor in caffeine-induced locomotion.[125]

4.5. Cholinergic Neurotransmission

Caffeine injections into rats can dose dependently increases acetylcholine level in the medial pre-frontal cortex.[126] This has occurred in the hippocampus, and appears to be secondary thorugh either adenosine A1 antagonism[127] or A2A agonism[106] although blocking the A2A receptor does not abolish the effects of caffeine on acetylcholine release.[106]

Caffeine tolerance (one week of 25mg/kg) is not associated with any tolerance development in acetylcholine release[126] whereas 30 days oral ingestion of 100mg/kg has been associated with tolerance development.[128]

Caffeine appears to be able to induce acetylcholine release from the brain, and this effect is susceptable to tolerance development

Upregulation of muscarinic and nicotinic acetylcholine receptors can occur after chronic exposure to caffeine by about 40-50%.[108]

The level of acetylcholine receptors is increased in response to chronic caffeine treatment

4.6. Dopaminergic Neurotransmission

Caffeine injection into non-habituated rats seems to increase dopamine levels in the medial prefrontal cortex (not the nuclear accumbens), which is about the only time caffeine can increase dopamine levels per se.[126] That being said, spikes in nuclear accumbens dopamine levels have been found in other animal studies, showing inconsistencies in the literature.[123] Caffeine tends to interact with dopamine signalling, but independent of actual spikes in dopamine.

Dopamine appears to mediate the increase in physical activity seen with naive caffeine ingestion as evidenced by a lack of apparent effect after dopamine depletion[129][130] or blocking the dopamine receptors.[131] Additionally, the dose-response curves of caffeine on spontaneous activity seem to parallel that of selective D1 and D2 agonists.[132]

The mechanism that caffeine increases activity by is via antagonizing adenosine A2A receptors (the standard mechanism of caffeine). Adenosine normally suppresses the effects of dopamine on locomotion (via working in opposition on neuronal excitation[124]) in the striatum where A2A and dopaminergic neurons co-exist, and preventing this suppression with an antagonist increases the effects of dopamine on D2, of which include spontaneous activity and (in rats) rotational behaviour when unilateral lesions are induced in the striatum.[133][134] Non-caffeine adenosine antagonists also share this effect on locomotion, further implicating A2A antagonism and dopamine as the cause rather than a separate, unseen effect of caffeine.[135] As for why A2A is mentioned more frequently than A1 in this section, it is since A2A receptors appear to co-exist with dopamine receptors in many parts of the brain (nuclear accumbens, striatum, tuberculum olfactorium) whereas although A1 are heterogeneously expressed in the brain, there is no pattern with dopamine receptors.[2] Interactions with motor control appear to be highly relevant to the striatum, where A2A predominates.

Due to the above interactions, dopamine antagonism (blocking) gives the appearance of caffeine tolerance by preventing locomotion in rats.[136] The dopamine receptors (D1, D2) can also become less responsive to standard dopamine agonists after caffeine tolerance develops[132] although their numbers do not seem to be increased or decreased.[108] Suggesting that the dopamine receptors get desensitized. Cross-tolerance can develop with chronic caffeine usage and dopamine receptors at any dose between 1-100mg/kg bodyweight in rats taken daily, although the higher dosages are more suspect[132] although the lower end of that range, 1mg/kg, doesn't hold much cross-tolernace potential.[137]

Interestingly, these same interactions can be positive. Intermittent caffeine intake (15mg/kg bodyweight, according to this review[2] about 375mg) every other day induces sensitization of motor activity in naive rats[138] and this is through reducing overall A2A receptor count in the striatum[139] and is seen as an indirect sensitization of dopamine receptors.[140]

Dopamine normally mediates locomotion, and caffeine allows dopamine to work better; this seems like caffeine causes spontaneous activity (twitching, foot tapping, urge to dance). This effect appears to be short-lived, and does not affect chronic users.

4.7. GABAergic Neurotransmission

Chronic caffeine ingestion can upregulate the GABA(A) receptor subtype by about 65% in some brain areas.[108]

4.8. Opioidergic Neurotransmission

Chronic caffeine ingestion can increase the protein content of the opiod receptor (delta).[141]

4.9. Memory and Learning

Caffeine is a relatively unreliable agent to increasing memory, as reports on its memory increasing abilities vary widely in the literature.

A few reports look at introversion and extroversion, and note that caffeine (in doses of around 200mg) is a cognitive booster and increases working memory only in those who are extroverts, usually judged by a question of "Are you a lively person" or something similar.[142][143] It shows related cognitive benefits in alleviating performance decline in the same manner.[144] A theory put forth recently[142] hinges on dopamine, either as modulating stress or arousal.[144] This is based off of past correlations with extroversion and dopamine function.[145]

In caffeine naive persons, ingesting 450mg of caffeine before a working memory test reduces performance. This was not seen with lower dosages, and may be due to 'too much' stimulation.[146]

4.10. Stimulation

Caffeine possesses psychostimulant effects in naive non-users of caffeine when ingested at 150mg or above, suppressing sedation self-report scores and elevating stimulant ratings.[146]

Mechanistically, the stimulatory effects of caffeine are mediated at first through Adenosine antagonism, specifically A2(A) receptors. This causes enhanced efficacy of dopamine transmission in the striatum where dopamine D2 and A2(A) receptors are both present in high numbers. After more effective D2 agonism, post-receptor effects include an increase in cAMP levels in the dopaminergic neuron which lead to phosphorylation of PKA and phosphorylation of an intermediate known as DARPP-32 which appears to be nearing the end of the stimulatory chain of events.[147] Phosphorylation of DARPP-32 by PKA causes it to become an inhibitor of Phosphoprotein phosphatase 1 (PP1).[148] Inhibition of PP1 enhances the overall dopaminergic signal sent through the neuron.[149]

4.11. Mood

Mood is a bit tricky, practically. The mere expectation of caffeine intake can improve mood even if no caffeine is consumed, suggesting a fair bit of overlay between caffeine and placebo in this regard.[150] Blinding is important in the research, but practically the effects seen with caffeine could merely be seen with expectation.

Regardless, 6mg/kg caffeine taken an hour before 90 minutes of cycling is able to improve mood throughout the ride in a double blind manner.[151]

4.12. Cerebral Blood Flow

Caffeine administration is able to reduce cerebral blood flow[152] and this has been noted via PET scans,[153] Xenon Clearance,[154] MRI,[155] and trans-cranial Doppler.[156] This reduction of blood flow tends to manifest itself as a reduction of cerebral blood pressure.

When comparing the ability of caffeine to alter blood flow between naive and habitual users, it was noted that caffeine administration to habitual caffeine users resulted in a reduction of cerebral blood flow while abstinence increased cerebral blood flow,[157] a later study using near infrared spectroscopy noted that while both habitual and naive users experience decreases in cerebral blood flow in response to low-dose caffeine (75mg), the naive users had an exaggerrated reduction.[158] Due to the difference in naive and habitual users in response to 75mg caffeine[158] yet fairly consistent results in both habitual users and naive with higher (200+) doses,[159][160][161] it is hypothesized that tolerance can develop to a limited degree with low doses,[158] with another study noting that one week deprivation of caffeine in habitual users was associated with a greater reduction of cerebral blood pressure in response to 200mg.[162]

Blood pressure can be reduce in the brain secondary to a reduction of blood flow, which may be slightly attenuated with tolerance (when using low doses) but may be more resiliant to tolerance than other aspects of caffeine.

Interestingly, however, 200mg caffeine reduces cerebral blood flow by around 34.5+/-2.6% in tolerant users yet it does not significantly affect blood oxygenation rates (5.2+/-6.4 average increase), suggesting the reduction of blood flow is not an impairment to neural function.[159] There tends to be a general dissociation between blood oxygenation in the brain and blood flow under the influence of caffeine.[159][160]

Although a reduction of blood flow occurs, this does not appear to be associated with less oxygen reaching the brain

4.13. Neuroprotection

Hypoxia (lack of oxygen) in neural tissue begets reoxygenation, which is associated with oxidative damage to the amygdala and anterograde amnesia; as these mechanisms of amnesia appear to be mediated by adenosine receptors which activat Caspase-1, inhibition of adenosine receptors with caffiene in rats is associated with attenuation of the amnesiac effects of hypoxia.[163]

4.14. Anxiety

Some persons experience anxiety with caffeine ingestion, an effect called 'anxiogenesis'.

The seen increase in brain lactate does not appear to be causative of anxiety, as chronic users who reset their tolerance to experience the same increase in brain lactate do not experience the same spikes in anxiety.[164]

The cause seems to be more genetic. Persons with a polymorphism in the adenosine A2A receptor. The '1976T > C' genotype of A2A appears to be highly related to anxiety from caffeine relative to the CC or heterozygous genotypes.[165][166][167] The polymorphism does not seem to be associated with anxiety in and of itself, only in response to caffeine.[165]

4.15. Stress

One study conducted in a model of psychosocial stress noted that 3.5mg/kg caffeine was associated with a 233% enhanced adrenaline release and 211% enhanced cortisol release in response to stress when compared to stress under placebo conditions, which was data pooled from naive and habitual users; augmentation of these hormonesdid not appear to be related to habitual caffeine intake.[168] Chronically, one animal study suggests that caffeine can reduce the adverse health effects of stress over a prolongered period of time when the stress and daily caffeine consumption co-exist.[169]

4.16. Parkinson's Disease

Parkinson's Disease is a disease characterized by a loss of dopaminergic neurons in the Substantia Nigra pars Compactum (SNc) and subsequent reduction in Dopamine levels in the brain.

Caffeine has been used as a treatment of motor-control side effects from Parkinson's disease (usually when treated with L-DOPA, or Levodopa).[170] The general mechanism of A2(A) antagonism shows effectiveness in non-human primapes for reducing motor control complications after destruction of dopaminergic neurons[171][172] and by itself in doses of 100-200mg appear to reduce motor control complications in Parkinson's Disease in a therapeutic manner.[173] Interestingly, they enhance motor activity yet do not induce dyskinesia in these animals.[171][172] When tested in humans, the A2(A) antagonist in question failed to reach statistical significance in reductions of motor control complications, but only trended towards benefit.[174] These results are different than ones using caffeine in pre-clinical, smaller trials[170] which tend to note some degree of improvement with A2(A) antagonism as an adjunct treatment rather than the sole treatment.[175][176][177]

Epidemiological studies suggest an inverse relationship between lifetime caffeine usage and Parkinson's Disease in men, suggesting a protective mechanism as well as a control mechanism.[178][179][180] It has been called one of the 12 most promising drugs for prevention of Parkinson's.[181]

Some interventions have been conducted on the above protective mechanisms. Co-administration of caffeine and MPTP (a dopaminergic neuronal toxin) reduced the overall destruction of dopaminergic neurons by MPMT.[182] Interestingly, this protective mechanism is hindered by estrogen (and the above societal correlations were seen mostly in men)[183] and does not get reduced after caffeine tolerance.[184]

A decent protective measure to reduce risk of Parkinson's over a lifetime, and could be a nice adjunct therapy for Parkinson's for people who have it; not potent enough to stand alone as therapy, however.

4.17. Addiction

Caffeine ingestion has been found to have reinforcing effects when participants select capsules containing caffeine (color coded with varying caffeine levels to blind subjects[185])

Caffeine has been linked to dopamine release in the nucleus accumbens (a phenomena thought, alongside glutamate release, to correlate highly with addiction[186]) following acute injections of 10-30mg/kg in rats[123] although these results are controversial, as null effects have been reported at similar doses.[126] Ex vivo, caffeine seems to induce dopamine and glutamine release in the nucleus shell rather than extracellular space.[187][123]

Several reviews suggest that there is insufficient evidence to establish a causative role of caffeine in addition[39][188] although it does somewhat interact with reward systems; this may be due to the limited evidence that supports an increase in dopamine release being acute, while chronic studies note that caffeine tolerance is associated with no dopamine release.[189]

4.18. Circadian Rhythm

One study has noted, in trained athletes, that caffeine supplementation in the morning reverses the lack of strength seen in mornings.[190] In both Wingate testing and resistance exercise, power output appears to peak in the early afternoon with slight suppression of maximal performance in the AM and later PM.[191][192]

Additionally, caffeine has been shown to increase the voluntary maximal load used in resistance training associated with sleep when blinded to caffeine.[193] This suggests an enhancement of cognition or confidence despite sleep deprivation.


Edit5. Cardiovascular Health

5.1. Absorption

Caffeine has been implicated in reducing the distribution of fatty acids and cholesterol in rats via reducing mesenteric lymph release of fatty acids into the blood.[194] Whereas both Green Tea Catechins and caffeine seem to reduce intestinal uptake of fatty acids and cholesterol, caffeine was implicated in reducing lymphatic release of fatty acids created in the body into the blood.[194]

Caffeine doesn't appear to reduce cholesterol levels below baseline in rats without dietary cholesterol intake.[195]

5.2. Blood Pressure

Increases in blood pressure may be related to adenosine receptors, and specifically two polymorphisms.[196] However, they are short lived. Spikes in blood pressure from caffeine occur significantly in persons who do not routinely use caffeine for 1-4 days, and then subside.[197] Other factors that increase that may influence blood pressure, such as catecholamines or renin, are not increased in persons consuming moderate amounts of caffeine for longer than 4 days.[197]

Alpha(2)Adrenergic receptors are also implicated in genetic variability to blood pressure spikes from caffeine.[196]

5.3. Blood flow and clotting

Caffeine can theoretically cause an increase in blood clotting, as it would inhibit the adenosine A2A receptor on platelets. Activation of this receptor results in reduced clotting, and mice without the receptor or its effects have an increase in platelet aggregation.[198]

However, caffeine appears to also have the ability to resensitize this receptor after prolonged usage which would increase adenosine's actions when caffeine is not consumed.[199][200]

It appears that, acutely, caffeine can increase thrombocytosis (platelet count) when ingested and augments the increase seen with exercise.[201] Long term effects are not known.

Coffee itself doesn't seem to interact with clotting factors much at moderate consumption[202] and tea appears to actually reduce platelet aggregation after stress.[203]

5.4. Risk for Heart Disease

A recent Meta-Analysis of over 140,000 persons from 5 large scale studies[204] found a J-shaped curve where 4 cups of coffee daily was associated with a significant decrease in heart attack risk (11% lower risk) and 1-3 cups daily had ranging values of 4-10% decreased risk compared to persons who did not consume coffee. The Relative Risk (RR) was 0.89 (4 cups daily) to 0.96 (1-2 cups daily), suggesting a minor but statistically significant reduction in risk associated with Coffee; a slight increase (RR=1.03) was noted with 11 cups daily.

If anything, the data suggests a very small influence of coffee and caffeine, chronically, on heart health. The RRs of the meta-analysis are quite minor, and the potency of the effects are not too clinically relevant


Edit6. Interaction with Glucose Metabolism

6.1. Blood Glucose and Insulin Sensitivity

Caffeine can increase blood glucose by reducing glucose disposal in muscles, via interfering with the actions of insulin.[205][206][207] During a sedentary state, caffeine can temporarily induce insulin resistance by about 13%[206] and reduce glucose disposal by 24%.[205] This, however, is not accompanied by an increase in insulin secretion as insulin levels remain fairly constant throughout caffeine ingestion.[207]

This interference is partially negated during exercise, however.[208]

The increasing of blood glucose seen via reduction of insulin sensitivity does not appear to be due to adenosine antagonism, seen as caffeine's main mechanism of action.[206]

Ingestion of coffee, however, can increase insulin sensitivity acutely in rats,[209] possibly by reducing the rate of glucose appearance in circulation mediated by Chlorogenic Acid.[210][211][212]

6.2. Glycogen

At rest, the amount of dietary carbohydrate stored as glycogen under the influence of caffeine appears to be reduced by 23% in sedentary persons,[205] while, in glycogen-depleted persons, it can enhance the rate of glycogen accrual.[213] In the experimentally induced glycogen depletion state, 8mg/kg caffeine was able to increase glycogen resynthesis rates by 66% over 4 hours when compared to the same amount of carbohydrates alone.[213]

In humans, the replenishment of glycogen during depletion is not associated with either AMPK (able to increase glucose uptake) and likely not Akt, as assessed by expression in a group experiencing enhanced glycogen replenishment against the same amount of carbohydrates without caffeine.[213] An enhanced phosphorylation (activation) of calmodulin-dependent protein kinase (CaMKThr286) was seen in the caffeine + carbohydrate group near the end of the study frame (with no differences at baseline or 1 hour after exercise), at times where CaMKThr286 was similar, rates of glycogen replenishment were similar. It is suspected that the calcium (Ca2+) release induced from caffeine can enhance CaMKThr286 activation,[214] which causes enhanced glucose uptake into muscle cells specifically.

6.3. Diabetes

Coffee itself is very well correlated with a reduced risk of developing diet-induced diabetes, although whether this is due to caffeine or other compounds such as Chlorogenic Acid that have shown anti-diabetic effects is not known.[215]

The first study to note a correlation between higher coffee intake and lesser risk of diabetes was in 2002 in which those who drank coffee at 2 cups daily were half as likely (Relative Risk Ratio of 0.50) to develop diabetes.[216] Various surveys conducted since then establish the correlation between coffee and reduced risk for diabetes, which is independent of lifestyle and race[217][218][219][220][221] and two meta-analysis' support these results.[222][223] The latter meta-analysis suggests a 7% reduction in diabetes risk with each cup of coffee consumed daily, and show that the relation holds true for decaffeinated coffee.[223][215]

The above promise for risk reduction of diabetes may not hold true for isolated caffeine. In addition to the latter meta-analysis finding benefit with decaffeinated coffee, isolated caffeine seems to increase blood glucose and induce insulin resistance transiently after consumption.[205][206][207] If mediated through adrenaline, long-term effects on insulin sensitivity may be distinct from acute, as the adrenaline increasing effects of caffeine disappear when tolerance develops over 7 days.[197]

Coffee can reduce the risk of diabetes, not overly significant from a clinical standpoint but it appears to be reliable. This may not be due to the caffeine content, but may be due to any of the myriad of other bioactives, such as Chlorogenic Acid or ferulic acid


Edit7. Obesity and Fat Mass

7.1. Metabolic Rate and Weight Loss

30 minutes after an oral dose of 4mg/kg caffeine (in obese women), a metabolic spike was seen in all subjects but to a widely varied degree; this spike is able to reduce body weight when in conjunction with a low-calorie regimen in all subjects though.[224] This dose, 4mg/kg bodyweight, is approximately equal to 3 cups of regular coffee (average caffeine content) for persons with a BMI in the normal range.[225]

Despite the high variance seen, average increases seem to be around 34kJ/m2/hour, which translates to 8.1 calories per hour for every meter of body surface area a person has.[225] The standard 'average' for adult humans of normal weight is 1.73m2, which translates into 14kcal per hour. Some studies note higher values (32.4kcal/h) with higher dosages of caffeine (400mg).[226]

The increase of Metabolic Rate may be dose dependent and be somewhat related to catecholamine release.[227][225] The increases in catecholamines seem to be correlated with serum caffeine levels[226] and increases linearly with increasing dosages up to 9mg/kg bodyweight.[119]

When looking at caffeine usage on the metabolic rate of athletes and sedentary persons, the end results conflict in studies. One study using 4mg/kg bodyweight in high level aerboic athletes (marathon runners, cross country skiers) found that caffeine significantly increased metabolic rate more than sedentary persons, achieving 80kJ/kg/min for the 120 minutes after ingestion (athete) vs. just under 60kJ/kg/min for sedentary, with no significant differences prior to testing.[228] The dose in the previous study equated to an average of 280mg, and another study using 300mg found the opposite results and that sedentary persons had an increased response.[229] Both studies measured O2 consumption at rest.

This heightening of the metabolic rate is fairly well studied, but long term interventions in humans with caffeine tend to suggest caffeine is not a good long-term fat loss agent. 24 weeks of 200mg caffeine intake does not result in fat loss[230] nor 100mg for 16 months when paired with 20g soluble fiber.[231] One study that was divided into a 4 week low-calorie weight loss phase and a 3 months maintenance phase (supplemented with Green Tea Catechins and caffeine) noted, however, that caffeine intake was associated with greater weight loss during the acute phase but was not significantly related to long-term weight maintenance.[232]

Caffeine has the mechanisms to increase metabolic rate and fat loss, but this is a mechanism that one can become desensitized to. Best usage for caffeine as a stimulant for weight loss should be intermittently and in conjunction with caloric deficits.

7.2. Food intake

Caffeine has been implicated in suppressing food intake in rats[233] although studies in humans are less promising. One study noted no significant suppression of appetite or food intake in men with 3mg/kg bodyweight caffeine[234] whereas another did note suppression of food intake in men, but not women, with 300mg caffeine.[235]

7.3. Substrate Cycles (Mechanism)

'Substrate Cycles' tends to refer to cycles such as the Cori Cycle (lactate) or free fatty acid-triglyceride cycles. Caffeine has been suggested to stimulate these cycles and encourage substrate turnover. This stems from correlations in plasma between caffeine and lactate as well as caffeine and triglycerides (as well as glycerol) in which regression analysis excludes caffeine as a causative variable.[226]

The spike in lactate has been found in other studies at rest[236][236] and during exercise.[237] Studies that look at lactate before and during exercise don't note much of a difference after caffeine ingestion.[236]

7.4. Phosphodiesterases (Mechanism)

Caffeine is known as a non-selective phosphodiesterase inhibitor.[238] As phosphodiesterases mediate the breakdown of cyclic AMP (cAMP) levels, their inhibition should theoretically lead to increased cAMP and increase lipolysis. That being said, it is unlikely that biological effects seen with caffeine supplementation will be due to PDE inhibition, as the dose of caffeine required to sufficiently inhibit PDE enzymes is beyond normal human consumption.[239][240][152]


Edit8. Skeletal Muscle and Physical Performance

8.1. Power Output

Studies show that a dose of caffeine will improve strength performance. One mechanism may be reducing the users perception of pain [241] while increasing calcium mobilization in the muscle cells,[242] which can increase power output.[243]

Despite biological plausiblity existing, experiments run with caffeine do not tend to show increased performance in a 1 rep max test.[244][245] It has been noted[190] that these null effects may be due to the time of force contraction being relatively long and contraction velocity is normally below 0.4 m s−1;[246][247] this would make a 1RM test insensitive to detect changes in power output.

Sub-maximal power output, in the 6-12 rep range, tends to be increased with caffeine as assessed by increased work volume.[244] At around 60% 1 rep max, about 11-12% greater workload can be achieved with an oral dose of 6mg/kg bodyweight.[244][248]

It has been noted that there may be 'responders' to caffeine intake as it pertains to strength increasing.[249]

It is possible for caffeine to increase 1-rep max strength, although studies seem to show null results. Muscle cells appear to have increased power output as assessed by Wingate testing, which may have implications for weight training in trained individuals.

8.2. Anaerobic Cardiovascular Exercise

The delay of muscle fatigue may be part neurological and part on the level of the skeletal muscle.

Caffeine ingestion in a population of tetrapalegics still shows anti-fatigue effects of caffeine via electrical stimulation.[250] In healthy persons, caffeine still potentiates muscle contraction as induced by electrical stimulation.[243] As electrical stimulation is independent of the central nervous system, caffeine seems to in part act on either neuro-muscular junctions or contractile apparatus in muscles.

Human studies note that intermittent sprinting is increased in experienced athletes consuming 5-6mg/kg bodyweight caffeine (most common research doses)[251][252] or in general with varying dosages in the higher range.[253][254] One study conducted in physically active men noted a 1.4% reduction in fastest sprinting speed with caffeine.[251]

8.3. Aerobic Exercise

Caffeine supplementation is able to increase endurance performance significantly. Performance (typically measured as time to exhaustion at 80% VO2 max) is increased in a dose dependent manner, and significance has been noted at doses of 2.5mg/kg body weight and 5mg/kg bodyweight, which would be 227mg and 454mg for a 200lb individual respectively. One study specifically looked at comparing these dosage ranges (used 3mg and 6mg/kg) and found no statistically significant difference between the two in trained cyclists.[255] The effects in older individuals (70+) are the same as youth.[236]

Improvements in endurance performance measured by time to exhaustion hover typically in the range of 1.2 - 1.4 fold increases, with the effect being clinically significant only in those not adapted to caffeine usage[256]. Those who self-classify as caffeine users do not have significant improvements in endurance performance.

An ingested dose of caffeine can last in the body for up to 6 hours in regards to improving endurance performance. Redosing for two-a-day events separated by a 6h time frame does not appear to be needed to maintain the increased performance as measured by studies measuring multiple daily exercise sessions[257].

One of the theories of caffeine increasing aerobic performance, by increase free fatty acids or lowering potassium levels, does not appear to be fruitful.[258] The theory of increasing endurance performance by increasing catecholamine (adrenaline, in particular) levels also appears to be less promising, as endurance performance peaks do not correlate well with maximum adrenaline secretion from caffeine.[119]

One possible mechanism is the reduction of perceived effort, and indirectly doing more work without trying harder. Many studies note a reduced perception of effort and pain associated with caffeine ingestion.[237][241][151]

8.4. Muscle Soreness

In a small group of caffeine naive persons given caffeine an hour prior to eccentric exercise (followed by a rep out set) noted that supplementation was able to reduce delayed onset muscle soreness when measured 48-72 hours after exercise, but not immediately (24 hours) nor after 4-5 days after exercise.[259]

8.5. Interactions with Sleep

Caffeine is known to increase power output in both a waking and sleep deprived condition (less than six hours) in elite athletes at the oral dose of 4mg/kg,[193] but the increase in power and workload is greater in sleep deprived persons and reached a level which is not significantly different than the placebo group of those with normal sleep.[193] This increase was associated with an increase in chosen workload, which only occurred in the participants who reported feeling the effects of caffeine.[193]

The impairment in voluntarily chosen weights after a poor night of sleep appears to be alleviated with a pre-workout dosage of caffeine, but seems to only occur in those who percieve an effect of the caffeine


Edit9. Interactions with Hormones

9.1. Testosterone

Caffeine, through chewing gum, has been implicated in increasing the Testosterone response to exercise; testosterone increased 53% as a response to exercise in both groups, and a further 12+/-14% with 240mg caffeine.[260] At 800mg before resistance training, it shows an increase of 15+/-12% above placebo in trained athletes;[261] These results have been somewhat replicated in a model of sleep deprivation with 4mg/kg caffeine, with an increase in testosterone being noted (6.5-12.9%, with a larger effect in those without sleep deprivation).[193]

All studies used salivary testosterone measures despite sample sizes of 9, 24, and 16 respectively, and did not measure free (bioavailable) testosterone.[260][261] The sleep deprivation study noted that the increases in testosterone correlated well with work volume and percieved stimulation which suggested the seen increases in testosterone were secondary to work performed,[193] and this theory works well with studies without exercise (the following on rifle marksmanship) where no statistically significant differences are seen.[262]

Caffeine appears to reliably increase testosterone when consumed prior to exercise possibly due to more work performed, but the magnitude of this increase (12%) is small and the variability (+/-15%) is quite high; an unreliable intervention for testosterone boosting

One animal study has noted increased testosterone levels with chronic cola ingestion independent of exercise, but aside from also existing with an increased in estrogen the mechanism and whether this can be attributed to caffeine per se is unknown.[263] A later study in humans using 5 cups of coffee for 4 weeks noted an increase in testosterone and a decrease in estradiol in men, but not women.[264]

Limited evidence for a testosterone boosting effect independent of exercise, but a build-up effect over time may exist

9.2. Sex Hormone Binding Globulin (SHBG)

Sex Hormone Binding Globulin (SHBG) is a protein carrier in the blood that can sequester and hold both androgens (testosterone) and estrogens (estradiol, with affinity for the former.[265] High SHBG status can suppress the effects of steroid hormones despite not reducing their content in the blood.

In postmenopausal women, caffeine intake and SHBG in serum appear to be positively and reliably correlated independent of source of caffeine.[266][267][268][269][270][271] This relationship is stronger among overweight/obese women, has been calculated at approximately 13% when comparing the highest group (371mg or more) against the lowest (71mg or less), and does not appear to exist in pre-menopausal women.[268] This positive association correlates nicely with the decrease in bioavailable testosterone seen in postmenopausal women with higher caffeine intakes.[266] When tested in an intervention setting in overweight healthy adults, 5 cups of coffee daily spread out over the course of the day failed to replicate the effects seen in epidemiological research; no relationship was seen between coffee intake and SHBG.[264]

Reliable positive correlations between postmenopausal women and an increase in SHBG from caffeine, which may not apply to other demographics

9.3. Cortisol

In sedentary persons, 3.3mg/kg caffeine at rest in habitual users after 10h abstinence is sufficient to increase serum cortisol 30%; secondary to an increase in ACTH by 36%.[272] These changes seem to be sensitive upon time and loading, with injections during sleep (a time period when caffeine is low) causing exacerbated spikes in cortisol and ACTH[273] and repeated caffeine dosing causing the increase seen in waking hours, when caffeine tends to be higher, insignificant at rest.[274]

Caffeine can increase cortisol at rest, which is seen in habitual users even after a short (10 hour) abstinence in a resting state

High (800mg) doses of caffeine may increase cortisol by up to 52+/-44%.[261] A dose of 3.3mg/kg (in Grapefruit juice) in otherwise healthy young men with a 1-5 cup of Coffee a day habit has also noted an increase in cortisol when paired with exercise, but this study did not show differences between the post-caffeine group and group with caffeine and exercise;[275] an increase in cortisol relative to placebo has been noted in trained persons after cycling for 2 hours at 65% VO2 max in response to 6mg/kg.[276]

Physical Stress increases secretion of cortisol, and this appears to be augmented under the influence of caffeine in sedentary or low-active persons

In competitive level cyclists given a low dose of caffeine (250mg), a reduction in exercise-induced caffeine levels is seen.[260] After a 60h washout in competitive cyclists given 6mg/kg caffeine (a dose known to increase serum cortisol in sedentary) no apparent increase in seen before or after exercise[277] and no apparent increase exists in resistance trained men given 5mg/kg.[278]

The effects of caffeine on cortisol may be attenuated or reversed in higher level athletes given low doses

In response to mental or occupational stress, caffeine works in a similar manner with 250mg able to augment stress-induced cortisol spikes in persons with a 1-5 cup of coffee a day habit with no differences in gender,[279] with slightly higher exacerbations following 3.3mg/kg;[280][281][282] caffeine increasing cortisol appears to be dose-dependent regardless of stressor placed.[283] This increase appears to be additive rather than synergistic,[282] and lower doses (200mg) after a single day of deprivation do not always result in cortisol increases.[284]

Caffeine appears to work similar in cognitive stress as it does in physical stress, augmenting a stress-induced spike in cortisol concentrations; seems more reliable at higher doses

Conversely, one study pairing smoking with caffeine intake (in smokers with a moderate caffeine habit) noted that smoking per se increased cortisol which was independent of the Nicotine content, and that 150mg caffeine failed to modify the increase in cortisol.[285]

Studies that measure urinary levels of cortisol note a 13% reduction when measured 4 hours after 300mg,[286]


Edit10. Interactions with Cancer

10.1. Skin Carcinoma

Caffeine is associated with a reduced risk of skin carcinoma, although with a Relative Risk Ratio of 0.82 for women and 0.88 for men when compared to the lowest quintile; a moderately weak correlation.[287]

10.2. Colon Cancer

Coffee has been associated with decreased risk of colorectal cancer,[288] but this does not seen to be attributable to caffeine due to the association with both caffeinated and decaffeinated coffee.


Edit11. Interactions with Various Organ Systems

11.1. Eyes

Persons exceeding 500mg caffeine daily appear to be at a slightly greater risk of exfoliation glaucoma or exfoliation glaucoma suspect (lead determinant of Glaucoma) when compared to abstainers, and a nonsignificantly increased risk rate relative to low consumers (125-500mg); the Relative Risk (RR) for 500mg relative to abstainers was 1.66.[289]


Edit12. Tolerance, Dependence and Withdrawal

12.1. Metabolic differences between Naive and Tolerant users

Neurally, those who have adapted to caffeine intake report less neural stimulation[290] and become less attentive after caffeine usage.[291] Spikes in systolic blood pressure that occur in naive users to caffeine do not occur in habitual users,[292][293][294][295] the degree appears to be 3-6mmHg systolic blood pressure. Diastolic appears to increase around 3mmHg as well, although one study using coffee and mental stress noted a 6mmHg decline.[292] That being said, not everybody develops tolerance to caffeine's influence on blood pressure spikes; about 50% of subjects do not either over 5 days[296] or 4 weeks of supplementation.[297]

Brain lactate increases quite drastically in persons unaccustomed to caffeine and exhibit minor changes in those accustomed to it, and a 1-2 month cessation from caffeine can restore the rise in brain lactate from caffeine to the levels seen with unaccustomed users.[164] This was hypothesized by the authors as possibly being due to the combination of decrease cerebral blood flow and increase glycolysis.[164]

The reduction in cerebral blood flow associated with caffeine does not seem to differ between naive and chronic users.[157] And the ergogenic effects of caffeine being able to increase intermittent sprint performance do not seem to be different between naive and chronic users.[298]

12.2. Withdrawal Symptoms

Withdrawal of caffeine, defined as a short-term rise of adverse effects in response to caffeine deprivation, tends to last for approximately 3 days after tolerance develops.[299] Some effects may last slightly longer or shorter, such as headaches which range from 2-6 days.[300] Headaches are commonly seen as the most problematic side-effect of withdrawal, and are caused by a temporary increase in cerebral blood pressure.[301][302] The magnitude of headache is positively correlated from the daily dose of caffeine one 'comes off' of, with the larger dose resulting in more of a headache.[157][155]

Cognition tends to decrease, and most commonly the aspects of attention and focus (decreased) and fatigue (increased).[303][185] In a study on managers (average intake of 575mg caffeine) who were subject to a blinded reduction in caffeine, systolic blood pressure was reduced and cognition on a few measured parameters (applied initiative, decisions per hour,) was reduced as well. Performance on a highly complex managerial task was not adversely affected by caffeine deprivation, however.[304] It appears that baseline cognition is reduced but cognitive potential may be unhindered.

Various other mood effects, such as increased irritability and sleepiness alongside decreased alertness are also common.[305][306][307] Productivity, as assessed by a combination of attentiveness and actions per minute, is also decreased.[304]

12.3. Withdrawal Mechanisms

As measured by EEG, an increase in theta and and alpha absolute power are seen acutely after caffeine ingestion is stopped, during the withdrawal process[308][305] which is slightly alleviated with caffeine ingestion. Increased theta waves are correlated with drowsiness and decreased alertness, and thus this reading serves as some tangible evidence beyond subjective measures.

Withdrawal symptoms can be reduced by blocking NMDA receptors from acting, and has been shown to do so in using memantine and neramexane.[299]

It was noted earlier that adenosine and acetylcholine receptors are upregulated in response to caffeine; these changes begin to reverse after 7 days cessation.[141]

During withdrawal from caffeine, rats still appear to be sensitive to amphetamine-based compounds as it pertains to increasing spontaneous activity.[309]

12.4. Tolerance Symptoms

Caffeine appears to be able to invoke cross-tolerance with compounds that act on either the D1 or D2 dopamine receptors, but do not impose cross-tolerance on drugs that invoke both receptors simultanously (amphetamines, cocaine, methylphenidate).[132]

It seems possible to consume caffeine routinely without developing tolerance, although the dose must be low. In one rat study 18.3-27mg/kg daily did not result in tolerance whereas 33-57.6mg/kg did.[310]

12.5. Mechanisms of Tolerance

Caffeine tolerance, in regards to neural stimulation, has been described as an insurmountable problem; one that cannot be overcome by simply increasing the dosage.[311][310][312] Insurmountable antagonisms are depicted as altering a dose-response curve by actually flattening the curve, rather than just shifting it to a higher dosage.[313] Insurmountability is also referred to as 'non-competitve antagonism' as it does reduce the effects of agonism, but not by direct binding to a receptor.

Possibly explanations for insurmountability include receptor internalization or a changing allosteric binding site or structure of the receptor have been proposed.[313][314] However, this is receptor insurmountability. That seen with caffeine is currently the phenotype insurmountability (salient results of caffeine ingestion) while the receptor or protein that mediates this effect is not known.

It has been proposed that, due to caffeine's ability to act as a competitive inhibitor of adenosine receptors, that tolerance may be vicariously due to upregulation and proliferation of adenosine receptors. This theory was due to caffeine administration causing increased adenosine receptor count[311][315] amongst others.[316][315]

This theory was questioned and tested, as there was no precedent for receptor upregulation causing a reduction in antagonist potency and the theory did not fit with dose-effect charts.[109] One study that compared spontaneous activity of rats given caffeine either naive or in a adapted (post-tolerance) state noted that while differences did exist between groups indicating neural stimulation, that both groups' adenosine receptors were equally effective in suppressing forskolin-induced cAMP build-up, and that caffeine was equally effective in inhibiting adenosine's actions.[109] Binding efficacy of caffeine to the receptors was unchanged.[109] Additionally, the notion of insurmountability is seen after caffeine ingestion but does not seem to apply to the adenosine receptor.

It is currently not known what causes tolerance. We are aware of what tolerance exists of by assessing differences in naive and chronic users, but do not know the mechanisms that underlie tolerance.

12.6. Dependence

Dependence may refer to one of two phenomena. Drug dependence is the act of continual self-administration of a psychoactive compound despite potential harm to the self or society.[317] Physical dependence is required intake of a compound in order to maintain a certain activity or state of the body.[7]


Edit13. Nutrient-Nutrient Interactions

13.1. L-Theanine

Theanine is an amino acid that is slightly sedative, it is commonly seen as synergistic with caffeine in regards to cognition.

L-Theanine is synergistic with caffeine in regards to attention switching[318] and alertness[319][320] and reduces susceptibility to distractions (focus).[320][321] However, alertness seems to be relatively subjective and may not be a reliable increase between these two compounds,[318] and increases in mood are either present of absent.[322][318][323] This may be due to theanine being a relatively subpar Nootropic in and of itself pertaining to the above parameters, but augmenting caffeine's effects; some studies do note that theanine does not affect the above parameters in and of itself.[324] Due to this, any insensitivity or habituation to caffeine would reduce the effects of the combination as L-theanine may work through caffeine.

L-Theanine does not appear to be synergistic with caffeine in regards to attention to a prolonged and monotonous task.[325] Additionally, the addition of L-Theanine to a mixture of caffeine and Green Tea Catechins does not further increase the fat loss potential of the aforementioned pairing in rats.[326]

The mechanism of action may be in reducing caffeine's stimulatory effects (as measured by EEG) while not inhibiting other non-stimulatory caffeine mechanisms of action,[327] which would assert L-Theanine in acting as a modulatory agent.[324]

The dosage used in many of the above cognitive enhancing studies were either low doses (80-100mg L-Theanine, 50mg caffeine). In supplemental form, a 200mg:200mg combination is routinely used.

Additionally, L-Theanine may attenuate the adverse effects on sleep from caffeine.[328]

Seems to work well for selective attention and focus, and is quite variable on mood and general alertness. L-Theanine just appears the quell the peak stimulation of caffeine yet not fully prevent its alertness increasing effects.

13.2. Taurine

Taurine is a non-essential sulfur containing amino acid derived from methionine (essential amino acid) that is sometimes paired with caffeine in Energy Drinks.

In one study on surgeons suffering from sleep deprivation and put through a surgical test, the combination of caffeine (150mg) and taurine (2g) seemed to improve speed of the test yet did not improve errors relative to a rested state. It was insignificantly better than caffeine in isolation and differed from placebo in time to complete the test.[329]

13.3. Ephedrine

Caffeine is one of the three components, alongside Ephedrine and aspirin, which comprise the ECA stack. Ephedrine and caffeine have potent synergism in relation to fat burning.

Many of the studies on the Ephedrine page are done with EC, or an ephedrine:caffeine combination at 25:200mg Ephedrine/Caffeine taken three times daily. This combination appears to be a reliable fat loss agent and appetite suppressant, although it should be noted the combination has differing effects than the plant source Ephedra which may not share the same safety profile.

The cumulative fat burning synergism between the two compounds may be around 64% more than the expected additive value,[330] which comes out to a doubling of the effects of ephedrine in isolation (ie. caffeine in addition to the synergism is just as potent as ephedrine in isolation).[331] The combination increases adrenaline much greater than either compound alone, and possible benefits (stimulant effects and appetite suppression) or drawbacks are increased with any effect mediated by adrenaline.[332]

Highly recommended to use caffeine alongside ephedrine. Epherine is not needed to derive the most benefit from caffeine, but the opposite seems to be quite true.

13.4. Methamphetamine (Meth)

A combination of caffeine and Meth in a 3:1 ratio is called 'Ya-Ba' in Thailand and the surrounding areas.[333][334] The addition of caffeine is said to increase the stimulatory effects of Meth.[335][334] The combination of the two at individually non-toxic dosages can exert toxic effects, and is theorized to be caffeine's non-toxic actions increasing the potential toxicity of Methamphetamine.[334] Specifically, Meth had a 24-hour survival rate of 83% and caffeine 100% at the dosages used (12.5mg/kg caffeine, 5mg/kg meth; four dosages injected) yet the combination had a 33% survival rate.[334]

The mechanism is hypothesized to be increase dopamine release leading to increase oxidation of neurons (dopamine quinones, hydroxyl radicals, superoxide radicals, etc.),[334] or that caffeine negates adenosine's protective effects on neurotoxicity.[336] Basically, caffeine can make dopamine transmission occur at a greater rate, but the rate that this occurs is one of neuronal toxicity.

Another amphetamine based compound, MDMA, has its monoamine inducing effects synergistically increased with caffeine[337] which sometimes results in tachycardia, hyperthermia, and subsequent death.[337][338][339] The idea of low-dose (250mg or so, extrapolating from animal models) caffeine potentiating the effects of drugs extends to cocaine and other amphetamines, and theoretically any drug that agonizes both D1 and D2 receptors simultanously.[132]

Theoretically the interactions sound good, but the potency of the street drugs MDMA and Methamphetamine are at a level where further synergism seems to just result in a reduced safety threshold and further potential harm. Not an advised combination.

13.5. Alcohol

Alcohol, otherwise known as ethanol or drinking alcohol, interacts with caffeine via reducing the drinker's perception of impaired judgement and actions from alcohol.[340] This decreased perception of impairment does not accompany an actual decrease in level of impairment, however.[341][342][343] The pair may also simply blunt fatigue and sedation from alcohol by preventing adenosine from acting.[344][345]

Additionally, the most common source of caffeine (energy drinks) may have another synergistic mechanism of action. The carbonation enhances the speed of alcohol absorption.[346]

It has been suggested that the combination may be a problem from a social stand-point, as the reduction of perceived impairment coupled with the anti-sedative effects may increase overall alcohol intake in general.[340]

Interestingly, the social correlates of alcohol (social validation, sexual behaviour, desire of masculinity among males, illicit drug use and seatbelt omission) are also correlated with caffeine use as well, although causation has not been established.[347][348][349]

At least one rat study noted that it could interact with anxiety when consumed with alcohol during adolescence, by synergistically reducing anxiety in males but increasing it in females.[350]

13.6. Green tea catechins

Green Tea Catechins are in part synergistic with caffeine, or otherwise have effects which practically go well with caffeine usage.

The primary green tea catechin, EGCG, is able to attenuate (reduce) the spike in catecholamines (adrenaline, noradrenaline) in the blood that caffeine induces.[351] Due to this, the expected rises in blood pressure and heart rate that may be a side-effect of caffeine are potentially negated[351] and this interaction may also explain attentuation in anxiety.[352] Additionally, EGCG may be effective at reducing the effects of dopamine agonism from a wide variety of compounds including caffeine and meth[353] although circulating levels of dopamine are not reduced.[351] These studies investigated EGCG and caffeine at 15 and 30mg/kg bodyweight and 25mg/kg bodyweight, respectively, via intraperitoneal injection.

The above is a bit odd, as EGCG is a known inhibitor of catechol-o-methyltransferase;[354] this enzyme degrades catecholamines, and inhibiting it should increase catecholamine levels. That being said, EGCG is also implicated in reducing catecholamine secretion from the adrenal glands induced by cholinergic neurons.[355][356] This latter mechanism is consistent with the observation that EGCG and caffeine results in less adrenaline and noradrenaline but not less dopamine, which does not originate from the adrenals.[351]

That being said, the dose of EGCG used in all the above experiments was quite high. Green Tea Catechins have a low bioavailability overall, and the above dosages (15 or 30mg/kg bodyweight) may be unpractical.

Green tea catechins and caffeine have complex interactions, but the general notion is that they attenuate stimulation (a smoother peak) and may be slightly synergistic in regards to fat burning

13.7. Propanolol

Propranolol is a member of the beta-blocker class of pharmaceuticals that is used to control blood pressure and heart disease risk in the obese and metabolically ill. Its 'beta' refers to the beta-adrenergic receptors, and its blocking action makes it the opposite of ephedrine.

Caffeine and propanolol appear to antagonize each other in various ways. Propanolol can reduce sperm motility which is countered by caffeine[357] at low to moderate dosages.[358]

Additionally, propanolol has been implicated in reducing the thermogenic response to a fat burning supplement which contains caffeine (alongside Green Tea Catechins, L-Tyrosine, and Capsaicin).[359]

13.8. Danshen

Danshen, otherwise known as Salvia miltiorrhiza, is a Chinese medication that is commonly seen as heart healthy. The active compounds, the tanshinones, can inhibit the CYP1A enzymes that degrade caffeine to paraxanthine and increase the time caffeine spends in the blood by 11-25% and increase half-life by 12-16%.[360][361] This effect occurs at 100-200mg/kg daily in rats, a human equivalent dose of 16-32mg/kg bodyweight. The effects over a period of 7 days appear to be the same as a single bolus of both.[361]

13.9. Genistein

Genistein is one of the two main isoflavones found in Soy, the other being Daidzein. In a trial using 1g Genistein daily for 14 days in healthy female volunteers, it was shown that Genistein consumption decreased metabolism of caffeine through CYP1A2 (28-51% reduction) as well as through Xanthine Oxidase (24-32% reduction) and shuttled caffeine to be metabolized through CYP2A6 (29-66% increase) with no effect on NAT2.[49] These four enzymes are the only ways caffeine can be metabolized, and Genistein causes a shift in metabolism.


Edit14. Safety and Toxicity

14.1. General Toxicology

The serum concentration of caffeine that is usually seen as toxic is in the range of 200uM.[34][362] If we assume the estimations that 1mg/kg bodyweight oral ingestion equates to a 5-10uM increase in caffeine approximately an hour after ingestion[51][34] then a toxic dose of caffeine is in the range of 20-40mg/kg bodyweight, or 1.8-3.6g for a 200lb person.

14.2. Caffeine and pregnancy

Various phenomena exist to suggest that caffeine may be harmful for unborn infants. Already established was a very effective intestinal uptake in humans (so it can be assumed most caffeine ingested is in the blood), however there does not appear to be a placental barrier to caffeine[363] nor does there appear to be a blood-brain barrier in the fetus.[364] Caffeine half-life is also increased from 2.5-4.5 hours in adult humans to a varying value between 75 and 100 hours in newborn or premature infants, with greater values seen in the younger.[365][366]

There is insufficient evidence at the moment as to a final stance on caffeine during pregnancy due to the problems of extrapolating rat studies onto humans.[367][368] Although it may not be needed to eliminate caffeine usage, it may be prudent to reduce caffeine intake, especially in the first trimester as the fetus is more sensitive at this time.

References

  1. Womack CJ, et al. The influence of a CYP1A2 polymorphism on the ergogenic effects of caffeine. J Int Soc Sports Nutr. (2012)
  2. Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use
  3. Effect of a pre-exercise energy supplement on the acute hormonal response to resistance exercise
  4. Hasegawa T, et al. Rapid determination of theophylline, theobromine and caffeine in dietary supplements containing guarana by ultra-performance liquid chromatography. Shokuhin Eiseigaku Zasshi. (2009)
  5. Vieira MA, et al. Phenolic acids and methylxanthines composition and antioxidant properties of mate (Ilex paraguariensis) residue. J Food Sci. (2010)
  6. Burdock GA, Carabin IG, Crincoli CM. Safety assessment of kola nut extract as a food ingredient. Food Chem Toxicol. (2009)
  7. Heishman SJ, Henningfield JE. Stimulus functions of caffeine in humans: relation to dependence potential. Neurosci Biobehav Rev. (1992)
  8. Barone JJ, Roberts HR. Caffeine consumption. Food Chem Toxicol. (1996)
  9. Frary CD, Johnson RK, Wang MQ. Food sources and intakes of caffeine in the diets of persons in the United States. J Am Diet Assoc. (2005)
  10. Knight CA, Knight I, Mitchell DC. Beverage caffeine intakes in young children in Canada and the US. Can J Diet Pract Res. (2006)
  11. Caffeine: Clinical and experimental effects in humans
  12. Shively CA, Tarka SM Jr. Methylxanthine composition and consumption patterns of cocoa and chocolate products. Prog Clin Biol Res. (1984)
  13. Gummadi SN, Bhavya B, Ashok N. Physiology, biochemistry and possible applications of microbial caffeine degradation. Appl Microbiol Biotechnol. (2012)
  14. Heritability and Genetic Covariation of Sensitivity to PROP, SOA, Quinine HCl, and Caffeine
  15. Zhang L, et al. Caffeine in your drink: natural or synthetic. Anal Chem. (2012)
  16. Caffeine Identification, Differentiation of Synthetic and Natural Caffeine
  17. Differentiation between natural and synthetic taurine using the 13C/12C isotope ratio
  18. Cabañero AI, Recio JL, Rupérez M. Liquid chromatography coupled to isotope ratio mass spectrometry: a new perspective on honey adulteration detection. J Agric Food Chem. (2006)
  19. Cabañero AI, Recio JL, Rupérez M. Simultaneous stable carbon isotopic analysis of wine glycerol and ethanol by liquid chromatography coupled to isotope ratio mass spectrometry. J Agric Food Chem. (2010)
  20. Jeukendrup AE, Randell R. Fat burners: nutrition supplements that increase fat metabolism. Obes Rev. (2011)
  21. Diepvens K, Westerterp KR, Westerterp-Plantenga MS. Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Am J Physiol Regul Integr Comp Physiol. (2007)
  22. Relationship between caffeine concentrations in plasma and saliva
  23. Carrillo JA, et al. Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine. Ther Drug Monit. (2000)
  24. Liguori A, Hughes JR, Grass JA. Absorption and subjective effects of caffeine from coffee, cola and capsules. Pharmacol Biochem Behav. (1997)
  25. Nicolazzo JA, Reed BL, Finnin BC. The effect of various in vitro conditions on the permeability characteristics of the buccal mucosa. J Pharm Sci. (2003)
  26. Thakur RA, Michniak BB, Meidan VM. Transdermal and buccal delivery of methylxanthines through human tissue in vitro. Drug Dev Ind Pharm. (2007)
  27. Kamimori GH, et al. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharm. (2002)
  28. Coffey RJ, et al. The acute effects of coffee and caffeine on human interdigestive exocrine pancreatic secretion. Pancreas. (1986)
  29. Cohen S, Booth GH Jr. Gastric acid secretion and lower-esophageal-sphincter pressure in response to coffee and caffeine. N Engl J Med. (1975)
  30. [The influence of coffee and caffeine on gastrin and acid secretion in man (author's transl)
  31. Blanchard J, Sawers SJ. Comparative pharmacokinetics of caffeine in young and elderly men. J Pharmacokinet Biopharm. (1983)
  32. Blanchard J, Sawers SJ. The absolute bioavailability of caffeine in man. Eur J Clin Pharmacol. (1983)
  33. Bonati M, et al. Caffeine disposition after oral doses. Clin Pharmacol Ther. (1982)
  34. Magkos F, Kavouras SA. Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr. (2005)
  35. Conway KJ, Orr R, Stannard SR. Effect of a divided caffeine dose on endurance cycling performance, postexercise urinary caffeine concentration, and plasma paraxanthine. J Appl Physiol. (2003)
  36. Cox GR, et al. Effect of different protocols of caffeine intake on metabolism and endurance performance. J Appl Physiol. (2002)
  37. Marks V, Kelly JF. Absorption of caffeine from tea, coffee, and coca cola. Lancet. (1973)
  38. Mumford GK, et al. Absorption rate of methylxanthines following capsules, cola and chocolate. Eur J Clin Pharmacol. (1996)
  39. Fredholm BB, et al. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev. (1999)
  40. Eteng MU, et al. Recent advances in caffeine and theobromine toxicities: a review. Plant Foods Hum Nutr. (1997)
  41. Tansy MF, Kendall FM. Experimental and clinical aspects of gastrocolic reflexes. Am J Dig Dis. (1973)
  42. Lohsiriwat S, Kongmuang P, Leelakusolvong S. Effects of caffeine on anorectal manometric findings. Dis Colon Rectum. (2008)
  43. Stacewicz-Sapuntzakis M, et al. Chemical composition and potential health effects of prunes: a functional food. Crit Rev Food Sci Nutr. (2001)
  44. Crozier TW, et al. Espresso coffees, caffeine and chlorogenic acid intake: potential health implications. Food Funct. (2012)
  45. Miners JO, Birkett DJ. The use of caffeine as a metabolic probe for human drug metabolizing enzymes. Gen Pharmacol. (1996)
  46. Lelo A, et al. Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man. Br J Clin Pharmacol. (1986)
  47. Kalow W, Tang BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther. (1991)
  48. Kashuba AD, et al. Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther. (1998)
  49. Chen Y, et al. Genistein alters caffeine exposure in healthy female volunteers. Eur J Clin Pharmacol. (2011)
  50. Caubet MS, et al. Analysis of urinary caffeine metabolites by HPLC-DAD: the use of metabolic ratios to assess CYP1A2 enzyme activity. J Pharm Biomed Anal. (2002)
  51. Carrillo JA, Benitez J. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet. (2000)
  52. Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man
  53. Kennedy JS, et al. Pharmacokinetics of intravenous caffeine: comparison of high-performance liquid chromatographic and gas chromatographic methods. J Chromatogr. (1987)
  54. Newton R, et al. Plasma and salivary pharmacokinetics of caffeine in man. Eur J Clin Pharmacol. (1981)
  55. Collomp K, et al. Effects of moderate exercise on the pharmacokinetics of caffeine. Eur J Clin Pharmacol. (1991)
  56. Burg AW, Werner E. Tissue distribution of caffeine and its metabolites in the mouse. Biochem Pharmacol. (1972)
  57. Comparison of the effects of caffeine and other methylxanthines on {Ca2+}i in rat ventricular myocytes
  58. Ståhle L, Arner P, Ungerstedt U. Drug distribution studies with microdialysis. III: Extracellular concentration of caffeine in adipose tissue in man. Life Sci. (1991)
  59. Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl). (2010)
  60. Kendler KS, Prescott CA. Caffeine intake, tolerance, and withdrawal in women: a population-based twin study. Am J Psychiatry. (1999)
  61. Hettema JM, Corey LA, Kendler KS. A multivariate genetic analysis of the use of tobacco, alcohol, and caffeine in a population based sample of male and female twins. Drug Alcohol Depend. (1999)
  62. Genetics of coffee consumption and its stability
  63. Kendler KS, et al. Genetic and environmental influences on alcohol, caffeine, cannabis, and nicotine use from early adolescence to middle adulthood. Arch Gen Psychiatry. (2008)
  64. Sachse C, et al. Functional significance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. (1999)
  65. Ghotbi R, et al. Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and Koreans. Eur J Clin Pharmacol. (2007)
  66. Djordjevic N, et al. Induction of CYP1A2 by heavy coffee consumption in Serbs and Swedes. Eur J Clin Pharmacol. (2008)
  67. Djordjevic N, et al. Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2 -163C>A polymorphism. Eur J Clin Pharmacol. (2010)
  68. Djordjevic N, et al. Comparison of N-Acetyltransferase-2 Enzyme Genotype-Phenotype and Xanthine Oxidase Enzyme Activity Between Swedes and Koreans. J Clin Pharmacol. (2011)
  69. Djordjevic N, et al. In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population. Eur J Clin Pharmacol. (2010)
  70. Begas E, et al. In vivo evaluation of CYP1A2, CYP2A6, NAT-2 and xanthine oxidase activities in a Greek population sample by the RP-HPLC monitoring of caffeine metabolic ratios. Biomed Chromatogr. (2007)
  71. Aklillu E, et al. Xanthine oxidase activity is influenced by environmental factors in Ethiopians. Eur J Clin Pharmacol. (2003)
  72. Saruwatari J, et al. A population phenotyping study of three drug-metabolizing enzymes in Kyushu, Japan, with use of the caffeine test. Clin Pharmacol Ther. (2002)
  73. Guerciolini R, Szumlanski C, Weinshilboum RM. Human liver xanthine oxidase: nature and extent of individual variation. Clin Pharmacol Ther. (1991)
  74. Carrillo JA, Benítez J. Caffeine metabolism in a healthy Spanish population: N-acetylator phenotype and oxidation pathways. Clin Pharmacol Ther. (1994)
  75. Perera V, et al. Pharmacokinetics of caffeine in plasma and saliva, and the influence of caffeine abstinence on CYP1A2 metrics. J Pharm Pharmacol. (2011)
  76. Tantcheva-Poór I, et al. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics. (1999)
  77. McLean C, Graham TE. Effects of exercise and thermal stress on caffeine pharmacokinetics in men and eumenorrheic women. J Appl Physiol. (2002)
  78. Vistisen K, Loft S, Poulsen HE. Cytochrome P450 IA2 activity in man measured by caffeine metabolism: effect of smoking, broccoli and exercise. Adv Exp Med Biol. (1991)
  79. Schrenk D, et al. A distribution study of CYP1A2 phenotypes among smokers and non-smokers in a cohort of healthy Caucasian volunteers. Eur J Clin Pharmacol. (1998)
  80. Butler MA, et al. Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites. Pharmacogenetics. (1992)
  81. Parsons WD, Neims AH. Effect of smoking on caffeine clearance. Clin Pharmacol Ther. (1978)
  82. Simon T, et al. Variability of cytochrome P450 1A2 activity over time in young and elderly healthy volunteers. Br J Clin Pharmacol. (2001)
  83. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine
  84. Carrillo JA, Benitez J. CYP1A2 activity, gender and smoking, as variables influencing the toxicity of caffeine. Br J Clin Pharmacol. (1996)
  85. Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase high-performance liquid chromatography
  86. Arnaud MJ. The pharmacology of caffeine. Prog Drug Res. (1987)
  87. Comparative metabolic disposition of {1-Me14C}caffeine in rats, mice, and Chinese hamsters
  88. Zhang M, et al. Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol. (2009)
  89. Lublin A, et al. FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity. PLoS One. (2011)
  90. Wanke V, et al. Caffeine extends yeast lifespan by targeting TORC1. Mol Microbiol. (2008)
  91. Powers RW 3rd, et al. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. (2006)
  92. Wanke V, et al. Regulation of G0 entry by the Pho80-Pho85 cyclin-CDK complex. EMBO J. (2005)
  93. Cameroni E, et al. The novel yeast PAS kinase Rim 15 orchestrates G0-associated antioxidant defense mechanisms. Cell Cycle. (2004)
  94. Fabrizio P, et al. Regulation of longevity and stress resistance by Sch9 in yeast. Science. (2001)
  95. Reinders A, et al. Saccharomyces cerevisiae cAMP-dependent protein kinase controls entry into stationary phase through the Rim15p protein kinase. Genes Dev. (1998)
  96. Liu Y, et al. Computational study of the binding modes of caffeine to the adenosine A2A receptor. J Phys Chem B. (2011)
  97. Paluska SA. Caffeine and exercise. Curr Sports Med Rep. (2003)
  98. Porkka-Heiskanen T. Methylxanthines and sleep. Handb Exp Pharmacol. (2011)
  99. Huang ZL, Urade Y, Hayaishi O. The role of adenosine in the regulation of sleep. Curr Top Med Chem. (2011)
  100. Ferre S, et al. Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain. Front Biosci. (2008)
  101. Elmenhorst D, et al. Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET. J Nucl Med. (2012)
  102. Ursin R, Bjorvatn B. Sleep-wake and eeg effects following adenosine a1 agonism and antagonism: similarities and interactions with sleep-wake and eeg effects following a serotonin reuptake inhibitor in rats. Sleep Res Online. (1998)
  103. de Ligt RA, IJzerman AP. Intrinsic activity at adenosine A1 receptors: partial and inverse agonism. Curr Pharm Des. (2002)
  104. Fredholm BB, et al. Nomenclature and classification of purinoceptors. Pharmacol Rev. (1994)
  105. Fredholm BB. Astra Award Lecture. Adenosine, adenosine receptors and the actions of caffeine. Pharmacol Toxicol. (1995)
  106. Van Dort CJ, Baghdoyan HA, Lydic R. Adenosine A(1) and A(2A) receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal. J Neurosci. (2009)
  107. Björklund O, et al. Decreased behavioral activation following caffeine, amphetamine and darkness in A3 adenosine receptor knock-out mice. Physiol Behav. (2008)
  108. Shi D, et al. Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain. Cell Mol Neurobiol. (1993)
  109. Holtzman SG, Mante S, Minneman KP. Role of adenosine receptors in caffeine tolerance. J Pharmacol Exp Ther. (1991)
  110. Varani K, et al. Caffeine alters A2A adenosine receptors and their function in human platelets. Circulation. (1999)
  111. Conlay LA, et al. Caffeine alters plasma adenosine levels. Nature. (1997)
  112. Haleem DJ, et al. 24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: implications for caffeine-induced depression. Life Sci. (1995)
  113. Khaliq S, et al. Altered brain serotonergic neurotransmission following caffeine withdrawal produces behavioral deficits in rats. Pak J Pharm Sci. (2012)
  114. Chen MD, et al. Effect of caffeine on the levels of brain serotonin and catecholamine in the genetically obese mice. Zhonghua Yi Xue Za Zhi (Taipei). (1994)
  115. Okada M, et al. Effects of adenosine receptor subtypes on hippocampal extracellular serotonin level and serotonin reuptake activity. J Neurochem. (1997)
  116. Chin A, et al. The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion. Am J Physiol Gastrointest Liver Physiol. (2012)
  117. Bach-Rojecky L. Analgesic effect of caffeine and clomipramine: a possible interaction between adenosine and serotonin systems. Acta Pharm. (2003)
  118. Carter AJ. Hippocampal noradrenaline release in awake, freely moving rats is regulated by alpha-2 adrenoceptors but not by adenosine receptors. J Pharmacol Exp Ther. (1997)
  119. Graham TE, Spriet LL. Metabolic, catecholamine, and exercise performance responses to various doses of caffeine. J Appl Physiol. (1995)
  120. Shi D, Daly JW. Chronic effects of xanthines on levels of central receptors in mice. Cell Mol Neurobiol. (1999)
  121. Conde SV, et al. Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats. Br J Nutr. (2012)
  122. Bangsbo J, et al. Acute and habitual caffeine ingestion and metabolic responses to steady-state exercise. J Appl Physiol. (1992)
  123. Solinas M, et al. Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci. (2002)
  124. Quarta D, et al. Adenosine receptor-mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N-methyl-D-aspartate receptor stimulation. J Neurochem. (2004)
  125. Powell KR, Holtzman SG. Lack of NMDA receptor involvement in caffeine-induced locomotor stimulation and tolerance in rats. Pharmacol Biochem Behav. (1998)
  126. Acquas E, Tanda G, Di Chiara G. Differential effects of caffeine on dopamine and acetylcholine transmission in brain areas of drug-naive and caffeine-pretreated rats. Neuropsychopharmacology. (2002)
  127. Carter AJ, et al. Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors. J Pharmacol Exp Ther. (1995)
  128. Corradetti R, et al. Chronic caffeine treatment reduces caffeine but not adenosine effects on cortical acetylcholine release. Br J Pharmacol. (1986)
  129. Finn IB, Iuvone PM, Holtzman SG. Depletion of catecholamines in the brain of rats differentially affects stimulation of locomotor activity by caffeine, D-amphetamine, and methylphenidate. Neuropharmacology. (1990)
  130. Monoamine synthesis and caffeine-induced locomotor activity
  131. Garrett BE, Holtzman SG. D1 and D2 dopamine receptor antagonists block caffeine-induced stimulation of locomotor activity in rats. Pharmacol Biochem Behav. (1994)
  132. Garrett BE, Holtzman SG. Caffeine cross-tolerance to selective dopamine D1 and D2 receptor agonists but not to their synergistic interaction. Eur J Pharmacol. (1994)
  133. Garrett BE, Holtzman SG. Does adenosine receptor blockade mediate caffeine-induced rotational behavior. J Pharmacol Exp Ther. (1995)
  134. Le Moine C, et al. Dopamine-adenosine interactions in the striatum and the globus pallidus: inhibition of striatopallidal neurons through either D2 or A2A receptors enhances D1 receptor-mediated effects on c-fos expression. J Neurosci. (1997)
  135. Holtzman SG. CGS 15943, a nonxanthine adenosine receptor antagonist: effects on locomotor activity of nontolerant and caffeine-tolerant rats. Life Sci. (1991)
  136. Powell KR, Iuvone PM, Holtzman SG. The role of dopamine in the locomotor stimulant effects and tolerance to these effects of caffeine. Pharmacol Biochem Behav. (2001)
  137. Garrett BE, Holtzman SG. The effects of dopamine agonists on rotational behavior in non-tolerant and caffeine-tolerant rats. Behav Pharmacol. (1995)
  138. Cauli O, Morelli M. Subchronic caffeine administration sensitizes rats to the motor-activating effects of dopamine D(1) and D(2) receptor agonists. Psychopharmacology (Berl). (2002)
  139. Tronci E, et al. Potentiation of amphetamine-mediated responses in caffeine-sensitized rats involves modifications in A2A receptors and zif-268 mRNAs in striatal neurons. J Neurochem. (2006)
  140. Cauli O, Pinna A, Morelli M. Subchronic intermittent caffeine administration to unilaterally 6-hydroxydopamine-lesioned rats sensitizes turning behaviour in response to dopamine D(1) but not D(2) receptor agonists. Behav Pharmacol. (2005)
  141. Shi D, et al. Effects of chronic caffeine on adenosine, dopamine and acetylcholine systems in mice. Arch Int Pharmacodyn Ther. (1994)
  142. Smillie LD, Gökçen E. Caffeine enhances working memory for extraverts. Biol Psychol. (2010)
  143. Personality, caffeine and human cognitive performance
  144. Revelle W, Amaral P, Turriff S. Introversion/extroversion, time stress, and caffeine: effect on verbal performance. Science. (1976)
  145. Extraversion and dopamine: Individual differences in response to changes in dopaminergic activity as a possible biological basis of extraversion
  146. Childs E, de Wit H. Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users. Psychopharmacology (Berl). (2006)
  147. Lindskog M, et al. Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine. Nature. (2002)
  148. Svenningsson P, Nairn AC, Greengard P. DARPP-32 mediates the actions of multiple drugs of abuse. AAPS J. (2005)
  149. Walaas SI, et al. Beyond the dopamine receptor: regulation and roles of serine/threonine protein phosphatases. Front Neuroanat. (2011)
  150. Dawkins L, et al. Expectation of having consumed caffeine can improve performance and mood. Appetite. (2011)
  151. Backhouse SH, et al. Caffeine ingestion, affect and perceived exertion during prolonged cycling. Appetite. (2011)
  152. Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Brain Res Rev. (1992)
  153. Caffeine and human cerebral blood flow: A positron emission tomography study
  154. Lunt MJ, et al. Comparison of caffeine-induced changes in cerebral blood flow and middle cerebral artery blood velocity shows that caffeine reduces middle cerebral artery diameter. Physiol Meas. (2004)
  155. Field AS, et al. Dietary caffeine consumption and withdrawal: confounding variables in quantitative cerebral perfusion studies. Radiology. (2003)
  156. Sigmon SC, et al. Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. Psychopharmacology (Berl). (2009)
  157. Mathew RJ, Wilson WH. Caffeine consumption, withdrawal and cerebral blood flow. Headache. (1985)
  158. Kennedy DO, Haskell CF. Cerebral blood flow and behavioural effects of caffeine in habitual and non-habitual consumers of caffeine: a near infrared spectroscopy study. Biol Psychol. (2011)
  159. Perthen JE, et al. Caffeine-induced uncoupling of cerebral blood flow and oxygen metabolism: a calibrated BOLD fMRI study. Neuroimage. (2008)
  160. Chen Y, Parrish TB. Caffeine's effects on cerebrovascular reactivity and coupling between cerebral blood flow and oxygen metabolism. Neuroimage. (2009)
  161. Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG and subjective effects
  162. Watson J, Deary I, Kerr D. Central and peripheral effects of sustained caffeine use: tolerance is incomplete. Br J Clin Pharmacol. (2002)
  163. Chiu GS, et al. Hypoxia/Reoxygenation Impairs Memory Formation via Adenosine-Dependent Activation of Caspase 1. J Neurosci. (2012)
  164. Dager SR, et al. Human brain metabolic response to caffeine and the effects of tolerance. Am J Psychiatry. (1999)
  165. Rogers PJ, et al. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology. (2010)
  166. Childs E, et al. Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. (2008)
  167. Alsene K, et al. Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. (2003)
  168. Lane JD, et al. Caffeine effects on cardiovascular and neuroendocrine responses to acute psychosocial stress and their relationship to level of habitual caffeine consumption. Psychosom Med. (1990)
  169. Alzoubi KH, et al. Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet. Behav Brain Res. (2012)
  170. Prediger RD. Effects of caffeine in Parkinson's disease: from neuroprotection to the management of motor and non-motor symptoms. J Alzheimers Dis. (2010)
  171. Kanda T, et al. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. (1998)
  172. Grondin R, et al. Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys. Neurology. (1999)
  173. Postuma RB, et al. Caffeine for treatment of Parkinson disease: A randomized controlled trial. Neurology. (2012)
  174. Fernandez HH, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. (2010)
  175. Hauser RA, et al. Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov Disord. (2008)
  176. Stacy M, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology. (2008)
  177. LeWitt PA, et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol. (2008)
  178. Ross GW, et al. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA. (2000)
  179. Ascherio A, et al. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann Neurol. (2001)
  180. Sääksjärvi K, et al. Prospective study of coffee consumption and risk of Parkinson's disease. Eur J Clin Nutr. (2008)
  181. Ravina BM, et al. Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment. Neurology. (2003)
  182. Schwarzschild MA, et al. Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson's disease. Neurology. (2003)
  183. Xu K, et al. Estrogen prevents neuroprotection by caffeine in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J Neurosci. (2006)
  184. Xu K, et al. Caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity shows no tolerance to chronic caffeine administration in mice. Neurosci Lett. (2002)
  185. Griffiths RR, Woodson PP. Reinforcing effects of caffeine in humans. J Pharmacol Exp Ther. (1988)
  186. Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev. (1987)
  187. De Luca MA, et al. Caffeine and accumbens shell dopamine. J Neurochem. (2007)
  188. Nehlig A. Are we dependent upon coffee and caffeine? A review on human and animal data. Neurosci Biobehav Rev. (1999)
  189. Quarta D, et al. Opposite modulatory roles for adenosine A1 and A2A receptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure. J Neurochem. (2004)
  190. Mora-Rodríguez R, et al. Caffeine ingestion reverses the circadian rhythm effects on neuromuscular performance in highly resistance-trained men. PLoS One. (2012)
  191. Souissi N, et al. Diurnal variation in Wingate test performances: influence of active warm-up. Chronobiol Int. (2010)
  192. Sedliak M, et al. Diurnal variation in maximal and submaximal strength, power and neural activation of leg extensors in men: multiple sampling across two consecutive days. Int J Sports Med. (2008)
  193. Cook C, et al. Acute caffeine ingestion increases voluntarily chosen resistance training load following limited sleep. Int J Sport Nutr Exerc Metab. (2012)
  194. Wang S, Noh SK, Koo SI. Epigallocatechin gallate and caffeine differentially inhibit the intestinal absorption of cholesterol and fat in ovariectomized rats. J Nutr. (2006)
  195. Fears R. The hypercholesterolaemic effect of caffeine in rats fed on diets with and without supplementary cholesterol. Br J Nutr. (1978)
  196. Renda G, et al. Genetic determinants of blood pressure responses to caffeine drinking. Am J Clin Nutr. (2012)
  197. Robertson D, et al. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. (1981)
  198. Ledent C, et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature. (1997)
  199. Caffeine and theophylline as adenosine receptor antagonists in humans
  200. Varani K, et al. Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. Cell Mol Life Sci. (2005)
  201. Bassini-Cameron A, et al. Effect of caffeine supplementation on haematological and biochemical variables in elite soccer players under physical stress conditions. Br J Sports Med. (2007)
  202. Bak AA, van Vliet HH, Grobbee DE. Coffee, caffeine and hemostasis: results from two randomized studies. Atherosclerosis. (1990)
  203. Steptoe A, et al. The effects of tea on psychophysiological stress responsivity and post-stress recovery: a randomised double-blind trial. Psychopharmacology (Berl). (2007)
  204. Habitual Coffee Consumption and Risk of Heart Failure: A Dose-Response Meta-Analysis
  205. Greer F, et al. Caffeine ingestion decreases glucose disposal during a hyperinsulinemic-euglycemic clamp in sedentary humans. Diabetes. (2001)
  206. Keijzers GB, et al. Caffeine can decrease insulin sensitivity in humans. Diabetes Care. (2002)
  207. Pizziol A, et al. Effects of caffeine on glucose tolerance: a placebo-controlled study. Eur J Clin Nutr. (1998)
  208. Thong FS, et al. Caffeine-induced impairment of insulin action but not insulin signaling in human skeletal muscle is reduced by exercise. Diabetes. (2002)
  209. Shearer J, et al. Quinides of roasted coffee enhance insulin action in conscious rats. J Nutr. (2003)
  210. van Dijk AE, et al. Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance. Diabetes Care. (2009)
  211. Bassoli BK, et al. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. (2008)
  212. Rodriguez de Sotillo DV, Hadley M, Sotillo JE. Insulin receptor exon 11+/- is expressed in Zucker (fa/fa) rats, and chlorogenic acid modifies their plasma insulin and liver protein and DNA. J Nutr Biochem. (2006)
  213. Pedersen DJ, et al. High rates of muscle glycogen resynthesis after exhaustive exercise when carbohydrate is coingested with caffeine. J Appl Physiol. (2008)
  214. Ca2+ and AMPK Both Mediate Stimulation of Glucose Transport by Muscle Contractions
  215. Natella F, Scaccini C. Role of coffee in modulation of diabetes risk. Nutr Rev. (2012)
  216. van Dam RM, Feskens EJ. Coffee consumption and risk of type 2 diabetes mellitus. Lancet. (2002)
  217. Carlsson S, et al. Coffee consumption and risk of type 2 diabetes in Finnish twins. Int J Epidemiol. (2004)
  218. Salazar-Martinez E, et al. Coffee consumption and risk for type 2 diabetes mellitus. Ann Intern Med. (2004)
  219. Sartorelli DS, et al. Differential effects of coffee on the risk of type 2 diabetes according to meal consumption in a French cohort of women: the E3N/EPIC cohort study. Am J Clin Nutr. (2010)
  220. Coffee and incidence of diabetes in Swedish women: a prospective 18-year follow-up study
  221. Tuomilehto J, et al. Coffee consumption and risk of type 2 diabetes mellitus among middle-aged Finnish men and women. JAMA. (2004)
  222. van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA. (2005)
  223. Huxley R, et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis. Arch Intern Med. (2009)
  224. Yoshida T, et al. Relationship between basal metabolic rate, thermogenic response to caffeine, and body weight loss following combined low calorie and exercise treatment in obese women. Int J Obes Relat Metab Disord. (1994)
  225. Acheson KJ, et al. Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals. Am J Clin Nutr. (1980)
  226. Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers
  227. Caffeine and coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals
  228. LeBlanc J, et al. Enhanced metabolic response to caffeine in exercise-trained human subjects. J Appl Physiol. (1985)
  229. Poehlman ET, et al. Influence of caffeine on the resting metabolic rate of exercise-trained and inactive subjects. Med Sci Sports Exerc. (1985)
  230. Astrup A, et al. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int J Obes Relat Metab Disord. (1992)
  231. Pasman WJ, Westerterp-Plantenga MS, Saris WH. The effectiveness of long-term supplementation of carbohydrate, chromium, fibre and caffeine on weight maintenance. Int J Obes Relat Metab Disord. (1997)
  232. Westerterp-Plantenga MS, Lejeune MP, Kovacs EM. Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation. Obes Res. (2005)
  233. Racotta IS, Leblanc J, Richard D. The effect of caffeine on food intake in rats: involvement of corticotropin-releasing factor and the sympatho-adrenal system. Pharmacol Biochem Behav. (1994)
  234. Caffeinated Coffee Does Not Acutely Affect Energy Intake, Appetite, or Inflammation but Prevents Serum Cortisol Concentrations from Falling in Healthy Men
  235. Caffeine reduces spontaneous energy intake in men but not in women
  236. Norager CB, et al. Metabolic effects of caffeine ingestion and physical work in 75-year old citizens. A randomized, double-blind, placebo-controlled, cross-over study. Clin Endocrinol (Oxf). (2006)
  237. Hadjicharalambous M, et al. Influence of caffeine on perception of effort, metabolism and exercise performance following a high-fat meal. J Sports Sci. (2006)
  238. Choi OH, et al. Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors. Life Sci. (1988)
  239. Smellie FW, et al. Alkylxanthines: inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phosphodiesterase activity. Life Sci. (1979)
  240. Are methylxanthine effects due to antagonism of endogenous adenosine?
  241. The effects of low-dose caffeine on perceived pain during a grip to exhaustion task
  242. Davis JK, Green JM. Caffeine and anaerobic performance: ergogenic value and mechanisms of action. Sports Med. (2009)
  243. Tarnopolsky M, Cupido C. Caffeine potentiates low frequency skeletal muscle force in habitual and nonhabitual caffeine consumers. J Appl Physiol. (2000)
  244. Astorino TA, Rohmann RL, Firth K. Effect of caffeine ingestion on one-repetition maximum muscular strength. Eur J Appl Physiol. (2008)
  245. Williams AD, et al. The effect of ephedra and caffeine on maximal strength and power in resistance-trained athletes. J Strength Cond Res. (2008)
  246. Izquierdo M, et al. Effects of long-term training specificity on maximal strength and power of the upper and lower extremities in athletes from different sports. Eur J Appl Physiol. (2002)
  247. González-Badillo JJ, Sánchez-Medina L. Movement velocity as a measure of loading intensity in resistance training. Int J Sports Med. (2010)
  248. Duncan MJ, Oxford SW. The effect of caffeine ingestion on mood state and bench press performance to failure. J Strength Cond Res. (2011)
  249. Astorino TA, et al. Minimal effect of acute caffeine ingestion on intense resistance training performance. J Strength Cond Res. (2011)
  250. Mohr T, et al. Caffeine ingestion and metabolic responses of tetraplegic humans during electrical cycling. J Appl Physiol. (1998)
  251. Glaister M, et al. Caffeine supplementation and multiple sprint running performance. Med Sci Sports Exerc. (2008)
  252. Schneiker KT, et al. Effects of caffeine on prolonged intermittent-sprint ability in team-sport athletes. Med Sci Sports Exerc. (2006)
  253. Astorino TA, Roberson DW. Efficacy of acute caffeine ingestion for short-term high-intensity exercise performance: a systematic review. J Strength Cond Res. (2010)
  254. Bishop D. Dietary supplements and team-sport performance. Sports Med. (2010)
  255. Desbrow B, et al. The effects of different doses of caffeine on endurance cycling time trial performance. J Sports Sci. (2012)
  256. Exercise endurance 1, 3, and 6 h after caffeine ingestion in caffeine users and nonusers
  257. Bell DG, McLellan TM. Effect of repeated caffeine ingestion on repeated exhaustive exercise endurance. Med Sci Sports Exerc. (2003)
  258. Van Baak MA, Saris WH. The effect of caffeine on endurance performance after nonselective beta-adrenergic blockade. Med Sci Sports Exerc. (2000)
  259. The Effect of Caffeine Ingestion on Delayed Onset Muscle Soreness
  260. Paton CD, Lowe T, Irvine A. Caffeinated chewing gum increases repeated sprint performance and augments increases in testosterone in competitive cyclists. Eur J Appl Physiol. (2010)
  261. Beaven CM, et al. Dose effect of caffeine on testosterone and cortisol responses to resistance exercise. Int J Sport Nutr Exerc Metab. (2008)
  262. Gillingham R, et al. Effect of caffeine on target detection and rifle marksmanship. Ergonomics. (2003)
  263. Celec P, Behuliak M. Behavioural and endocrine effects of chronic cola intake. J Psychopharmacol. (2010)
  264. Wedick NM, et al. The effects of caffeinated and decaffeinated coffee on sex hormone-binding globulin and endogenous sex hormone levels: a randomized controlled trial. Nutr J. (2012)
  265. Södergård R, et al. Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem. (1982)
  266. Ferrini RL, Barrett-Connor E. Caffeine intake and endogenous sex steroid levels in postmenopausal women. The Rancho Bernardo Study. Am J Epidemiol. (1996)
  267. Goto A, et al. Coffee and caffeine consumption in relation to sex hormone-binding globulin and risk of type 2 diabetes in postmenopausal women. Diabetes. (2011)
  268. Kotsopoulos J, et al. Relationship between caffeine intake and plasma sex hormone concentrations in premenopausal and postmenopausal women. Cancer. (2009)
  269. Nagata C, Kabuto M, Shimizu H. Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex hormone-binding globulin in premenopausal Japanese women. Nutr Cancer. (1998)
  270. London S, et al. Alcohol and other dietary factors in relation to serum hormone concentrations in women at climacteric. Am J Clin Nutr. (1991)
  271. Lucero J, et al. Early follicular phase hormone levels in relation to patterns of alcohol, tobacco, and coffee use. Fertil Steril. (2001)
  272. Lovallo WR, et al. Stress-like adrenocorticotropin responses to caffeine in young healthy men. Pharmacol Biochem Behav. (1996)
  273. Lin AS, et al. Effects of intravenous caffeine administered to healthy males during sleep. Depress Anxiety. (1997)
  274. Lovallo WR, et al. Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels. Psychosom Med. (2005)
  275. Sung BH, et al. Effects of caffeine on blood pressure response during exercise in normotensive healthy young men. Am J Cardiol. (1990)
  276. Laurent D, et al. Effects of caffeine on muscle glycogen utilization and the neuroendocrine axis during exercise. J Clin Endocrinol Metab. (2000)
  277. Whitham M, Walker GJ, Bishop NC. Effect of caffeine supplementation on the extracellular heat shock protein 72 response to exercise. J Appl Physiol. (2006)
  278. Woolf K, Bidwell WK, Carlson AG. The effect of caffeine as an ergogenic aid in anaerobic exercise. Int J Sport Nutr Exerc Metab. (2008)
  279. Lovallo WR, et al. Cortisol responses to mental stress, exercise, and meals following caffeine intake in men and women. Pharmacol Biochem Behav. (2006)
  280. Pincomb GA, et al. Caffeine enhances the physiological response to occupational stress in medical students. Health Psychol. (1987)
  281. Lovallo WR, et al. Caffeine may potentiate adrenocortical stress responses in hypertension-prone men. Hypertension. (1989)
  282. Pincomb GA, et al. Effect of behavior state on caffeine's ability to alter blood pressure. Am J Cardiol. (1988)
  283. Nickell PV, Uhde TW. Dose-response effects of intravenous caffeine in normal volunteers. Anxiety. (1994-1995)
  284. Giles GE, et al. Differential cognitive effects of energy drink ingredients: caffeine, taurine, and glucose. Pharmacol Biochem Behav. (2012)
  285. Gilbert DG, et al. Effects of nicotine and caffeine, separately and in combination, on EEG topography, mood, heart rate, cortisol, and vigilance. Psychophysiology. (2000)
  286. Lane JD. Neuroendocrine responses to caffeine in the work environment. Psychosom Med. (1994)
  287. Song F, Qureshi AA, Han J. Increased caffeine intake is associated with reduced risk of Basal cell carcinoma of the skin. Cancer Res. (2012)
  288. Sinha R, et al. Caffeinated and decaffeinated coffee and tea intakes and risk of colorectal cancer in a large prospective study. Am J Clin Nutr. (2012)
  289. The Relationship between Caffeine and Coffee Consumption and Exfoliation Glaucoma or Glaucoma Suspect: A Prospective Study in Two Cohorts
  290. Evans SM, Griffiths RR. Caffeine tolerance and choice in humans. Psychopharmacology (Berl). (1992)
  291. Zwyghuizen-Doorenbos A, et al. Effects of caffeine on alertness. Psychopharmacology (Berl). (1990)
  292. Kennedy MD, et al. The cumulative effect of coffee and a mental stress task on heart rate, blood pressure, and mental alertness is similar in caffeine-naïve and caffeine-habituated females. Nutr Res. (2008)
  293. Sharp DS, Benowitz NL. Pharmacoepidemiology of the effect of caffeine on blood pressure. Clin Pharmacol Ther. (1990)
  294. Ammar R, et al. Evaluation of electrocardiographic and hemodynamic effects of caffeine with acute dosing in healthy volunteers. Pharmacotherapy. (2001)
  295. Myers MG, Reeves RA. The effect of caffeine on daytime ambulatory blood pressure. Am J Hypertens. (1991)
  296. Lovallo WR, et al. Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension. (2004)
  297. Farag NH, et al. Hemodynamic mechanisms underlying the incomplete tolerance to caffeine's pressor effects. Am J Cardiol. (2005)
  298. Woolf K, Bidwell WK, Carlson AG. Effect of caffeine as an ergogenic aid during anaerobic exercise performance in caffeine naïve collegiate football players. J Strength Cond Res. (2009)
  299. Sukhotina IA, et al. Caffeine withdrawal syndrome in social interaction test in mice: effects of the NMDA receptor channel blockers, memantine and neramexane. Behav Pharmacol. (2004)
  300. Headache caused by caffeine withdrawal among moderate coffee drinkers switched from ordinary to decaffeinated coffee: a 12 week double blind trial
  301. Couturier EG, et al. Influence of caffeine and caffeine withdrawal on headache and cerebral blood flow velocities. Cephalalgia. (1997)
  302. Jones HE, et al. Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity. Psychopharmacology (Berl). (2000)
  303. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl). (2004)
  304. Streufert S, et al. Effects of caffeine deprivation on complex human functioning. Psychopharmacology (Berl). (1995)
  305. Keane MA, James JE, Hogan MJ. Effects of dietary caffeine on topographic EEG after controlling for withdrawal and withdrawal reversal. Neuropsychobiology. (2007)
  306. Ratliff-Crain J, O'Keeffe MK, Baum A. Cardiovascular reactivity, mood, and task performance in deprived and nondeprived coffee drinkers. Health Psychol. (1989)
  307. Goldstein A, Kaizer S, Whitby O. Psychotropic effects of caffeine in man. IV. Quantitative and qualitative differences associated with habituation to coffee. Clin Pharmacol Ther. (1969)
  308. Reeves RR, et al. Topographic quantitative EEG measures of alpha and theta power changes during caffeine withdrawal: preliminary findings from normal subjects. Clin Electroencephalogr. (1995)
  309. Holtzman SG. Complete, reversible, drug-specific tolerance to stimulation of locomotor activity by caffeine. Life Sci. (1983)
  310. Gasior M, et al. Changes in the ambulatory activity and discriminative stimulus effects of psychostimulant drugs in rats chronically exposed to caffeine: effect of caffeine dose. J Pharmacol Exp Ther. (2000)
  311. Boulenger JP, et al. Chronic caffeine consumption increases the number of brain adenosine receptors. Life Sci. (1983)
  312. Newland MC, Brown K. Behavioral characterization of caffeine and adenosine agonists during chronic caffeine exposure. Behav Pharmacol. (1997)
  313. Vauquelin G, et al. New insights in insurmountable antagonism. Fundam Clin Pharmacol. (2002)
  314. Kenakin T, Jenkinson S, Watson C. Determining the potency and molecular mechanism of action of insurmountable antagonists. J Pharmacol Exp Ther. (2006)
  315. Ahlijanian MK, Takemori AE. Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice. Life Sci. (1986)
  316. Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain
  317. World Health Organization Expert committee on drug dependence
  318. Einöther SJ, et al. L-theanine and caffeine improve task switching but not intersensory attention or subjective alertness. Appetite. (2010)
  319. Giesbrecht T, et al. The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness. Nutr Neurosci. (2010)
  320. Owen GN, et al. The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci. (2008)
  321. Bryan J. Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev. (2008)
  322. Haskell CF, et al. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. (2008)
  323. Rogers PJ, et al. Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology (Berl). (2008)
  324. Kelly SP, et al. L-theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance. J Nutr. (2008)
  325. Foxe JJ, et al. Assessing the effects of caffeine and theanine on the maintenance of vigilance during a sustained attention task. Neuropharmacology. (2012)
  326. Zheng G, et al. Anti-obesity effects of three major components of green tea, catechins, caffeine and theanine, in mice. In Vivo. (2004)
  327. Kakuda T, et al. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem. (2000)
  328. Jang HS, et al. L-theanine partially counteracts caffeine-induced sleep disturbances in rats. Pharmacol Biochem Behav. (2012)
  329. Aggarwal R, et al. Effect of caffeine and taurine on simulated laparoscopy performed following sleep deprivation. Br J Surg. (2011)
  330. Astrup A, et al. Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double-blind, placebo-controlled study. Metabolism. (1991)
  331. Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: human studies. Int J Obes. (1986)
  332. Haller CA, Jacob P 3rd, Benowitz NL. Enhanced stimulant and metabolic effects of combined ephedrine and caffeine. Clin Pharmacol Ther. (2004)
  333. Kulsudjarit K. Drug problem in southeast and southwest Asia. Ann N Y Acad Sci. (2004)
  334. Sinchai T, et al. Caffeine potentiates methamphetamine-induced toxicity both in vitro and in vivo. Neurosci Lett. (2011)
  335. Kuribara H. Caffeine enhances the stimulant effect of methamphetamine, but may not affect induction of methamphetamine sensitization of ambulation in mice. Psychopharmacology (Berl). (1994)
  336. Delle Donne KT, Sonsalla PK. Protection against methamphetamine-induced neurotoxicity to neostriatal dopaminergic neurons by adenosine receptor activation. J Pharmacol Exp Ther. (1994)
  337. Ikeda R, et al. Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain. Eur J Pharmacol. (2011)
  338. McNamara R, et al. Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA ("Ecstasy") and MDA ("Love"). Neuropharmacology. (2006)
  339. Camarasa J, Pubill D, Escubedo E. Association of caffeine to MDMA does not increase antinociception but potentiates adverse effects of this recreational drug. Brain Res. (2006)
  340. Weldy DL. Risks of alcoholic energy drinks for youth. J Am Board Fam Med. (2010)
  341. Marczinski CA, Fillmore MT. Clubgoers and their trendy cocktails: implications of mixing caffeine into alcohol on information processing and subjective reports of intoxication. Exp Clin Psychopharmacol. (2006)
  342. Ferreira SE, et al. Effects of energy drink ingestion on alcohol intoxication. Alcohol Clin Exp Res. (2006)
  343. O'Brien MC, et al. Caffeinated cocktails: energy drink consumption, high-risk drinking, and alcohol-related consequences among college students. Acad Emerg Med. (2008)
  344. Oteri A, et al. Intake of energy drinks in association with alcoholic beverages in a cohort of students of the School of Medicine of the University of Messina. Alcohol Clin Exp Res. (2007)
  345. Liguori A, Robinson JH. Caffeine antagonism of alcohol-induced driving impairment. Drug Alcohol Depend. (2001)
  346. Roberts C, Robinson SP. Alcohol concentration and carbonation of drinks: the effect on blood alcohol levels. J Forensic Leg Med. (2007)
  347. Jones HA, Lejuez CW. Personality correlates of caffeine dependence: the role of sensation seeking, impulsivity, and risk taking. Exp Clin Psychopharmacol. (2005)
  348. Miller KE. Wired: energy drinks, jock identity, masculine norms, and risk taking. J Am Coll Health. (2008)
  349. Miller KE. Energy drinks, race, and problem behaviors among college students. J Adolesc Health. (2008)
  350. Hughes RN. Adult anxiety-related behavior of rats following consumption during late adolescence of alcohol alone and in combination with caffeine. Alcohol. (2011)
  351. Han JY, et al. Increases in blood pressure and heart rate induced by caffeine are inhibited by (-)-epigallocatechin-3-O-gallate: involvement of catecholamines. J Cardiovasc Pharmacol. (2011)
  352. Park KS, et al. (-)-Epigallocatechin-3-O-gallate (EGCG) reverses caffeine-induced anxiogenic-like effects. Neurosci Lett. (2010)
  353. Park KS, et al. (-)-Epigallocatethin-3-O-gallate counteracts caffeine-induced hyperactivity: evidence of dopaminergic blockade. Behav Pharmacol. (2010)
  354. Zhu BT, et al. Molecular modelling study of the mechanism of high-potency inhibition of human catechol-O-methyltransferase by (-)-epigallocatechin-3-O-gallate. Xenobiotica. (2008)
  355. Lim DY, et al. Comparison of green tea extract and epigallocatechin gallate on blood pressure and contractile responses of vascular smooth muscle of rats. Arch Pharm Res. (2003)
  356. Lim DY. Comparison of green tea extract and epigallocatechin gallate on secretion of catecholamines from the rabbit adrenal medulla. Arch Pharm Res. (2005)
  357. Hong CY, Chaput de Saintonge DM, Turner P. The inhibitory action of procaine, (+)-propranolol and (+/-)-propranolol on human sperm motility: antagonism by caffeine. Br J Clin Pharmacol. (1981)
  358. Rogberg L, Fredricsson B, Pousette A. Effects of propranolol and caffeine on movement characteristics of human sperm. Int J Androl. (1990)
  359. Belza A, et al. The beta-adrenergic antagonist propranolol partly abolishes thermogenic response to bioactive food ingredients. Metabolism. (2009)
  360. Wang X, et al. Effects of major tanshinones isolated from Danshen (Salvia miltiorrhiza) on rat CYP1A2 expression and metabolism of model CYP1A2 probe substrates. Phytomedicine. (2009)
  361. Wang X, Yeung JH. Effects of the aqueous extract from Salvia miltiorrhiza Bunge on caffeine pharmacokinetics and liver microsomal CYP1A2 activity in humans and rats. J Pharm Pharmacol. (2010)
  362. Fredholm BB. On the mechanism of action of theophylline and caffeine. Acta Med Scand. (1985)
  363. Ikeda GJ, et al. Blood levels of caffeine and results of fetal examination after oral administration of caffeine to pregnant rats. J Appl Toxicol. (1982)
  364. Tanaka H, et al. Caffeine and its dimethylxanthines and fetal cerebral development in rat. Brain Dev. (1984)
  365. Parsons WD, Neims AH. Prolonged half-life of caffeine in healthy tem newborn infants. J Pediatr. (1981)
  366. Aranda JV, et al. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr. (1977)
  367. Adén U. Methylxanthines during pregnancy and early postnatal life. Handb Exp Pharmacol. (2011)
  368. Kuczkowski KM. Caffeine in pregnancy. Arch Gynecol Obstet. (2009)
  369. Vandenberghe K, et al. Caffeine counteracts the ergogenic action of muscle creatine loading. J Appl Physiol. (1996)
  370. Doherty M, et al. Caffeine is ergogenic after supplementation of oral creatine monohydrate. Med Sci Sports Exerc. (2002)
  371. Lee CL, Lin JC, Cheng CF. Effect of caffeine ingestion after creatine supplementation on intermittent high-intensity sprint performance. Eur J Appl Physiol. (2011)
  372. Fukuda DH, et al. The possible combinatory effects of acute consumption of caffeine, creatine, and amino acids on the improvement of anaerobic running performance in humans. Nutr Res. (2010)
  373. Smith AE, et al. The effects of a pre-workout supplement containing caffeine, creatine, and amino acids during three weeks of high-intensity exercise on aerobic and anaerobic performance. J Int Soc Sports Nutr. (2010)
  374. Spradley BD, et al. Ingesting a pre-workout supplement containing caffeine, B-vitamins, amino acids, creatine, and beta-alanine before exercise delays fatigue while improving reaction time and muscular endurance. Nutr Metab (Lond). (2012)
  375. Vanakoski J, et al. Creatine and caffeine in anaerobic and aerobic exercise: effects on physical performance and pharmacokinetic considerations. Int J Clin Pharmacol Ther. (1998)
  376. Agonist-Directed Desensitization of the β2-Adrenergic Receptor
  377. Kenakin TP. Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat Rev Drug Discov. (2009)
  378. Fang Y. Label-Free Receptor Assays. Drug Discov Today Technol. (2011)
  379. Fang Y, Ferrie AM. Label-free optical biosensor for ligand-directed functional selectivity acting on beta(2) adrenoceptor in living cells. FEBS Lett. (2008)
  380. Receptor internalization and ERK1/2 phosphorylation are dependent on the agonist exposure time
  381. The desensitization and resensitization patterns of quiescent A431 cells induced by epinephrine is sensitive to stimulation duration and several inhibitors
  382. January B, et al. beta2-adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists. J Biol Chem. (1997)
  383. Characterization of β2-Adrenergic Receptor Dephosphorylation: Comparison with the Rate of Resensitization
  384. Sears MR. Adverse effects of beta-agonists. J Allergy Clin Immunol. (2002)
  385. Nelson HS. Is there a problem with inhaled long-acting beta-adrenergic agonists. J Allergy Clin Immunol. (2006)
  386. Astrup A, et al. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr. (1985)
  387. Karapetian GK, et al. Effect of Caffeine on LT, VT and HRVT. Int J Sports Med. (2012)
  388. Glaister M, et al. Caffeine and sprinting performance: dose responses and efficacy. J Strength Cond Res. (2012)
  389. Bloomer RJ, et al. Effects of 1,3-dimethylamylamine and caffeine alone or in combination on heart rate and blood pressure in healthy men and women. Phys Sportsmed. (2011)
  390. Carr AJ, Gore CJ, Dawson B. Induced alkalosis and caffeine supplementation: effects on 2,000-m rowing performance. Int J Sport Nutr Exerc Metab. (2011)
  391. Del Coso J, et al. Dose response effects of a caffeine-containing energy drink on muscle performance: a repeated measures design. J Int Soc Sports Nutr. (2012)
  392. Wedick NM, et al. Effects of caffeinated and decaffeinated coffee on biological risk factors for type 2 diabetes: a randomized controlled trial. Nutr J. (2011)
  393. Kim TW, et al. Caffeine increases sweating sensitivity via changes in sudomotor activity during physical loading. J Med Food. (2011)
  394. Barry RJ, Clarke AR, Johnstone SJ. Caffeine and opening the eyes have additive effects on resting arousal measures. Clin Neurophysiol. (2011)
  395. Astorino TA, et al. Effect of caffeine intake on pain perception during high-intensity exercise. Int J Sport Nutr Exerc Metab. (2011)
  396. Shechter M, et al. Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease. Am J Cardiol. (2011)
  397. Gavrieli A, et al. Caffeinated coffee does not acutely affect energy intake, appetite, or inflammation but prevents serum cortisol concentrations from falling in healthy men. J Nutr. (2011)
  398. Duvnjak-Zaknich DM, et al. Effect of caffeine on reactive agility time when fresh and fatigued. Med Sci Sports Exerc. (2011)
  399. Hunt MG, Momjian AJ, Wong KK. Effects of diurnal variation and caffeine consumption on Test of Variables of Attention (TOVA) performance in healthy young adults. Psychol Assess. (2011)
  400. Pontifex KJ, et al. Effects of caffeine on repeated sprint ability, reactive agility time, sleep and next day performance. J Sports Med Phys Fitness. (2010)
  401. Ganio MS, et al. Effect of ambient temperature on caffeine ergogenicity during endurance exercise. Eur J Appl Physiol. (2011)
  402. Hameleers PA, et al. Habitual caffeine consumption and its relation to memory, attention, planning capacity and psychomotor performance across multiple age groups. Hum Psychopharmacol. (2000)
  403. Astorino TA, et al. Effect of two doses of caffeine on muscular function during isokinetic exercise. Med Sci Sports Exerc. (2010)
  404. Hendrix CR, et al. Acute effects of a caffeine-containing supplement on bench press and leg extension strength and time to exhaustion during cycle ergometry. J Strength Cond Res. (2010)
  405. Lamina S, Musa DI. Ergogenic effect of varied doses of coffee-caffeine on maximal aerobic power of young African subjects. Afr Health Sci. (2009)
  406. Adan A, Serra-Grabulosa JM. Effects of caffeine and glucose, alone and combined, on cognitive performance. Hum Psychopharmacol. (2010)
  407. Mednick SC, et al. Comparing the benefits of caffeine, naps and placebo on verbal, motor and perceptual memory. Behav Brain Res. (2008)
  408. Astrup A, et al. Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am J Clin Nutr. (1990)
  409. Anderson DE, Hickey MS. Effects of caffeine on the metabolic and catecholamine responses to exercise in 5 and 28 degrees C. Med Sci Sports Exerc. (1994)

(Common misspellings for Caffeine include caffin, caffene, caffein)

(Common phrases used by users for this page include what are the possible effects of caffeine in the amygdala, cycle caffeine bodybuilding, caffeine smoke residue, caffeine euphoria, caffeine acts on the which part of the brain to cause wakefulness and alertness., asprin, caffeine increase meth high)

(Users who contributed to this page include dbarvinok, gwern, Baltir, shrillthrill, gadingading, , djeik, )