Caffeine

Last Updated: September 28 2022

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

Caffeine is most often used for.



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1.

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.[4][5] 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.[6]

It is seen as the worlds most popular drug, and 92-98% of persons in North America (1984 data) consume some form of caffeine.[4] 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.[7] 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.[8] 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).[9]

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.[5] Soda tends to be 15-29mg per 180mL. This variability tends to undermine the accuracy of society-wide estimates mentioned previously.[8]

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.[10]

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.[11]

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.[11]

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.

{OLD-IMG-ID:51}

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.[12]

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,[13][14] taurine,[15] sugar (for honey products),[16] and alcohol products[17] 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[13] 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.[18][19]

2.

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.[20][21][22]

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.[23][24] 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.[25]

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,[26] but at a weaker potency than these other components (evidenced by decaffeinated coffee causing significantly more gastric acid release than isolated caffeine).[27] The increase of gastrin induced by coffee is not due to caffeine.[28]|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%[29][30] up to acute dosages of 10mg/kg bodyweight, the highest studied in humans.[31] This absorption tends to occur almost completely within 45 minutes of ingestion.[32][30][22]

Most caffeine is taken up from the gut 45 minutes after oral ingestion[30] and reaches peak values in the blood between 15 and 120 minutes dependent on individual physiology and vehicle (liquid, capsule, gum, etc.).[31] A slightly more precise estimate may be 30-60 minutes post oral ingestion,[33][34] 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.[32]

Caffeine absorption is slightly delayed from soda and chocolate relative to coffee,[35][36][37] and capsules have faster absorption than does coffee.[36] Caffeine in a chewing gum format is absorbed faster than capsules, as caffeine can be absorbed through the buccal muscoa (mouth).[25]

Caffeine, when in the stomach, can act upon gastric myenteric and submucous nerves to induce gastric emptying.[38][32] The influx of digestive metabolites into the small intestines may stimulate the gastrocolic reflex[39] 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).[40] 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,[41] and is an active component of coffee.[42]

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 metabolized 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.[8]

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.[43][44] 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.[45][46]

Approximately 84% of ingested caffeine is initially demethylated by CYP1A into Paraxanthine by acting on the 3-carbon.[47] 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)[47][48]

Xanthine oxidase can convert the metabolite 1-methylxanthine into 1-methylurate.[48]

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.[8]

The half-life of caffeine varies widely, due to aforementioned variations in CYP1A. One study noted a range of 2.7-9.9 hours[30] with highly similar ranges in another group of persons by the same researchers.[29]

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.[49] A steady state volume of distribution appears to occur at 500-800mL/kg with dosages below 250mg.[50][51][52] Doses above 250mg start to increase this amount[52][32] and habitual users of caffeine are associated with greater distribution.[53]

Caffeine appears to be readily distributed between serum and extra-cellular fluid, and then the cell. This appears in the mouse[54] and isolated rat cultures[55] with nearly perfect correlation, although the correlation is likely to be less in humans.[56]

The circulating levels of caffeine in the Extra-Cellular tissue of adipose (fat mass) is not significantly different than that circulating in plasma.[56] 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.[57] When looking at heavy caffeine intake (more than 625mg daily) inheritability spikes to 0.77.[58] Studies that assess both genders individually note no significant differences in heritability.[59][60] These differences appear to rise during adolescence, however, and then stabilize; prior to adolescence there is less of a heritable influence on caffeine.[61]

Genetic variations in the CYP1A enzyme that degrades caffeine can alter its ergogenic (performance increasing) effects, with the AA homozygotes outperforming the C allele carriers during endurance exercise.[62]

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).[63] 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.[63] A higher 'CYP1A 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,[63]

Activity of the enzyme can be upregulated by smoking, increasing caffeine metabolic rate.[64][63] Heavy coffee drinking may also increase CYP1A activity[65] although perhaps only for the AA genotype.[66]

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.[67] This difference between genders is not overly potent, and some studies fail to find such a significant difference.[68][69]

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[70]), Japanese (11%[71]), Caucasian (20%[72]), and Spanish (4%[73]). Even without consideration to demographics, a 2-4 fold difference can be found among tested women.[46]

NAT (N-Acetyl Transferase) appears to work faster in Koreans than it does in Swedes, on average.[67]

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[74] and intake of coffee is correlated with increased aromatase activity at an extra 1.45-fold increase per 1L of coffee consumed.[75]

Exercise does not tend to influence caffeine pharmacokinetics,[76] although one study did note that a higher Cmax was seen with exercise relative to sedentary persons.[53]

Many nutraceuticals commonly found in foods, such as the Bioflavonoid 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.[77][78][79][80]

Age does not influence Aromatase activity or variability.[81] Gender doesn't influence aromatase activity as it pertains to caffeine for the most part,[82][76] but at least some studies suggest women may have less active aromatase.[83][84]

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.[85][8] Metabolites also differ, with trimethyl derivatives accounting for 40% of total derivatives in rats but only 6% of total derivatives in man.[86][8]

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.[8] This is with consideration to the differences in metabolic half-life.

3.

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[87]) abolished these benefits; tannic acid and Baicalein (from Scutellaria baicalensis) also proved to increase lifespan via DAF-16 translocation.[88]

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),[89] which via Sch9 (mammalian ortholog S6K[90]) phosphorylates PKA and prevents nuclear actions of Rim15[91] (mammalian ortholog LATS[92]) which normally mediates oxidant defense and stress response genes;[93][94] bypassing TORC1 abolishes the longevity promoting effects of caffeine,[89] 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[89]).

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

4.

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.[95] As adenosine mediates the perception of drowsiness, preventing its actions results in alertness.[96][97][98] It is non-selective (hits all isomers of adenosine receptors) although it shows slightly more affinity for the A1 receptor,[99] 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.[100] 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.[101][102] 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.[8] 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.[103][104]

The A2A subset, when activated, actually promotes wakefulness rather than induces sleepiness.[105] 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.[8] 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.[106] A3 has a KD approaching 80uM[103][8] 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,[107] although binding efficacy and the post-translational effects of adenosine antagonism are not altered in chronic vs. naive mice subject to caffeine.[108] The receptors may also become sensitive to adenosine agonism, as assessed by human platelet A2A.[109] Following this, adenosine levels circulating in the body may also increase following chronic caffeine ingestion in rats.[110]

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.[107] Additionally, brain levels of serotonin itself may increase.[111] 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)[112] and that the increase in serotonin may be more significant in obese mice relative to lean, despite occurring in both.[113] Tryptophan levels are also increased in the brain during caffeine usage.[111]

Serotonin appears to be increased with caffeine ingestion via adenosine receptor antagonism.[114] This is seen since caffeine is a non-selective antagonist, as selective antagonism of A2 subsets reduce serotonin levels.[114][115]

The serotonergic system may interact with the analgesic (painkilling) effects of caffeine, which primarily works via caffeine's adenosine antagonism.[116]

Cessation of caffeine is associated with a transient decline in brain serotonin levels, which is associated with temporary memory impairment.[112] 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.[111] 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.[117]

Acutely, caffeine ingestion increases adrenaline and noradrenaline levels in the body of persons who consume it. This increase seems to be fairly dose dependent.[118]

Chronic caffeine ingestion is able to downregulate (reduce) the amount of beta-adrenergic receptors in the brain by up to 25% in some areas.[107] This effect in independent of adenosine antagonism.[119] Caffeine, chronically, has also been shown to decrease circulating catecholamine levels and prevent against diet-induced insulin resistance in rats[120] and prolonged caffeine usage at the same dose causes a lessening of adrenergic (adrenaline-mediated) effects in humans, not just those induced by caffeine.[121]

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,[122] theoretically downstream of adenosine A1 receptor antagonism and via NMDA receptors.[123]

NMDA activation does not appear to be a factor in caffeine-induced locomotion.[124]

4.5

Cholinergic Neurotransmission

Caffeine injections into rats can dose dependently increases acetylcholine level in the medial pre-frontal cortex.[125] This has occurred in the hippocampus, and appears to be secondary thorugh either adenosine A1 antagonism[126] or A2A agonism[reference|url=http://www.ncbi.nlm.nih.gov/pubmed/19158311|title=Adenosine A(1) and A(2A) receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal|published=2009 Jan 21|authors=Van Dort CJ, Baghdoyan HA

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