We are all familiar with coffee and caffeine. What you might not know is that caffeine belongs to a wider category of chemical compounds called methylxanthines. These compounds — abundant in cocoa, tea, and coffee — may protect the heart and brain, improve physical performance, boost metabolism, and more. However, their over-consumption can be harmful. Read on to learn the potential benefits, safety precautions, and best natural sources of xanthines.
What are Xanthines?
Methylxanthines are chemical compounds derived from the purine base xanthine. Some well-known natural xanthines include caffeine, theobromine, and theophylline.
At least half of the world’s population drinks tea, which contains caffeine and small amounts of theophylline and theobromine .
Cocoa and chocolate, derived from the seeds of Theobroma cacao, contain theobromine, which is the main chemical responsible for their health benefits. Also, some caffeine is present [2, 3].
Coffee, the most popular source of dietary caffeine, is extracted from the Arabica coffee and related species.
Caffeine is mainly broken down by the liver and, interestingly, one of its by-products is theobromine .
Methylxanthines, specifically theobromine and caffeine, are the main factors responsible for particular chocolate cravings, revealing their huge impact on taste and food preferences .
If your interest is mainly in caffeine, jump to this post.
Mechanisms of Action
The general methylxanthine mechanisms of action include [6, 7, 8, 9, 10, 11, 12, 13, 14, 15]:
1) Mobilization of intracellular calcium
2) Inhibition of phosphodiesterases (PDEs)
3) Inhibition of gamma-aminobutyric acid (GABAA) receptors
4) Inhibition of high affinity ATP-dependent cyclic nucleotide transporters
5) Blocking of adenosine receptors, mainly A1 and A2A
The predominant health effects that stem from these mechanisms are increased wakefulness and alertness during the day. Methylxanthines also have other effects such as relaxing smooth muscles, stimulating urine production and fluid loss, and increasing heart muscle contraction .
However, much higher doses may be required to mobilize intracellular calcium, inhibit PDEs or modulate GABAA receptors, or to unselectively inhibit ABCC5 and ABCC4 transporters [8, 17].
This leaves the action on adenosine receptors and inhibition of cAMP-degradation as the primary mechanism behind the effects of dietary methylxanthines.
To give a practical example: when adenosine accumulates in the brain and saturates adenosine receptors, we feel dizzy and sleepy. Xanthines bind to the same receptors as adenosine (antagonism), which prevents this effect and keeps us alert and awake.
Also, maintaining a high level of circulating cAMP may increase heart rate and promote fat metabolism .
Xanthines Health Benefits
1) Respiratory Conditions
Whether dietary cocoa consumption or methylxanthines are significantly effective in preventing cough or diminishing cough intensity is yet to be determined, however, the evidence is promising [19, 20].
Theophylline is an active component of different FDA-approved drugs for asthma and other respiratory conditions .
Theobromine may be helpful for asthma, cough, and other respiratory tract problems, too.
A clinical trial of 289 subjects (DB-RCT) showed a mild improvement in a persistent cough with the use of a theobromine-based compound .
In a study of 21 young adults with asthma, theobromine capsules increased bronchial diameter, which increased airflow to the lungs .
The anti-inflammatory potential of theobromine may be responsible for this effect. It can reduce the levels of inflammatory cytokines such as IFN-y and TNF-a [2, 24].
According to a review of 7 clinical studies, caffeine can help open the airways and relieve bronchitis symptoms including wheezing, coughing, and breathlessness .
2) Attention and Alertness
Multiple clinical reviews have confirmed the potential of caffeine to increase mental alertness in low-to-moderate doses (40-300 mg). The effects were even more pronounced in non-regular users and during sleep deprivation [26, 27, 28].
In a study of 36 participants, caffeine exhibited dose-dependent effects on alertness and attention. When people who usually do not drink caffeinated products consumed high doses of caffeine, they had a higher increase in brain function. Regular and tolerant users may still feel the same effects, but to a smaller extent .
A lack of sleep can cause delays in reaction times. In a study of 20 sleep-deprived participants, a total daily dose of 800 mg of caffeine helped improve reaction speed and accuracy .
In one study, twelve young adults either had sufficient sleep (9 hours) or a lack-of-sleep (4 hours). 100 mg of caffeine improved both groups’ coordination, judgment, memory, and reaction time during a driving task .
However, some reviews have underlined the tolerance to its stimulant effects, abuse potential, and a potential toxicity that comes with higher doses [32, 33].
3) Physical Performance
A comprehensive clinical review summarized 21 meta-analyses on caffeine and physical performance. A large body of evidence suggests that “caffeine ingestion improves exercise performance in a broad range of exercise tasks.” It showed beneficial effects on :
- Muscle endurance
- Muscle strength
- Aerobic endurance
- Anaerobic power
Caffeine particularly helps anaerobic exercises like sprinting or jumping. This effect may arise from its anti-fatigue effects and by improving endurance, physical strength, and power output .
In a small study of 10 healthy subjects, theophylline delayed the onset of fatigue during intermittent high-intensity exercise .
4) Heart Disease
A recent review of 14 studies found that moderate chocolate consumption (up to 6 servings or 180 g per week) reduced the risk of heart disease and stroke .
Two different reviews found a protective role for cocoa and its major compound, theobromine, in metabolic and heart health [38, 39].
Circulation (Blood Flow)
High cholesterol, metabolic syndrome, and blood vessel stiffness are common in postmenopausal women. Chronic consumption of flavanol-rich cocoa enhanced blood circulation in postmenopausal women with high cholesterol [40, 41, 42, 43].
Methylxanthines are able to increase the blood concentration of a particular chemical compound called (-)-epicatechin, which may also improve blood circulation .
Theobromine, abundant in cocoa, may cause blood pressure to decrease by widening the blood vessels and stimulating urination (diuretic) .
A study of 42 high-risk volunteers found that a daily intake of 40 grams of cocoa powder improved the HDL/LDL cholesterol ratio .
Whole cocoa drink wasn’t effective but pure theobromine significantly raised HDL (“good”) cholesterol and reduces LDL (“bad”) cholesterol in another study of 152 healthy volunteers .
However, one study of 44 healthy subjects found that theobromine might not be effective when baseline HDL is too low and when blood triglycerides are too high .
In a study of 30 adults, caffeine was associated with a significant increase in total blood cholesterol and LDL (bad) cholesterol .
In a study of 84 healthy patients, theobromine significantly lowered blood pressure at doses between 250 and 1,000 mg .
Another study of 24 participants showed that theobromine can help high blood pressure. Within 1 hour of consumption, 700 mg of theobromine successfully lowered the participant’s blood pressure .
Moreover, a 2017 Cochrane review including 35 trials on cocoa consumption and heart health found its blood pressure-lowering effect .
A meta-analysis of 16 studies showed that 410 mg of caffeine daily raised the risk for high blood pressure, even in healthy people. However, the ingestion of caffeine through coffee only had a small effect on blood pressure .
5) Weight Loss
Many supplements are promoted to stimulate weight loss, but none of them has yet been supported by strong clinical evidence and approved by the health authorities. A healthy, calorie-controlled diet and increased physical activity remain the only proven strategies for weight control .
A combination of ephedrine and caffeine enhanced fat burning and weight loss and reduced blood lipids in five trials of over 500 participants [55, 56, 57, 58, 59].
That said, pure ephedrine and Ephedra-based products are banned by the FDA due to their high abuse potential and adverse effects on heart health [60, 61, 62].
Caffeine remained a popular ingredient in over-the-counter fat burning supplements. It may increase energy usage and improve metabolic rate, which helps prevent weight gain .
A meta-analysis published in 2019 included 13 clinical trials of 606 participants. The authors concluded that “caffeine intake might promote weight, BMI and body fat reduction” .
By breaking down stored fat, caffeine shows potential benefits in weight loss management. In a study of 2,100 participants, the ones who drank 2 to 4 cups of caffeinated coffee a day were more successful at shedding weight than those who did not .
A study in rats showed a marked improvement in weight loss by associating theophylline with a low-calorie diet .
6) Cognition and Brain Health
Preliminary evidence shows that patients with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, may potentially benefit from methylxanthines and their food sources, such as tea, coffee, and cocoa. However, it is still unclear if those compounds can help slow neurodegeneration or prevent these conditions [67, 8].
In one study, out of 430 healthy subjects, those who consumed caffeinated coffee had a lower risk of developing Parkinson’s disease. It even reduced the risk in those genetically predisposed to develop the condition .
In a long-term study of 1,400 people, drinking 3 to 5 cups of coffee per day at midlife could decrease dementia or Alzheimer’s disease (AD) risk by about 65% at old age .
In one review, coffee had a positive effect on brain function. Moderate caffeinated coffee consumption decreased the risk of dementia and AD later in life. However, caffeinated tea had no effects .
In a 30-patient study, cocoa-based drinks with varying amounts of theobromine and other chocolate flavanols were consumed. As these flavanols took effect, participants had improved performance on mental tasks and reduced mental fatigue .
No valid clinical evidence supports the use of xanthines for any of the conditions in this section. Below is a summary of up-to-date animal studies, cell-based research, or low-quality clinical trials which should spark further investigation. However, you shouldn’t interpret them as supportive of any health benefit.
7) Mood and Mental Health
In a large cohort study of 43,599 men and 164,825 women, people who consumed caffeinated coffee had a lower rate of suicide. This could be due to caffeine’s ability to increase dopamine .
However, higher amounts (600 mg) can increase tension and anxiety, which can negatively affect mood .
The effects of caffeine on depression are also conflicting: there are studies showing both increased and decreased rates associated with caffeine consumption [73, 74, 75, 76].
The explanation for conflicting results may lie in caffeine’s abuse potential and tolerance to both adverse and beneficial effects. Additionally, sudden caffeine withdrawal can lead to a worsening of depressive symptoms. Further research is warranted [77, 32, 33].
Excretion of Theophylline
Theophylline is excreted unaltered in the urine (up to 10%) [78, 79].
Drug clearance is increased in:
- Children aged 1 to 12 years [80, 81]
- Adolescents aged 12 to 16 years 
- Adult and elderly smokers [82, 83]
- Those with cystic fibrosis [84, 85]
The drug clearance is reduced in the elderly and in subjects with acute congestive heart failure [86, 87].
Half-life is also extremely variable:
- 30 hours for premature infants 
- 24 hours for neonates, 3.5 hours for children aged 1 to 9 
- 8 hours for adults who are not smoking, 5 hours for adult smokers [84, 90]
- ~3.5 hours for subjects with cystic fibrosis 
- 24 hours for subjects with liver impairment 
- 12 hours for subjects with congestive heart failure NYHA class I-II 
- 24 hours for subjects with NYHA class III-IV congestive heart failure 
Side Effects and Safety
All methylxanthines are generally safe and well-tolerated in moderate amounts normally present in foods and drinks. High doses of methylxanthines, especially caffeine, may potentially cause [94, 95, 96, 97, 33]:
Caffeine may also elevate blood pressure in high doses .
Theobromine’s effect on blood pressure seems to be associated with a particular SNP: ADORA2A – rs4822492 .
Theobromine and caffeine are toxic to animals. Theobromine may even be deadly for dogs [3, 99].
Theophylline is a drug with a low therapeutic index, which means its use must be carefully monitored to avoid toxicity. It can cause nausea and occasionally diarrhea, palpitations, tachycardia (abnormal heart rate), and fainting [100, 101].
Anxiety, agitation, dizziness, and depression are other side effects reported in the literature. Theophylline toxicity can be treated with beta-blocker drugs [102, 103, 104].
Drug and Substance Interactions
Phenytoin: Combination therapy with theophylline leads to an increase in the clearance of theophylline, reducing its blood half-life [105, 106].
Allopurinol: Co-assumption with theophylline and xanthines, in general, may result in increased blood concentration of xanthines. The toxic effects of allopurinol are increased by the simultaneous use of erythromycin, cimetidine, and fluoroquinolones (ciprofloxacin, levofloxacin, and others) .
Cimetidine: Inhibits theophylline clearance, making it more dangerous and long-lasting [108, 109, 110].
Caffeine, on the other hand, may interact with:
Natural Sources and Supplementation
Coffee is extracted from dried Coffea arabica, Coffea canephora, Coffea Iberica, and other Rubiaceae seeds .
Coffee seeds have 1 to 2% of caffeine and theophylline/theobromine traces. They are biochemically bound with chlorogenic acids (5 to 7%) and the roasting process releases free alkaloids as it degrades chlorogenic acid in gallic and caffeic acid .
Moreover, N-methylnicotinic acid is degraded to nicotinic acid during the roasting process. Aroma and flavor are given by volatile oils and tannins [117, 118].
Tea derives from the leaf buds of Camellia Sinensis. It contains caffeine (1 to 4%), theobromine, and theophylline (0.05%). Theaflavins are also being studied as protective agents against oxidative stress .
Cocoa is widely recognized as a standalone drink, but it is even the basis for chocolate preparation. Cocoa seeds are made from oils (35 to 50%, strictly cocoa butter or theobroma oil), theobromine (1 to 4%) and caffeine (0.2 to 0.5%) .
Derived from Ilex paraguariensis leaves, maté is common in South American culture. The dried leaf contains 0.8 to 1.8% of caffeine and 0.3 to 0.9% of theophylline. High doses of chlorogenic acids are also present (10 to 16%) .
Derived from Paullinia cupana seeds, guarana is a caffeine clone. Indeed, guaranine has almost the same molecular structure as caffeine. Guarana has a rough percentage of 3 to 5% of guaranine. Minimal, non-relevant quantities of theophylline (0 to 0.25%) and theobromine (0.02 to 0.06%) are also present .
A Note on Cocoa Quality and Added Sugars
A common problem discussed by many researchers is that the health benefits of theobromine and cocoa are hard to obtain with commercial, sugar-enriched cocoa. Thus, there’s no established recommended daily intake of cocoa .
The below doses may not apply to you personally. If your doctor suggests using methylxanthines in a supplement form, work with them to find the optimal dosage according to your health condition and other factors.
Theobromine is mainly found in cacao beans .
- A 70% dark chocolate bar can have as much as 810 mg of theobromine, while a milk chocolate bar has 65 mg .
- A single block of unsweetened chocolate has 375 mg of theobromine .
A standard dosage of theobromine ranges from 50-1,000 mg, depending on the product. Dosages of 500 mg have the greatest benefits with little to no negative side effects .
There is no single recommended dosage as it should tailor to individual differences, their genetic variability and their history with caffeine. An effective dose can range from 32 to 1,400 mg .
Medium doses (225-360 mg) were effective at improving physical performance, while 100-600 mg can help improve brain performance .
However, doses above 250 mg can cause symptoms that mimic anxiety. Additionally, prolonged use of at least 100 mg/day can cause tolerance and/or dependence .
Theobromine has been described as the best caffeine alternative by those who do not tolerate caffeine for its stimulating effects, which appears stronger if you are caffeine resistant.
Even though it acts upon the same receptors, theobromine can be taken at lower doses and has less addictive effects than caffeine. Because of this, users are much more likely to avoid an overdose.
In addition, theobromine addiction cases have not been reported yet.
Caffeine addiction, however, is common in regular users.
Faster heartbeats are also common in severe caffeine users.
There is anecdotal evidence about endurance athletes and an improvement in their stamina through theophylline assumption, most certainly due to its effect on the enlargement of bronchial walls and subsequently improved oxygen circulation.