What are Xanthines?
At least half the world population drinks tea (which contains caffeine and small amounts of theophylline and theobromine) prepared from the leaves of the Camellia sinensis, a shrub native to southern China, but now extensively grown in other countries .
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 .
Nevertheless, you cannot get the beneficial effects of theobromine just by supplementing caffeine alone.
Methylxanthines, specifically theobromine and caffeine, are the main factors responsible for particular chocolate cravings, revealing their huge impact on tastes and food preferences .
If your interest is mainly in caffeine, you can refer to this article.
Mechanisms of Action
Those biochemical mechanisms include:
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
All of these mechanisms are involved in numerous processes, but most common and useful ones are:
- Increased wakefulness during the day
- More alertness during the day
Moreover, methylxanthines also have other effects such as relaxing smooth muscles, stimulating urine production and fluid loss, and increasing heart muscle contraction .
This leaves the action on adenosine receptors and inhibition of cAMP-degradation as the only logical mechanism related to the consumption 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 has a variety of benefits as its a key mediator for many processes in our body, from memory consolidation to fat loss pathways. It is able, among other effects, to increase heart rate and promote fat loss .
Health Benefits of Xanthines
To better navigate through the various benefits of these chemical compounds, the effects have been divided into two main categories: “quality of life,” which offers useful benefits to everyday life and common conditions, and “clinical effects,” which lists a more scientifically in-depth approach of all the major effects of xanthines on less common clinical conditions.
Xanthine Health Benefits
1) May Help in Weight Loss
A 2016 epidemiological study comparing the daily consumption of coffee and caffeinated beverages of 2,129 individuals found that caffeine consumption was associated with weight loss maintenance .
One study of 60 females evaluated caffeine consumption on weight regain after caloric restriction, where caffeine appeared as a way to better tolerate caloric shift and weight loss, preventing weight regain .
Caffeine also promotes high levels of cAMP, which promotes fat loss .
2) May Improve Circulation in High Cholesterol
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 [23, 24, 25, 26].
Methylxanthines are able to increase the blood concentration of a particular chemical compound called (-)-epicatechin. This chemical improves blood circulation and appears to be the major component responsible for cocoa flavanol intake benefits .
3) Help with Coughing
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 [28, 29].
Theobromine seems to be useful in the treatment of asthma and other respiratory tract problems such as a cough. A study on animals used vagus nerve preparations in which theobromine helped with cough symptoms (through inhibition of the depolarization effect of capsaicin, an action on afferent nerves) .
A clinical trial of 289 subjects (DB-RCT) showed a mild improvement in a persistent cough with the use of a theobromine-based compound .
4) May Improve Endurance
5) Promote Dental Health
One study of 80 subjects (DB-RCT) found that theobromine-containing toothpaste improved tooth hypersensitivity .
6) May Prevent Pregnancy-Induced Hypertension
A systematic review of both experimental and observational studies showed that moderate theobromine supplementation through dietary cocoa helped prevent pregnancy-induced high blood pressure [34, 35].
7) Can Improve Cholesterol Levels
Another study (DB-RCT) of 152 men and women found that theobromine increased HDL levels .
However, one study of 44 healthy subjects (DB-RCT) found that theobromine might not be effective when baseline HDL is too low and when blood triglycerides are too high .
8) Can Lower Blood Pressure
In a double-blind, placebo-controlled study of 42 healthy individuals, theobromine showed a marked effect in lowering central systolic blood pressure .
Moreover, a 2017 Cochrane review including 35 trials on cocoa consumption and heart health found that these had a lowering effect on blood pressure .
9) May Improve Metabolic Parameters and Heart Health
A recent review of 14 studies found that chocolate consumption reduced the risk of heart diseases, stroke, and diabetes .
A large umbrella review of meta-analysis found that caffeine consumption might be beneficial for improving cardiovascular health .
Another recent review found improvement with heart protection and regular coffee consumption .
10) Reduce Inflammation
Systemic inflammation appears to be linked almost to every chronic disease. Some examples are :
11) May Reduce Oxidative Stress
Caffeine and its byproducts theobromine and xanthine exhibit both antioxidant and pro-oxidant properties. They may also contribute to the overall antioxidant and chemopreventive properties of caffeine-bearing beverages, such as tea .
Effects of Xanthines on Clinical Conditions
12) May Help with Brain Diseases
Evidence shows that patients with Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis may potentially benefit from methylxanthine supplementation.
Biomedical analogs of methylxanthines are becoming valid agents against neurodegeneration. However, it is still unclear if those compounds can help slow neurodegeneration or prevent these conditions [55, 8].
13) Might Act as an Anti-Cancer Compound
Functional studies have demonstrated that theophylline has a direct action on:
- Inducing cellular death and renewal
- Improving cells lifespan
- Decreased splicing of SRSF3, a gene related to improved aging
All of these effects make theophylline a potential anti-cancer drug .
14) Help with Depression
However, sudden caffeine withdrawal can lead to a worsening of depressive symptoms .
15) Are Useful for Chronic Asthma in Children
Thirty‐six studies with 2,838 participants were analyzed in a Cochrane systematic review. The results found that xanthines can alleviate symptoms and reduce the requirement for rescue medication in children with mild-to-moderate asthma.
16) Have Anti-Tumor Effects
17) May Improve Steroid Tolerance
A study in cells found that theophylline can restore a normal sensitivity to steroids to reduce inflammation .
Excretion of Theophylline
Drug clearance is increased in:
- Children aged 1 to 12 years [64, 65]
- Adolescents aged 12 to 16 years 
- Adult and elderly smokers [66, 67]
- Those with cystic fibrosis [68, 69]
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 [68, 74]
- ~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, Limitations, and Drug Interactions
Caffeine has a marked effect on elevating blood pressure in high doses .
As previously stated, theobromine might actually lower blood pressure.
With the same mechanism of action on A2A receptors, researchers only speculated that this opposite effect could be due to the different absorption rates of caffeine and theobromine as a study on rats and several ones in humans show [84, 85, 86].
Reasons for this toxicity are unknown.
Theophylline, however, is characterized by having a low therapeutic index. As in the case of many other drugs for asthma, its use must be carefully monitored to avoid toxicity.
Toxicity can cause convulsions and they must be considered as a brain emergency .
In addition to seizures in the event of toxicity, severe arrhythmias (abnormal heart rhythms) may occur .
The drug can reach toxic levels when taken with fatty meals. This effect is called “dose dumping” .
Theophylline toxicity can be treated with beta-blocker drugs .
Limitations and Caveats
Although methylxanthines have been extensively studied, many of their interactions are still unknown.
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) .
Natural Sources, Forms of Supplementation, and Dosage
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 .
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 the same molecular structure as caffeine. It 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 all the health benefits of theobromine and theobromine+flavanol-rich cocoa are hard to obtain with commercial, sugar-enriched cocoa. Thus, there is not still a recommended daily intake of cocoa .
Forms of Supplementation
All of the methylxanthines come in pure powder form, but can be found in capsules.
Dosages between 250 mg and 500 mg of theobromine were used without any side effects in a clinical study .
For theophylline, a dose of 4.5 mg/kg was used in a study of 10 healthy individuals .
Theobromine and theophylline are not so popular as supplements yet, despite their many health benefits.
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 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.
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