Print Friendly, PDF & Email

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 have numerous beneficial effects on health and could help with losing weight or cholesterol problems. Xanthines may also aid with clinical conditions like Alzheimer’s disease, Parkinson’s disease, asthma, chronic obstructive pulmonary disease (COPD), and even some types of cancer. However, the over-consumption of xanthines can be harmful to health. Read more to understand the benefits of xanthines and how to use them.

Introduction

Methylxanthines are chemical compounds derived from the purine base xanthine. Some well-known natural xanthines include caffeine, theobromine, and theophylline.

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 [R].

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 [R, R].

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 [R].

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 [R].

If your interest is mainly in caffeine, you can refer to this article.

Mechanisms of Action

The general methylxanthine mechanisms of action have been widely discussed by several researchers [R, R, R, R, R, R, R, R, R, R]:

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

5) Blocking of adenosine receptors, mainly A1 and A2A

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 [R].

However, higher doses may be required to mobilize intracellular calcium, inhibit PDEs or modulate GABAA receptors, or to unselectively inhibit ABCC5 and ABCC4 transporters [R, R].

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 [R].

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) Xanthines May Help in Weight Loss

A study in rats showed a marked improvement in weight loss by associating theophylline with a low-calorie diet [R].

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 [R].

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 [R].

A trial of 90 obese subjects (DB-RCT) found that caffeine and low dose ephedrine were successful weight loss supplements for visceral fat loss [R].

Caffeine also promotes high levels of cAMP, which promotes fat loss [R].

2) Xanthines 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 [R, R, R, R].

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 [R].

3) Xanthines 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 [R, R].

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) [R].

A clinical trial of 289 subjects (DB-RCT) showed a mild improvement in a persistent cough with the use of a theobromine-based compound [R].

4) Xanthines May Improve Endurance

In a small study of 10 healthy subjects, theophylline delayed the onset of fatigue during intermittent high-intensity exercise [R].

5) Xanthines Promote Dental Health

One study of 80 subjects (DB-RCT) found that theobromine-containing toothpaste improved tooth hypersensitivity [R].

6) Xanthines 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 [R, R].

7) Xanthines Can Improve Cholesterol Levels

A study of 42 high-risk volunteers found that a daily intake of 40 grams of cocoa powder improved the HDL/LDL cholesterol ratio [R].

Another study (DB-RCT) of 152 men and women found that theobromine increased HDL levels [R].

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 [R].

8) Xanthines 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 [R].

Also, in another placebo-controlled study of 24 healthy females, beneficial effects on pressure and mood were observed [R].

Moreover, a 2017 Cochrane review including 35 trials on cocoa consumption and heart health found that these had a lowering effect on blood pressure [R].

9) Xanthines 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 [R].

Two different reviews found a protective role for cocoa and its major compound, theobromine, in metabolic and heart health [R, R].

A large umbrella review of meta-analysis found that caffeine consumption might be beneficial for improving cardiovascular health [R].

Another recent review found improvement with heart protection and regular coffee consumption [R].

10) Xanthines Reduce Inflammation

Systemic inflammation appears to be linked almost to every chronic disease. Some examples are [R]:

Acting as phosphodiesterase inhibitors, a medical analog of methylxanthines such as pentoxifylline is able to decrease pro-inflammatory cytokines such as interferon-gamma or TNF-alpha.

Caffeine, by blocking adenosine receptors, may have a great impact on lowering systemic inflammation [R, R].

11) Xanthines 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 [R].

Effects of Xanthines on Clinical Conditions

12) Xanthines 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 [R, R].

13) Xanthines Might Act as an Anti-Cancer Compound

Functional studies have demonstrated that theophylline has a direct action on:

  1. Inducing cellular death and renewal
  2. Improving cells lifespan
  3. Decreased splicing of SRSF3, a gene related to improved aging

All of these effects make theophylline a potential anti-cancer drug [R].

14) Xanthines Help with Depression

A review of 8 studies and 38,223 participants revealed a marked improvement in depression with caffeine intake [R].

However, sudden caffeine withdrawal can lead to a worsening of depressive symptoms [R].

15) Xanthines 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 [R].

16) Xanthines Have Anti-Tumor Effects

In the lab, theobromine exhibited a potential antitumor effect in the growth of malignant glioblastoma cells [R, R].

17) Xanthines May Improve Steroid Tolerance

A study in cells found that theophylline can restore a normal sensitivity to steroids to reduce inflammation [R].

Excretion of Theophylline

Theophylline is excreted unaltered in the urine (up to 10%) [R, R]

Drug clearance is increased in:

  • Children aged 1 to 12 years [R, R]
  • Adolescents aged 12 to 16 years [R]
  • Adult and elderly smokers [R, R]
  • Those with cystic fibrosis [R, R]

The drug clearance is reduced in the elderly and in subjects with acute congestive heart failure [R, R].

Half-life is also extremely variable:

  • 30 hours for premature infants [R]
  • 24 hours for neonates, 3.5 hours for children aged 1 to 9 [R]
  • 8 hours for adults who are not smoking, 5 hours for adult smokers [R, R]
  • ~3.5 hours for subjects with cystic fibrosis [R]
  • 24 hours for subjects with liver impairment [R]
  • 12 hours for subjects with congestive heart failure NYHA class I-II [R]
  • 24 hours for subjects with NYHA class III-IV congestive heart failure [R]

Side Effects

High doses of methylxanthines could potentially cause [R, R, R, R, R]:

  1. A headache
  2. Nausea
  3. Anxiety
  4. Mood shift
  5. Rapid heartbeat
  6. Death

Caffeine has a marked effect on elevating blood pressure in high doses [R].

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 [R, R, R].

Theobromine increases blood pressure only when a particular SNP is present (ADORA2A – rs4822492) [R].

Theobromine is toxic to animals, even deadly for dogs [R, R].

Reasons for this toxicity are unknown.

Growing evidence in the last decade indicates that theobromine has psychoactive actions in humans that are qualitatively different from those of caffeine [R, R].

Theobromine is not toxic to humans [R, R, R].

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.

The drug can cause nausea and occasionally diarrhea, palpitations, tachycardia (abnormal heart rate), atrial fibrillation, and fainting [R, R].

It can also cause a headache, tremor, insomnia, irritability, dizziness, and convulsions.

Anxiety, agitation, dizziness, lightheadedness, and depression are other side effects reported in the literature [R, R].

Toxicity can cause convulsions and they must be considered as a brain emergency [R].

In addition to seizures in the event of toxicity, severe arrhythmias (abnormal heart rhythms) may occur [R].

The drug can reach toxic levels when taken with fatty meals. This effect is called “dose dumping” [R].

Theophylline toxicity can be treated with beta-blocker drugs [R].

Limitations and Caveats

Although methylxanthines have been extensively studied, many of their interactions are still unknown.

Drug Interactions

Phenytoin: Combination therapy with theophylline leads to an increase in the clearance of theophylline, reducing its blood half-life [R, R].

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) [R].

Cimetidine: Inhibits theophylline clearance, making it more dangerous and long-lasting [R, R, R].

Natural Sources and Forms of Supplementation

Coffee

Coffee is extracted from dried Coffea arabica, Coffea canephora, Coffea Iberica, and other Rubiaceae seeds [R].

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 chinic and caffeic acid [R].

Moreover, N-methylnicotinic acid is degraded to nicotinic acid during the roasting process. Aroma and flavor are given by volatile oils and tannins [R, R, R].

Tea

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 [R].

Cocoa

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%) [R].

Maté

Derived from Ilex paraguariensis leaves, maté is common in the 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%) [R].

Guarana

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 [R].

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 [R].

Forms of Supplementation

All of the methylxanthines come in pure powder form, but can be found in capsules.

Dosage

Dosages between 250 mg and 500 mg of theobromine were used without any side effects in a clinical study [R].

For theophylline, a dose of 4.5 mg/kg was used in a study of 10 healthy individuals [R].

User Experience

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.

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

HOW WOULD YOU RATE THIS ARTICLE?

1 Star2 Stars3 Stars4 Stars5 Stars (1 votes, average: 4.00 out of 5)
Loading...
TWEET
0

1 COMMENT

  • FC

    Kola Nuts contain caffeine (2–3.5%) and theobromine (1.0–2.5%). Powder seems to have weaker effect than roasted coffee eqivalent quantity.

  • Leave a Reply

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.