Health Benefits of Methylxanthines in Cacao and Chocolate

One may wonder why methylxanthines are so abundant in beverages used by humans for centuries, or in cola-drinks that have been heavily consumed since their appearance. It is likely that humans have stuck to any brew containing compounds with psychoactive properties, resulting in a better daily life, i.e., more efficient thinking, exploring, hunting, etc., however, without the serious side effects of drugs of abuse. The physiological effects of methylxanthines have been known for a long time and they are mainly mediated by the so-called adenosine receptors. Caffeine and theobromine are the most abundant methylxanthines in cacao and their physiological effects are notable. Their health-promoting benefits are so remarkable that chocolate is explored as a functional food. The consequences of adenosine receptor blockade by natural compounds present in cacao/chocolate are here reviewed. Palatability and health benefits of methylxanthines, in general, and theobromine, in particular, have further contributed to sustain one of the most innocuous and pleasant habits: chocolate consumption.

• Publication year

  2013

• Venue

  Nutrients

• Publication date

  2013-10-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3390/nu5104159PMID 24145871PMCID 3820066
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Disposition of Toxic Drugs and Chemicals in Man

  2015cited by this paper
• Dietary cocoa ameliorates obesity-related inflammation in high fat-fed mice

  2014cited by this paper
• Caffeine in Floral Nectar Enhances a Pollinator's Memory of Reward

  2013cited by this paper
• Dietary nutrients associated with short and long sleep duration. Data from a nationally representative sample.

  2013cited by this paper
• Acute caffeine administration impact on working memory-related brain activation and functional connectivity in the elderly: a BOLD and perfusion MRI study.

  2013cited by this paper
• Chocolate, gut microbiota, and human health

  2013cited by this paper
• The effect of caffeine on working memory load-related brain activation in middle-aged males.

  2013cited by this paper
• Diversity of Cacao Trees in Waslala, Nicaragua: Associations between Genotype Spectra, Product Quality and Yield Potential

  2013cited by this paper
• Psychopharmacology of theobromine in healthy volunteers

  2013cited by this paper
• Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial.

  2013cited by this paper
• Potential Toxicity of Caffeine when Used as a Dietary Supplement for Weight Loss

  2012cited by this paper
• Potential Toxicity of Caffeine When Used as a Dietary Supplement for Weight Loss

  2012cited by this paper
• Cocoa Polyphenols and Their Potential Benefits for Human Health

  2012cited by this paper
• Regular consumption of cocoa powder with milk increases HDL cholesterol and reduces oxidized LDL levels in subjects at high-risk of cardiovascular disease.

  2012cited by this paper
• Spectral Analysis of Naturally Occurring Methylxanthines (Theophylline, Theobromine and Caffeine) Binding with DNA

  2012cited by this paper
• Ritual Black Drink consumption at Cahokia

  2012cited by this paper
• Chemical and Nutritional Composition of Tejate, a Traditional Maize and Cacao Beverage from the Central Valleys of Oaxaca, Mexico

  2012cited by this paper
• Functional interactions between the gut microbiota and host metabolism

  2012cited by this paper
• Evaluation of human enamel surfaces treated with theobromine: a pilot study.

  2012cited by this paper
• Striatal Pre- and Postsynaptic Profile of Adenosine A2A Receptor Antagonists

  2011cited by this paper
• Arousal Effect of Caffeine Depends on Adenosine A2A Receptors in the Shell of the Nucleus Accumbens

  2011cited by this paper
• Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study.

  2011cited by this paper
• Caffeine potentiates methamphetamine-induced toxicity both in vitro and in vivo.

  2011cited by this paper
• Apnea of prematurity: from cause to treatment

  2011cited by this paper
• The "high" risk of energy drinks.

  2011cited by this paper
• Impacts of methylxanthines and adenosine receptors on neurodegeneration: human and experimental studies.

  2011cited by this paper
• Abnormal calcium handling in atrial fibrillation is linked to up-regulation of adenosine A2A receptors.

  2011cited by this paper
• Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

  2011cited by this paper
• Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans

  2011cited by this paper
• Caffeine Exposure and the Risk of Parkinson's Disease: A Systematic Review and Meta-Analysis of Observational Studiess

  2010cited by this paper
• Is Caffeine a Cognitive Enhancer?

  2010cited by this paper
• Effects on Peripheral and Central Blood Pressure of Cocoa With Natural or High-Dose Theobromine: A Randomized, Double-Blind Crossover Trial

  2010cited by this paper
• Genetics of caffeine consumption and responses to caffeine

  2010cited by this paper
• Caffeine for asthma.

  2010cited by this paper
• Caffeine impact on neonatal morbidities

  2010cited by this paper
• Caffeine and the Control of Cerebral Hemodynamics

  2010cited by this paper
• Caffeine versus theophylline for apnea in preterm infants.

  2010cited by this paper
• Regulation of cerebrospinal fluid production by caffeine consumption

  2009cited by this paper
• [Coffee and mental health].

  2009cited by this paper
• The effect of alkylxanthines and other phosphodiesterase inhibitors on adenosine-receptor mediated decrease in lipolysis and cyclic AMP accumulation in rat fat cells.

  2009cited by this paper
• Midlife Coffee and Tea Drinking and the Risk of Late-Life Dementia: A Population-Based CAIDE Study

  2009cited by this paper
• Café y salud mental

  2009cited by this paper
• Does caffeine modulate verbal working memory processes? An fMRI study

  2008cited by this paper
• Revealing the paradox of drug reward in human evolution

  2008cited by this paper
• Simultaneous HPLC determination of caffeine, theobromine, and theophylline in food, drinks, and herbal products.

  2008cited by this paper
• Simultaneous determination of theobromine, (+)-catechin, caffeine, and (-)-epicatechin in standard reference material baking chocolate 2384, cocoa, cocoa beans, and cocoa butter.

  2008cited by this paper
• Determination of theobromine, theophylline, and caffeine in by-products of cupuacu and cacao seeds by high-performance liquid chromatography.

  2007cited by this paper
• Chocolate as a cough suppressant: rationale and justification for an upcoming clinical trial.

  2007cited by this paper
• Presynaptic Control of Striatal Glutamatergic Neurotransmission by Adenosine A1–A2A Receptor Heteromers

  2006cited by this paper
• Adenosine A2A receptors are expressed in human atrial myocytes and modulate spontaneous sarcoplasmic reticulum calcium release.

  2006cited by this paper
• Coffee and Health: A Review of Recent Human Research

  2006cited by this paper
• Theobromine inhibits sensory nerve activation and cough

  2005cited by this paper
• Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons.

  2005cited by this paper
• Effects of theobromine should be considered in future studies.

  2005cited by this paper
• Is coffee a functional food?

  2005cited by this paper
• Methylxanthines are the psycho-pharmacologically active constituents of chocolate

  2004cited by this paper
• Does caffeine intake protect from Alzheimer's disease?

  2002cited by this paper
• Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells.

  2001cited by this paper
• Caffeine for asthma.

  2001cited by this paper
• Caffeine versus theophylline for apnea in preterm infants.

  2000cited by this paper
• Chocolate: food or drug?

  1999cited by this paper
• Caffeine: A User's Guide

  1997cited by this paper
• The brain ryanodine receptor: a caffeine-sensitive calcium release channel.

  1991cited by this paper
• Coffee drinking and prevalence of bronchial asthma.

  1990cited by this paper
• Caffeine and theophylline analogues: correlation of behavioral effects with activity as adenosine receptor antagonists and as phosphodiesterase inhibitors.

  1988cited by this paper
• Chocolate toxicity in dogs

  1987cited by this paper
• Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man.

  1986cited by this paper
• The bronchodilator effect and pharmacokinetics of theobromine in young patients with asthma.

  1985cited by this paper
• Methyl xanthines enhance taste: evidence for modulation of taste by adenosine receptor.

  1985cited by this paper
• Xanthine derivatives as adenosine receptor antagonists.

  1982cited by this paper
• PURINE ANTAGONISTS IN THE IDENTIFICATION OF ADENOSINE‐RECEPTORS IN GUINEA‐PIG TRACHEA AND THE ROLE OF PURINES IN NON‐ADRENERGIC INHIBITORY NEUROTRANSMISSION

  1980cited by this paper
• Effects of short-term and long-term theobromine administration to male dogs.

  1980cited by this paper
• Purinergic inhibition of diazepam binding to rat brain (in vitro).

  1979cited by this paper
• THEOBROMINE SODIUM SALICYLATE AS A VASODILATOR.

  1936cited by this paper
• THE USE OF THEOBROMINE FOR PAIN OF ARTERIOSCLEROTIC ORIGIN.

  1926cited by this paper
• EFFECT OF VARIOUS AGENTS ON THE BLOOD FLOW THROUGH THE CORONARY ARTERIES AND VEINS

  1910cited by this paper

• Immunosenescence and Allergy: Molecular and Cellular Links Between Inflammaging, Neuro-Immune Aging, and Response to Biologic Therapies

  2026cites this paper
• (Poly)phenol and methylxanthine metabolites and their association with cognitive and cardiometabolic health in older people.

  2026cites this paper
• Catalytic activity of a palladium–Bistheophylline polymer complex with N–Pd–N coordination linkages in copper–free Sonogashira coupling reaction

  2026cites this paper
• Animal Dietary Exposure to Methylxanthines through the Inclusion of Former Food Products (FFPs) in Feed

  2026cites this paper
• Crystal structure of trans-bis(7-benzyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione)dichloridopalladium(II) hemihydrate

  2026cites this paper
• Enhancing the bioactive profile of dark chocolates with encapsulated native berry peel extracts

  2026cites this paper
• Relationships between consumption of theobromine in cocoa products and cardiovascular risk factors in 2015–2020 National health and nutrition examination survey

  2026cites this paper
• Investigation on some quality parameters of probiotic UF-Iranian white cheese containing caffeine

  2025cites this paper
• Chocolate-Induced Sinus Tachycardia: A Sweet Surprise

  2025cites this paper
• Functional expression mechanisms of food-derived components based on target proteins.

  2025cites this paper
• Targeted metabolomics for quantitative assessment of polyphenols and methylxanthines in fermented and unfermented cocoa beans from 18 genotypes of the Brazilian Amazon.

  2025cites this paper
• Nutritional Quality Fingerprinting of Wild and Farmed Cyprinus carpio: A UHPLC-MS/MS-Based Traceability Strategy

  2025cites this paper
• Supercritical Fluid and Pressurized Liquid Extraction of Bioactive Compounds from Guarana (Paullinia cupana) Byproducts

  2025cites this paper
• Theobromine synergizes with nicotine to enhance animal motor abilities and cognitive function

  2025cites this paper
• Cocoa-carob blend acute intake modifies miRNAs related to insulin sensitivity in type 2 diabetic subjects: a randomised controlled nutritional trial.

  2025cites this paper
• Progress in Methylxanthine Biosynthesis: Insights into Pathways and Engineering Strategies

  2025cites this paper
• Effect of non-conventional organic fertilizer (horn and hoof meal) on the development of cacao (Theobroma cacao L.)

  2025cites this paper
• Relationship between physicochemical properties of roasted cocoa beans and climate patterns: quality and safety implications

  2025cites this paper
• Effects of caffeine and its metabolites, theobromine and theophylline, on performance and physiological parameters in cyclists: A randomized, double-blind, placebo-controlled, crossover trial.

  2025cites this paper
• Unique Composition and Sustainability Aspects of the EETP801 Amazonian Cocoa Cultivar vs. CCN51 and Commercial Cocoas

  2025cites this paper
• Is There a Future Without Gluten Restrictions for Celiac Patients? Update on Current Treatments

  2025cites this paper
• Facile hydrothermal synthesis and electrocatalytic activity of rods-like silver tungstate decorated graphitic carbon nitride nanocomposite: A selective electrochemical detection of theobromine

  2025cites this paper
• Development and validation of the Meiji Nutritional Profiling System for children

  2025cites this paper
• The differences non-volatile compound and flavor attributes in several Indonesian cocoa genotypes using medium scale fermentation

  2025cites this paper
• Comprehensive machine learning assessment of zebrafish behaviour and biochemical markers in response to caffeine exposure

  2025influential citation
• Transcriptomic analysis reveals the mechanisms underlying the differential effects of caffeine, theophylline, and theobromine in regulating hepatic fat accumulation.

  2025cites this paper
• An updated review on chemical compositions of cocoa products and by-products with a focus on toxic elements and organic pollutants.

  2025cites this paper
• Compositional analysis of baru (Dipteryx alata Vogel) pulp highlighting its industrial potential.

  2025cites this paper
• Integrated in silico and in vitro exploration of the anti-VEGFR-2 activities of a semisynthetic xanthine alkaloid inhibiting breast cancer

  2025cites this paper
• Theobromine is Associated with Slower Epigenetic Ageing

  2025cites this paper
• Modulation of Antioxidant and Methylxanthines Profiles in Dark Chocolate Via Cocoa Fermentation with Hanseniaspora Thailandica and Pichia Kudriavzevii

  2025cites this paper
• The medical use of Málaka wine and cola nuts in late 19th/early 20th century Greece

  2024cites this paper
• Development of Spirulina Rich Chocolate and its Optimization Using Response Surface Methodology

  2024cites this paper
• The effects of dark chocolate on cognitive performance during cognitively demanding tasks: A randomized, single-blinded, crossover, dose-comparison study

  2024cites this paper
• Design and Synthesis of β‐O‐Glucosylated 5‐(Arylidene)‐6‐Aminouracils: Towards Water‐Soluble 8‐Aryl Xanthines as Effective Enzyme Inhibitors

  2024cites this paper
• Diet enriched with high-phenolic cocoa potentiates hippocampal brain-derived neurotrophic factor expression and neurogenesis in healthy adult micewith subtle effects on memory.

  2024cites this paper
• Novel Insecticidal Butenolide‐Containing Methylxanthine Derivatives: Synthesis, Crystal Structure, Biological Activity Evaluation, DFT Calculation and Molecular Docking

  2024cites this paper
• Should Caffeine Be Avoided Following Free Flaps: Fact or Fiction?

  2024cites this paper
• Improvement in Kidney damage resulting from stanozolol intramuscular injections in rats by Natural Cocoa Powder (NCP) Administration.

  2024cites this paper
• The Potential of Plant Extracts Used in Cosmetic Product Applications—Antioxidants Delivery and Mechanism of Actions

  2024cites this paper
• Influence of geographical origin in the physical and bioactive parameters of single origin dark chocolate

  2024cites this paper
• Theobroma spp.: A review of it's chemical and innovation potential for the food industry

  2024cites this paper
• Studies on the synthesis, crystal structures, biological activities and molecular docking of novel natural methylxanthine derivatives containing piperazine moiety

  2024cites this paper
• Simultaneous Detection Method of 11 Respiratory Drug Substances Including Theobromine, Oxymetazoline, etc. in Adulterated Dietary Supplements Using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry Analysis.

  2024cites this paper
• Vegan and sugar-substituted chocolates: assessing fatty acids, methylxanthines, minerals, volatiles and sensory profiles

  2024cites this paper
• Factors affecting consumer perception and acceptability of chocolate beverages

  2024cites this paper
• Health benefits and mechanisms of theobromine

  2024cites this paper
• A narrative review of theophylline: is there still a place for an old friend?

  2024cites this paper
• Synthesis, spectroscopic analysis, quantum chemical calculations and in silico biological activity studies of a new series of 8-aryl xanthine

  2024cites this paper
• Cocoa Shell as a Bulking Agent in Nutritionally Improved Cocoa Spreads with Sugar Substitutes

  2024cites this paper
• Microbial Metabolism of Caffeine and Potential Applications in Bioremediation.

  2024cites this paper
• Characterization of the microbiota dynamics associated with Moniliophthora roreri, causal agent of cocoa frosty pod rot disease, reveals new viral species

  2023cites this paper
• Exploring the Nutritional Composition and Bioactive Compounds in Different Cocoa Powders

  2023cites this paper
• Propentofylline Improves Thiol-Based Antioxidant Defenses and Limits Lipid Peroxidation following Gliotoxic Injury in the Rat Brainstem

  2023cites this paper
• How Healthy Is It to Fortify Cocoa-Based Products with Cocoa Flavanols? A Comprehensive Review

  2023cites this paper
• Design, synthesis, anticancer and in silico assessment of 8-piperazinyl caffeinyl-triazolylmethyl hybrid conjugates

  2023cites this paper
• Methylxanthine for the prevention and treatment of apnea in preterm infants.

  2023cites this paper
• Synthesis and Biological Activity Evaluation of Novel Chalcone Analogues Containing a Methylxanthine Moiety and Their N-Acyl Pyrazoline Derivatives.

  2023cites this paper
• ÇİKOLATA TÜKETİMİ VE NOSTALJİ EĞİLİMİ

  2023cites this paper
• Evaluation of theobromine content and the relationship between cocoa percentages in dark chocolates

  2023cites this paper
• Identification of dietary components in association with abdominal aortic calcification.

  2023cites this paper
• Effect of Flavanol-Rich Cacao Extract on the Profile of Mood State in Healthy Middle-Aged Japanese Women: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

  2023cites this paper
• Augmented Dark Chocolate with Probiotics: A Lifestyle Approach to Address Symptoms of Parkinson’s Disease

  2023cites this paper
• Identification and quantification of (poly)phenol and methylxanthine metabolites in human cerebrospinal fluid: evidence of their ability to cross the BBB

  2023cites this paper
• Theobromine content in chocolate products: a review

  2022cites this paper
• Maternal Supplementation with a Cocoa Extract during Lactation Deeply Modulates Dams’ Metabolism, Increases Adiponectin Circulating Levels and Improves the Inflammatory Profile in Obese Rat Offspring

  2022cites this paper
• Pengaruh konsumsi coklat hitam dengan peningkatan fungsi memori verbal pada mahasiswa Fakultas Kedokteran Universitas Tarumanagara angkatan 2018-2019

  2022cites this paper
• Neuroprotective Effects of Theobromine in permanent bilateral common carotid artery occlusion rat model of cerebral hypoperfusion

  2022cites this paper
• Factors That Influence Sustainable Selection and ReselectionIntentions Regarding Soluble/Instant Coffee—The Case of Serbian Consumers

  2022cites this paper
• Synthesis, Crystal Structures, and Biological Activity Evaluation of Novel Xanthine Derivatives Containing a Pyrethroid Moiety.

  2022cites this paper
• Biocatalytic Production and Purification of the High-value Biochemical Paraxanthine

  2022cites this paper
• Current Naturopathy to Combat Alzheimer’s Disease

  2022cites this paper
• Supercritical fluid chromatography coupled to high-resolution tandem mass spectrometry: an innovative one-run method for the comprehensive assessment of chocolate quality and authenticity

  2022cites this paper
• Exploring a cocoa–carob blend as a functional food with decreased bitterness: Characterization and sensory analysis

  2022cites this paper
• Determining the Authenticity of Cocoa Solid in Chocolates Using Chemical Markers, Antioxidant Activity, and Multivariate Analysis

  2022cites this paper
• Theobromine content of non fermented cacao powder with steam roasting related with health

  2022cites this paper
• The impact of different dark chocolate dietary patterns on synaptic potency and plasticity in the hippocampal CA1 area of the rats under chronic isolation stress

  2022cites this paper
• Methylxanthines Induce a Change in the AD/Neurodegeneration-Linked Lipid Profile in Neuroblastoma Cells

  2022cites this paper
• Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension

  2022cites this paper
• Abiotic Factors from Different Ecuadorian Regions and Their Contribution to Antioxidant, Metabolomic and Organoleptic Quality of Theobroma cacao L. Beans, Variety “Arriba Nacional”

  2022cites this paper
• Effect of wheat bran oil concentrates on quality and nutrition of WBO dark compound chocolates

  2021cites this paper
• Methylxanthines in Food Products

  2021cites this paper
• Antioxidant and Sensory Evaluation of Cocoa (Theobroma cacao L.) Tea Formulated with Cocoa Bean Hull of Different Origins

  2021cites this paper
• Comparative Approach to Interaction of Zinc Dication with Theobromine and Theophilline-A DFT Treatment

  2021cites this paper
• Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+)-catechin

  2021cites this paper
• The Effect of Clove Leaves Essential Oil Addition on Physicochemical and Sensory Characteristics of Milk Chocolate Bar

  2021cites this paper
• Chemical Characterization of Quality-Related Compounds in Cocoa Matrices: An Overview of Analytical Methods Applied for Their Analysis

  2021cites this paper
• Methamphetamine Blocks Adenosine A2A Receptor Activation via Sigma 1 and Cannabinoid CB1 Receptors

  2021cites this paper
• Identification of Methylxanthines and Phenolic Compounds by UPLC-DAD-ESI-MS OTOF and Antioxidant Capacities of Beans and Dark Chocolate Bars from Three Trinitario×Forastero Cocoa (Theobroma cacao L.) Hybrids

  2021cites this paper
• Introduction: Bioactive Compounds and Elements in Human Nutrition

  2021cites this paper
• Methylxanthine for the prevention and treatment of apnea in preterm infants

  2021cites this paper
• Rational Protein Engineering of Bacterial N-demethylases to Create Biocatalysts for the Production of Methylxanthines

  2021cites this paper
• 5-Hydroxytryptamine, Glutamate, and ATP: Much More Than Neurotransmitters

  2021cites this paper
• Impacts of cocoa pod maturity upon harvest and bean fermentation period on producing chocolate with potential health benefits.

  2021cites this paper
• Antioxidant Supplements versus Health Benefits of Brief/Intermittent Exposure to Potentially Toxic Physical or Chemical Agents

  2021cites this paper
• Microglial Adenosine Receptors: From Preconditioning to Modulating the M1/M2 Balance in Activated Cells

  2021cites this paper
• Chocolate culture: Preferences, emotional implications and awareness of Italian consumers

  2021cites this paper
• Unravelling the Microbial Mechanisms Underlying the Psychobiotic Potential of a Bifidobacterium breve Strain.

  2021cites this paper
• Labels on bars of solid chocolate and chocolate bar sweets in the Polish market: A nutritional approach and implications for the consumer

  2021cites this paper
• Nutraceuticals Supporting Cognitive Function in Mild Cognitive Impairment

  2021cites this paper