Cacao contains many bioactive components and essential minerals that interact with our natural biochemical pathways to provide many health benefits. Scientific studies have shown that these compounds assist with cardiovascular health, mental health, immune health, bone health, metabolic health, skin health, mental health, and more. Together, these compounds work to elevate mood, enhance cognitive function, support the immune and cardiovascular systems, boost metabolic function, and improve nutritional health.

Polyphenols and Flavanols

Flavanols are a group of secondary metabolites found in cacao beans and are mainly responsible for the bitter flavour of cacao1,2. The most important flavanols in cacao are the catechins, the epicatechins, and the procyanidins which act as antioxidant and anti-inflammatory compounds in the body3–6. These biological effects are crucial for managing cardiovascular health3–5,7,8, blood pressure5,7,9, oxidative stress1,3,5,6,9, chronic inflammation4,5,8, and aging10,11. Common sources of free radicals in our everyday environment include pollution, tobacco smoke, UV radiation from the sun, heavy metal exposure, and more12. A build-up of free radicals and other reactive species in our bodies can lead to cell damage and oxidative stress that may cause inflammation, accelerated aging, cardiovascular diseases, diabetes mellitus, and even cancer1,4,12.


Cacao flavanols exhibit antioxidant properties4, which means that they scavenge free radicals and other reactive species to protect our cells. They also encourage the activity of our natural antioxidant enzymes, such as glutathione peroxidase (GPx) and glutathione reductase (GR)4. In addition, cacao flavanols inhibit the activity of enzymes that act as key inflammatory mediators, such as NF-κB, tumour necrosis factor (TNF)-α, cyclooxygenase (COX)-2 and lipoxygenases (LOX)4. Several studies in humans have shown that consumption of cacao flavanols reduces blood pressure to healthy levels9,13,14 and increases antioxidant levels in the blood15.


One of the ways in which we measure the level of flavanols present in our cacao products is by the gallic acid equivalent (GAE) method. With this method, the antioxidant capacity of the cacao is measured by using a mixture of the compounds phosphomolybdate and phosphotungstate. These compounds react with flavanols and other compounds with antioxidant capabilities. The amount of reactions that occur can be measured, giving the levels of antioxidant products present in the cacao16. We can also directly measure the presence of the flavanol, catechin, which is particularly common in cacao.


Overall, cacao flavanols are able to mediate our bodies’ natural inflammatory response, reduce oxidative stress and assist in the management of our cardiovascular health. Consistent intake of high levels of flavanols can lead to improved immune function,4,10 increased mental clarity,10,17 reduced risk of developing cardiovascular disease,18 and improved antioxidant activity to improve skin health and slow aging5,6,11,19,20.

Figure: General structure of catechin and epicatechin.

Theobromine

Theobromine is a compound derived from caffeine and has a similar structure, allowing it to act through similar biological pathways21,22. Both theobromine and caffeine are present in raw cacao and both act by blocking receptors for the adenosine molecule throughout the body,21,22 inhibiting the function of phosphodiesterase (PDE) enzymes,23,24 and as antioxidants in a similar way to flavanols25.


Adenosine is a molecule that is naturally produced in our bodies and exhibits functions within our central nervous system (CNS), peripheral nervous system (PNS), cardiovascular system, immune system, sleep-wake cycle, and more21,22,26–28. Adenosine is important for regulating our sleep-wake cycle through binding to more receptors throughout the day to make us feel more tired and eventually sleepy at bedtime28. Blocking these receptors can help to ease chronic fatigue and produce an uplifting effect for better cognitive function. While caffeine does the same thing, it does so directly on the brain and more potently so that it may negatively impact our normal sleep-wake cycles,21,22,29 while theobromine is thought to act mainly through the PNS as a less intense stimulant than caffeine and more as a support for our natural functions30. Caffeine has also been reported to cause many side effects such as addiction and dependence, sleep disorders, anxiety and panic attacks, allergy and asthma, and cardiovascular problems31–34.


Theobromine also inhibits the function of PDE enzymes. These are naturally present in our bodies and are responsible for breaking down cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signalling molecules, which have a myriad of functions in different organs and muscles35. When the breakdown of cAMP and cGMP is delayed, they are able to exert their functions for longer. Theobromine can inhibit PDE enzymes and help to improve respiratory function, reduce high blood pressure and pulmonary hypertension, and improve sexual function35. It can also boost energy, enhance mood and cognitive function, support cardiovascular health and produce an all-round uplifting effect by mediating adenosine36.

Theobromine is not unique to cacao and can be naturally found in other plants such as tea, coffee, and kola nuts. However, these plants all have higher proportions of caffeine to theobromine and may act as direct stimulants on the brain and produce unwanted side effects37,38. Cacao possesses higher proportions of theobromine to caffeine and it is important to consider this ratio when choosing cacao for its health benefits as this ratio can vary between 2.5:1 to 23:129. Our ceremonial Criollo cacao has a ratio of 29:1 - theobromine:caffeine. Perfect for the uplifting effects without the negative side-effects of over-stimulation.

Structures of adenosine, caffeine, theobromine.

Tryptamine and tryptophan

Cacao contains several biogenic amines, the most important of these being tryptophan and one of its metabolites, tryptamine. Tryptophan is one of the nine essential amino acids that humans require to sustain life. These amines act as biochemical precursors for several important compounds, including vitamin B3,39 melatonin,40 and serotonin41. When there is rapid depletion of tryptophan, cognitive function can be affected and even lead to depressive moods42–44.


Tryptamine has the ability to ignite receptors in one of the serotonergic pathways, known as the 5-HT2a pathway. The 5-HT2a receptors are found all throughout the central nervous system (CNS) and with activation by tryptamine, they can mediate attention, mood, memory, learning, sleep and other cognitive processes45–48. This is also the same pathway in which the traditional spiritual medicine Ayahuasca acts. Ayahuasca is a brew made from the Banisteriopsis caapi vine and the Psychotria viridis leaves of the Amazon jungle. This traditional brew contains the molecule dimethyltryptamine, or DMT, and activates the 5-HT2a pathways to induce a hallucinogenic effect. These brews are typically consumed as part of a spiritual ceremony led by a shaman to lead one to the spiritual world and help cure one of illnesses and ailments49,50. One study also showed that taking Ayahuasca in the daytime could influence sleep without negatively affecting the quality of sleep51. Considering the close relationship between DMT, tryptamines, and serotonin, and the influence of tryptamines and serotonin on regulating sleep48,52, the 5-HT2a pathway may also be responsible for vivid “cacao dreams” that some people have experienced after taking lots of cacao.


Even though tryptamine works in the same pathway as DMT, it is found in many other foods and is not nearly potent enough to induce the same psychoactive effects53. By acting as precursors for our natural neurotransmitters or directly activating serotonergic pathways themselves, tryptophan and tryptamine can influence the body to improve mood, cognitive function, memory and learning, sleep and dreams, and more43,44

Tryptamine, tryptophan.

Serotonin, melatonin, vitamin B3 (niacin).

PEA

Phenylethylamine (PEA) is another important amine compound found in cacao54 that can regulate neurotransmitter release in the brain by activating the trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2)55–58. By binding to TAAR1 in humans, PEA can exert similar effects to dopamine, the neurotransmitter that normally binds to this receptor, and upregulate the release of dopamine59,60. Inhibition of VMAT2 delays dopamine depletion after its release and allows enhances the natural effects of dopamine61. There are several important dopaminergic pathways that play important roles in feelings of pleasure and reward62 and PEA is thus able to elevate those feelings through our natural pathways. PEA is primarily involved in influencing mood to elevate feelings of happiness and satisfaction, enhance attention span, and even relieve feelings of anxiety and depression63,64.

Structure of PEA (left) and dopamine (dopamine).

NAEs

Cacao contains compounds called N-acylethanolamines (NAEs), which are similar to our bodies own natural anandamide65,66. Anandamide is one of your body’s endocannabinoids and is named after the Sanskrit word, anand, meaning “bliss,” as it is known to induce a feeling of euphoria when released67,68. Endocannabinoids are natural regulatory molecules that work within your endocrine system to recover and maintain homeostasis. This can help your body respond to the physiological and psychological stressors we experience in our everyday life68,69. However, anandamide is broken down quickly by the fatty acid amide hydrolase (FAAH) enzyme and does not last for very long in our bodies after being released70,71.


Cacao does not contain anandamide itself but contains NAEs which are similar in structure to anandamide65. The main three NAEs in cacao are oleoylethanolamide (OEA), palmitoylethanolamide (PEA) (not to be confused with phenylethylamine), and linoleoylethanolamide (LEA)65,66. NAEs in cacao have been found to bind to FAAH, which may lengthen the function of natural anandamide and provide numerous health benefits from mediating our natural ECS. They have also been found to be anti-inflammatory, provide natural pain relief, and even aid weight loss by promoting the use of stored fat for energy72–75. Altogether, this can help mediate our natural stress and hormone responses to boost energy levels and metabolism, enhance cognitive function, improve mood, reduce chronic pain, and support immunity.


It is important to note that NAEs in cacao do not directly act on the brain receptors as cannabinoids found in cannabis. NAEs work accumulatively over time to help mediate our natural endocrine and endocannabinoid systems and provide long-term benefits without reducing sensitivity. These compounds are also very similar to macamides, a group of natural cannabinoids unique to the sacred Maca plant of Junin, Peru. To learn more about macamides, see our page about macamides and the ECS here: themacaexperts.com/maca/learn-about-maca/how-does-maca-work-to-improve-health/.

OEA, PEA, LEA

Minerals

Cacao contains several essential minerals, including magnesium, calcium, zinc, phosphorus, and iron8,76,77. Zinc is required for healthy brain signalling, cognitive function and modulation of sleep78,79. Iron is an important component of our blood and transport of oxygen around the body80,81. Magnesium is a mineral that interacts with energy molecules, such as ATP, and with more than 600 enzymes in our body for healthy function82–84. It plays important roles in healthy muscle function, protein formation, regulation of our nervous systems, energy metabolism and even in maintenance of our DNA84. Calcium is a mineral that makes up much of our bones and teeth and as an electrolyte, plays an essential role in biochemical processes in our brain, muscles and more85,86. Mineral deficiencies, such as anaemia and calcium deficiency, are becoming more prevalent in today’s modern world87–91. These deficiencies can lead to many health issues like migraine headaches, osteoporosis, immune dysfunction, chronic fatigue and more88,91,92. This is why it is important to ensure your diet contains these essential micronutrients and prevent the development of associated health issues92. Fortunately, cacao is a naturally-occurring powerhouse of minerals that are essential for our health and well-being and support the normal function of our brain, heart, lungs, immune system, muscle function, and more. We recommend a daily serving of 20-40g of our cacao to help meet the recommended dietary intakes for these essential nutrients.

 Recommended Daily Intake (RDI)93Mineral Concentration in Seleno Health Cacao Amount per serving (20g)
Zinc (Zn)8-14 mg/day95 mg/kg1.9 mg (24% RDI)
Magnesium (Mg)310-420 mg/day7,500 mg/kg150 mg (48% RDI)
Iron (Fe)8 mg/day (18 mg/day for those who are menstruating or consuming less meat)106 mg/kg2.1 mg (27% RDI)
Potassium (K)2,800-3,800 mg/day25,200 mg/kg504 mg (18% RDI)
Copper (Cu)1.2-1.7 mg/day47 mg/kg0.94 mg (78% RDI)
Phosphorus (P)1,000 mg/day7,810 mg/kg156 mg (16% RDI)
Calcium (Ca)1,000-1,300 mg/day2,140 mg/kg43 mg (4.3% RDI)
.
Zinc (Zn)
Recommended Daily Intake (RDI)93
8-14 mg/day

Mineral Concentration in Seleno Health Cacao
95 mg/kg

Amount per serving (20g)
1.9 mg (24% RDI)


Magnesium (Mg)
Recommended Daily Intake (RDI)93
310-420 mg/day

Mineral Concentration in Seleno Health Cacao
7,500 mg/kg

Amount per serving (20g)
150 mg (48% RDI)


Iron (Fe)
Recommended Daily Intake (RDI)93
8 mg/day (18 mg/day for those who are menstruating or consuming less meat)

Mineral Concentration in Seleno Health Cacao
106 mg/kg

Amount per serving (20g)
2.1 mg (27% RDI)


Potassium (K)
Recommended Daily Intake (RDI)93
2,800-3,800 mg/day

Mineral Concentration in Seleno Health Cacao
25,200 mg/kg

Amount per serving (20g)
504 mg (18% RDI)


Copper (Cu)
Recommended Daily Intake (RDI)93
1.2-1.7 mg/day

Mineral Concentration in Seleno Health Cacao
47 mg/kg

Amount per serving (20g)
0.94 mg (78% RDI)


Phosphorus (P)
Recommended Daily Intake (RDI)93
1,000 mg/day

Mineral Concentration in Seleno Health Cacao
7,810 mg/kg

Amount per serving (20g)
156 mg (16% RDI)


Calcium (Ca)
Recommended Daily Intake (RDI)93
1,000-1,300 mg/day

Mineral Concentration in Seleno Health Cacao
2,140 mg/kg

Amount per serving (20g)
43 mg (4.3% RDI)


Liquid error (templates/article.gem-556303679668-template line 16): Error in tag 'section' - 'blog-learn' is not a valid section type

References

(1) Kim, J.; Kim, J.; Shim, J.; Lee, C. Y.; Lee, K. W.; Lee, H. J. Cocoa Phytochemicals: Recent Advances in Molecular Mechanisms on Health. Crit. Rev. Food Sci. Nutr.2014, 54 (11), 1458–1472. https://doi.org/10.1080/10408398.2011.641041.

(2) McShea, A.; Ramiro-Puig, E.; Munro, S. B.; Casadesus, G.; Castell, M.; Smith, M. A. Clinical Benefit and Preservation of Flavonols in Dark Chocolate Manufacturing. Nutr. Rev.2008, 66 (11), 630–641. https://doi.org/10.1111/j.1753-4887.2008.00114.x.

(3) Fraga, C. G.; Litterio, M. C.; Prince, P. D.; Calabró, V.; Piotrkowski, B.; Galleano, M. Cocoa Flavanols: Effects on Vascular Nitric Oxide and Blood Pressure. J. Clin. Biochem. Nutr.2011, 48 (1), 63–67. https://doi.org/10.3164/jcbn.11-010FR.

(4) Goya, L.; Martín, M. Á.; Sarriá, B.; Ramos, S.; Mateos, R.; Bravo, L. Effect of Cocoa and Its Flavonoids on Biomarkers of Inflammation: Studies of Cell Culture, Animals and Humans. Nutrients2016, 8 (4). https://doi.org/10.3390/nu8040212.

(5) Keen, C. L.; Holt, R. R.; Oteiza, P. I.; Fraga, C. G.; Schmitz, H. H. Cocoa Antioxidants and Cardiovascular Health. Am. J. Clin. Nutr.2005, 81 (1), 298S-303S. https://doi.org/10.1093/ajcn/81.1.298S.

(6) Cádiz-Gurrea, M. L.; Lozano-Sanchez, J.; Contreras-Gámez, M.; Legeai-Mallet, L.; Fernández-Arroyo, S.; Segura-Carretero, A. Isolation, Comprehensive Characterization and Antioxidant Activities of Theobroma Cacao Extract. J. Funct. Foods2014, 10, 485–498. https://doi.org/10.1016/j.jff.2014.07.016.

(7) Davison, K.; Howe, P. R. C. Potential Implications of Dose and Diet for the Effects of Cocoa Flavanols on Cardiometabolic Function. J. Agric. Food Chem.2015, 63 (45), 9942–9947. https://doi.org/10.1021/acs.jafc.5b01492.

(8) Ellam, S.; Williamson, G. Cocoa and Human Health. Annu. Rev. Nutr.2013, 33 (1), 105–128. https://doi.org/10.1146/annurev-nutr-071811-150642.

(9) Murphy, K. J.; Chronopoulos, A. K.; Singh, I.; Francis, M. A.; Moriarty, H.; Pike, M. J.; Turner, A. H.; Mann, N. J.; Sinclair, A. J. Dietary Flavanols and Procyanidin Oligomers from Cocoa (Theobroma Cacao) Inhibit Platelet Function. Am. J. Clin. Nutr.2003, 77 (6), 1466–1473. https://doi.org/10.1093/ajcn/77.6.1466.

(10) Mastroiacovo, D.; Kwik-Uribe, C.; Grassi, D.; Necozione, S.; Raffaele, A.; Pistacchio, L.; Righetti, R.; Bocale, R.; Lechiara, M. C.; Marini, C.; Ferri, C.; Desideri, G. Cocoa Flavanol Consumption Improves Cognitive Function, Blood Pressure Control, and Metabolic Profile in Elderly Subjects: The Cocoa, Cognition, and Aging (CoCoA) Study—a Randomized Controlled Trial. Am. J. Clin. Nutr.2015, 101 (3), 538–548. https://doi.org/10.3945/ajcn.114.092189.

(11) Aging and vascular responses to flavanol-rich cocoa | Ovid https://oce-ovid-com.helicon.vuw.ac.nz/article/00004872-200608000-00017/HTML.

(12) Phaniendra, A.; Jestadi, D. B.; Periyasamy, L. Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases. Indian J. Clin. Biochem. IJCB2015, 30 (1), 11–26. https://doi.org/10.1007/s12291-014-0446-0.

(13) Taubert, D.; Roesen, R.; Schömig, E. Effect of Cocoa and Tea Intake on Blood Pressure: A Meta-Analysis. Arch. Intern. Med.2007, 167 (7), 626–634. https://doi.org/10.1001/archinte.167.7.626.

(14) Ried, K.; Sullivan, T.; Fakler, P.; Frank, O. R.; Stocks, N. P. Does Chocolate Reduce Blood Pressure? A Meta-Analysis. BMC Med.2010, 8, 39. https://doi.org/10.1186/1741-7015-8-39.

(15) Wang, J. F.; Schramm, D. D.; Holt, R. R.; Ensunsa, J. L.; Fraga, C. G.; Schmitz, H. H.; Keen, C. L. A Dose-Response Effect from Chocolate Consumption on Plasma Epicatechin and Oxidative Damage. J. Nutr.2000, 130 (8), 2115S-2119S. https://doi.org/10.1093/jn/130.8.2115S.

(16) Singleton, V. L.; Orthofer, R.; Lamuela-Raventós, R. M. [14] Analysis of Total Phenols and Other Oxidation Substrates and Antioxidants by Means of Folin-Ciocalteu Reagent. In Methods in Enzymology; Oxidants and Antioxidants Part A; Academic Press, 1999; Vol. 299, pp 152–178. https://doi.org/10.1016/S0076-6879(99)99017-1.

(17) Protective Effects of Flavanol-Rich Dark Chocolate on Endothelial Function and Wave Reflection During Acute Hyperglycemia | Hypertension https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.112.193995 (accessed May 23, 2021).

(18) Sansone, R.; Rodriguez-Mateos, A.; Heuel, J.; Falk, D.; Schuler, D.; Wagstaff, R.; Kuhnle, G. G. C.; Spencer, J. P. E.; Schroeter, H.; Merx, M. W.; Kelm, M.; Heiss, C.; for the Flaviola Consortium, E. U. 7th F. P. Cocoa Flavanol Intake Improves Endothelial Function and Framingham Risk Score in Healthy Men and Women: A Randomised, Controlled, Double-Masked Trial: The Flaviola Health Study. Br. J. Nutr.2015, 114 (8), 1246–1255. https://doi.org/10.1017/S0007114515002822.

(19) Bowe, W. P.; Patel, N.; Logan, A. C. Acne Vulgaris: The Role of Oxidative Stress and the Potential Therapeutic Value of Local and Systemic Antioxidants. J. Drugs Dermatol. JDD2012, 11 (6), 742–746.

(20) Al-Shobaili, H. A. Oxidants and Anti-Oxidants Status in Acne Vulgaris Patients with Varying Severity. Ann. Clin. Lab. Sci.2014, 44 (2), 202–207.

(21) Franco, R.; Oñatibia-Astibia, A.; Martínez-Pinilla, E. Health Benefits of Methylxanthines in Cacao and Chocolate. Nutrients2013, 5 (10), 4159–4173. http://dx.doi.org.helicon.vuw.ac.nz/10.3390/nu5104159.

(22) Martínez-Pinilla, E.; Oñatibia-Astibia, A.; Franco, R. The Relevance of Theobromine for the Beneficial Effects of Cocoa Consumption. Front. Pharmacol.2015, 6. https://doi.org/10.3389/fphar.2015.00030.

(23) Sugimoto, N.; Miwa, S.; Hitomi, Y.; Nakamura, H.; Tsuchiya, H.; Yachie, A. Theobromine, the Primary Methylxanthine Found in Theobroma Cacao, Prevents Malignant Glioblastoma Proliferation by Negatively Regulating Phosphodiesterase-4, Extracellular Signal-Regulated Kinase, Akt/Mammalian Target of Rapamycin Kinase, and Nuclear Factor-Kappa B. Nutr. Cancer2014, 66 (3), 419–423. https://doi.org/10.1080/01635581.2013.877497.

(24) Yoneda, M.; Sugimoto, N.; Katakura, M.; Matsuzaki, K.; Tanigami, H.; Yachie, A.; Ohno-Shosaku, T.; Shido, O. Theobromine Up-Regulates Cerebral Brain-Derived Neurotrophic Factor and Facilitates Motor Learning in Mice. J. Nutr. Biochem.2017, 39, 110–116. https://doi.org/10.1016/j.jnutbio.2016.10.002.

(25) Antioxidant and prooxidant properties of caffeine, theobromine and xanthine https://www.medscimonit.com/download/index/idArt/13137 (accessed May 30, 2021).

(26) Haskó György; Pacher Pál. Regulation of Macrophage Function by Adenosine. Arterioscler. Thromb. Vasc. Biol.2012, 32 (4), 865–869. https://doi.org/10.1161/ATVBAHA.111.226852.

(27) Barletta Kathryn E.; Ley Klaus; Mehrad Borna. Regulation of Neutrophil Function by Adenosine. Arterioscler. Thromb. Vasc. Biol.2012, 32 (4), 856–864. https://doi.org/10.1161/ATVBAHA.111.226845.

(28) Basheer, R.; Strecker, R. E.; Thakkar, M. M.; McCarley, R. W. Adenosine and Sleep–Wake Regulation. Prog. Neurobiol.2004, 73 (6), 379–396. https://doi.org/10.1016/j.pneurobio.2004.06.004.

(29) ZOUMAS, B.; KREISER, W.; MARTIN, R. Theobromine and Caffeine Content of Chocolate Products. J. Food Sci.2006, 45, 314–316. https://doi.org/10.1111/j.1365-2621.1980.tb02603.x.

(30) Mitchell, E. S.; Slettenaar, M.; vd Meer, N.; Transler, C.; Jans, L.; Quadt, F.; Berry, M. Differential Contributions of Theobromine and Caffeine on Mood, Psychomotor Performance and Blood Pressure. Physiol. Behav.2011, 104 (5), 816–822. https://doi.org/10.1016/j.physbeh.2011.07.027.

(31) Sharif, S.; Guirguis, A.; Fergus, S.; Schifano, F. The Use and Impact of Cognitive Enhancers among University Students: A Systematic Review. Brain Sci.2021, 11 (3), 355. https://doi.org/10.3390/brainsci11030355.

(32) Wee, J. H.; Min, C.; Park, M. W.; Park, I.-S.; Park, B.; Choi, H. G. Energy-Drink Consumption Is Associated with Asthma, Allergic Rhinitis, and Atopic Dermatitis in Korean Adolescents. Eur. J. Clin. Nutr.2020, 1–11. https://doi.org/10.1038/s41430-020-00812-2.

(33) Patocka, J.; Navratilova, Z.; Krejcar, O.; Kuca, K. Coffee, Caffeine and Cognition: A Benefit or Disadvantage? Lett. Drug Des. Discov.2019, 16 (10), 1146–1156. https://doi.org/10.2174/1570180816666190620142158.

(34) Lane, J. D.; Manus, D. C. Persistent Cardiovascular Effects with Repeated Caffeine Administration. Psychosom. Med.1989, 51 (4), 373–380.

(35) Francis, S. H.; Blount, M. A.; Corbin, J. D. Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions. Physiol. Rev.2011, 91 (2), 651–690. https://doi.org/10.1152/physrev.00030.2010.

(36) van den Bogaard, B.; Draijer, R.; Westerhof, B. E.; van den Meiracker, A. H.; van Montfrans, G. A.; van den Born, B.-J. H. Effects on Peripheral and Central Blood Pressure of Cocoa with Natural or High-Dose Theobromine: A Randomized, Double-Blind Crossover Trial. Hypertens. Dallas Tex 19792010, 56 (5), 839–846. https://doi.org/10.1161/HYPERTENSIONAHA.110.158139.

(37) PubChem. Theobromine https://pubchem.ncbi.nlm.nih.gov/compound/5429 (accessed May 30, 2021).

(38) Gennaro, M. C.; Abrigo, C. Caffeine and Theobromine in Coffee, Tea and Cola-Beverages: Simultaneous Determination by Reversed-Phase Ion-Interaction HPLC. Fresenius J. Anal. Chem.1992, 343 (6), 523–525. https://doi.org/10.1007/BF00322162.

(39) Ikeda, M.; Tsuji, H.; Nakamura, S.; Ichiyama, A.; Nishizuka, Y.; Hayaishi, O. Studies on the Biosynthesis of Nicotinamide Adenine Dinucleotide. J. Biol. Chem.1965, 240 (3), 1395–1401. https://doi.org/10.1016/S0021-9258(18)97589-7.

(40) Wurtman, R. J.; Anton-tay, F. The Mammalian Pineal as a Neuroendocrine Transducer11Studies Described in This Report Were Supported by Grants from the National Aeronautics and Space Administration (NGR-22-009-272) and the National Institutes of Health (AM-11709 and AM-11237). In Proceedings of the 1968 Laurentian Hormone Conference; Astwood, E. B., Ed.; Recent Progress in Hormone Research; Academic Press: Boston, 1969; Vol. 25, pp 493–522. https://doi.org/10.1016/B978-0-12-571125-8.50014-4.

(41) Fernstrom, J. D. Role of Precursor Availability in Control of Monoamine Biosynthesis in Brain. Physiol. Rev.1983, 63 (2), 484–546. https://doi.org/10.1152/physrev.1983.63.2.484.

(42) Riedel, W. J.; Klaassen, T.; Schmitt, J. A. J. Tryptophan, Mood, and Cognitive Function. Brain. Behav. Immun.2002, 16 (5), 581–589. https://doi.org/10.1016/S0889-1591(02)00013-2.

(43) Silber, B. Y.; Schmitt, J. A. J. Effects of Tryptophan Loading on Human Cognition, Mood, and Sleep. Neurosci. Biobehav. Rev.2010, 34 (3), 387–407. https://doi.org/10.1016/j.neubiorev.2009.08.005.

(44) Jenkins, T. A.; Nguyen, J. C. D.; Polglaze, K. E.; Bertrand, P. P. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients2016, 8 (1). https://doi.org/10.3390/nu8010056.

(45) Aghajanian, G. K.; Marek, G. J. Serotonin, via 5-HT2A Receptors, Increases EPSCs in Layer V Pyramidal Cells of Prefrontal Cortex by an Asynchronous Mode of Glutamate Release. Brain Res.1999, 825 (1), 161–171. https://doi.org/10.1016/S0006-8993(99)01224-X.

(46) Marek, G. J.; Wright, R. A.; Gewirtz, J. C.; Schoepp, D. D. A Major Role for Thalamocortical Afferents in Serotonergic Hallucinogen Receptor Function in the Rat Neocortex. Neuroscience2001, 105 (2), 379–392. https://doi.org/10.1016/S0306-4522(01)00199-3.

(47) Bortolozzi, A.; Díaz‐Mataix, L.; Scorza, M. C.; Celada, P.; Artigas, F. The Activation of 5-HT2A Receptors in Prefrontal Cortex Enhances Dopaminergic Activity. J. Neurochem.2005, 95 (6), 1597–1607. https://doi.org/10.1111/j.1471-4159.2005.03485.x.

(48) Radulovacki, P.; Djuricic-Nedelson, M.; Chen, E. H.; Radulovacki, M. Human Tryptamine Metabolism Decreases during Night Sleep. Brain Res. Bull.1983, 10 (1), 43–45. https://doi.org/10.1016/0361-9230(83)90072-2.

(49) The Ayahuasca Phenomenon https://maps.org/articles/5408-the-ayahuasca-phenomenon (accessed May 16, 2021).

(50) Smith, R. L.; Canton, H.; Barrett, R. J.; Sanders-Bush, E. Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors. Pharmacol. Biochem. Behav.1998, 61 (3), 323–330. https://doi.org/10.1016/S0091-3057(98)00110-5.

(51) Daytime Ayahuasca administration modulates REM and slow-wave sleep in healthy volunteers | SpringerLink https://link-springer-com.helicon.vuw.ac.nz/article/10.1007/s00213-007-0963-0 (accessed May 30, 2021).

(52) Callaway, J. C. A Proposed Mechanism for the Visions of Dream Sleep. Med. Hypotheses1988, 26 (2), 119–124. https://doi.org/10.1016/0306-9877(88)90064-3.

(53) Wüst, N.; Rauscher-Gabernig, E.; Steinwider, J.; Bauer, F.; Paulsen, P. Risk Assessment of Dietary Exposure to Tryptamine for the Austrian Population. Food Addit. Contam. Part Chem. Anal. Control Expo. Risk Assess.2017, 34 (3), 404–420. https://doi.org/10.1080/19440049.2016.1269207.

(54) PubChem. Phenethylamine https://pubchem.ncbi.nlm.nih.gov/compound/1001 (accessed May 17, 2021).

(55) Pei, Y.; Asif-Malik, A.; Canales, J. J. Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. Front. Neurosci.2016, 10. https://doi.org/10.3389/fnins.2016.00148.

(56) Miller, G. M. The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity. J. Neurochem.2011, 116 (2), 164–176. https://doi.org/10.1111/j.1471-4159.2010.07109.x.

(57) Wimalasena, K. Vesicular Monoamine Transporters: Structure-Function, Pharmacology, and Medicinal Chemistry. Med. Res. Rev.2011, 31 (4), 483–519. https://doi.org/10.1002/med.20187.

(58) Xie, Z.; Miller, G. M. Beta-Phenylethylamine Alters Monoamine Transporter Function via Trace Amine-Associated Receptor 1: Implication for Modulatory Roles of Trace Amines in Brain. J. Pharmacol. Exp. Ther.2008, 325 (2), 617–628. https://doi.org/10.1124/jpet.107.134247.

(59) Grandy, D. K.; Miller, G. M.; Li, J.-X. “TAARgeting Addiction” The Alamo Bears Witness to Another Revolution. Drug Alcohol Depend.2016, 159, 9–16. https://doi.org/10.1016/j.drugalcdep.2015.11.014.

(60) Sotnikova, T. D.; Budygin, E. A.; Jones, S. R.; Dykstra, L. A.; Caron, M. G.; Gainetdinov, R. R. Dopamine Transporter-Dependent and -Independent Actions of Trace Amine Beta-Phenylethylamine. J. Neurochem.2004, 91 (2), 362–373. https://doi.org/10.1111/j.1471-4159.2004.02721.x.

(61) Barroso, N.; Rodriguez, M. Action of Beta-Phenylethylamine and Related Amines on Nigrostriatal Dopamine Neurotransmission. Eur. J. Pharmacol.1996, 297 (3), 195–203. https://doi.org/10.1016/0014-2999(95)00757-1.

(62) Ikemoto, S. Brain Reward Circuitry beyond the Mesolimbic Dopamine System: A Neurobiological Theory. Neurosci. Biobehav. Rev.2010, 35 (2), 129–150. https://doi.org/10.1016/j.neubiorev.2010.02.001.

(63) Irsfeld, M.; Spadafore, M.; Prüß, B. M. β-Phenylethylamine, a Small Molecule with a Large Impact. WebmedCentral2013, 4 (9).

(64) Sabelli, H.; Fink, P.; Fawcett, J.; Tom, C. Sustained Antidepressant Effect of PEA Replacement. J. Neuropsychiatry Clin. Neurosci.1996, 8 (2), 168–171. https://doi.org/10.1176/jnp.8.2.168.

(65) Marzo, V. D.; Sepe, N.; Petrocellis, L. D.; Berger, A.; Crozier, G.; Fride, E.; Mechoulam, R. Trick or Treat from Food Endocannabinoids? Nature1998, 396 (6712), 636–636. https://doi.org/10.1038/25267.

(66) Tomaso, E. di; Beltramo, M.; Piomelli, D. Brain Cannabinoids in Chocolate. Nature1996, 382 (6593), 677–678. https://doi.org/10.1038/382677a0.

(67) Devane, W. A.; Hanus, L.; Breuer, A.; Pertwee, R. G.; Stevenson, L. A.; Griffin, G.; Gibson, D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor. Science1992, 258 (5090), 1946–1949. https://doi.org/10.1126/science.1470919.

(68) Fuss, J.; Steinle, J.; Bindila, L.; Auer, M. K.; Kirchherr, H.; Lutz, B.; Gass, P. A Runner’s High Depends on Cannabinoid Receptors in Mice. Proc. Natl. Acad. Sci.2015, 112 (42), 13105–13108. https://doi.org/10.1073/pnas.1514996112.

(69) Hill, M. N.; Patel, S.; Campolongo, P.; Tasker, J. G.; Wotjak, C. T.; Bains, J. S. Functional Interactions between Stress and the Endocannabinoid System: From Synaptic Signaling to Behavioral Output. J. Neurosci.2010, 30 (45), 14980–14986. https://doi.org/10.1523/JNEUROSCI.4283-10.2010.

(70) Hwang, J.; Adamson, C.; Butler, D.; Janero, D. R.; Makriyannis, A.; Bahr, B. A. Enhancement of Endocannabinoid Signaling by Fatty Acid Amide Hydrolase Inhibition: A Neuroprotective Therapeutic Modality. Life Sci.2010, 86 (15–16), 615–623. https://doi.org/10.1016/j.lfs.2009.06.003.

(71) Gaetani, S.; Dipasquale, P.; Romano, A.; Righetti, L.; Cassano, T.; Piomelli, D.; Cuomo, V. Chapter 5 The Endocannabinoid System as A Target for Novel Anxiolytic and Antidepressant Drugs. In International Review of Neurobiology; Academic Press, 2009; Vol. 85, pp 57–72. https://doi.org/10.1016/S0074-7742(09)85005-8.

(72) Lambert, D. M.; Vandevoorde, S.; Diependaele, G.; Govaerts, S. J.; Robert, A. R. Anticonvulsant Activity of N-Palmitoylethanolamide, a Putative Endocannabinoid, in Mice. Epilepsia2001, 42 (3), 321–327. https://doi.org/10.1046/j.1528-1157.2001.41499.x.

(73) Calignano, A.; La Rana, G.; Piomelli, D. Antinociceptive Activity of the Endogenous Fatty Acid Amide, Palmitylethanolamide. Eur. J. Pharmacol.2001, 419 (2), 191–198. https://doi.org/10.1016/S0014-2999(01)00988-8.

(74) Verme, J. L.; Fu, J.; Astarita, G.; Rana, G. L.; Russo, R.; Calignano, A.; Piomelli, D. The Nuclear Receptor Peroxisome Proliferator-Activated Receptor-α Mediates the Anti-Inflammatory Actions of Palmitoylethanolamide. Mol. Pharmacol.2005, 67 (1), 15–19. https://doi.org/10.1124/mol.104.006353.

(75) Thabuis, C.; Tissot-Favre, D.; Bezelgues, J.-B.; Martin, J.-C.; Cruz-Hernandez, C.; Dionisi, F.; Destaillats, F. Biological Functions and Metabolism of Oleoylethanolamide. Lipids2008, 43 (10), 887. https://doi.org/10.1007/s11745-008-3217-y.

(76) Wiranda -; Syukur, S.; Aziz, H. DETERMINATION OF CALCIUM (Ca) AND MAGNESIUM (Mg) CONTENT IN CACAO (Theobroma Cacao Linn) FERMENTATION AND NON FERMENTATION BY SPECTROPHOTOMETRY. J. Ris. Kim.2015, 3 (1), 96. https://doi.org/10.25077/jrk.v3i1.104.

(77) Shittu, T. A.; Badmus, B. A. Statistical Correlations between Mineral Element Composition, Product Information and Retail Price of Powdered Cocoa Beverages in Nigeria. J. Food Compos. Anal.2009, 22 (3), 212–217. https://doi.org/10.1016/j.jfca.2008.10.006.

(78) Cherasse, Y.; Urade, Y. Dietary Zinc Acts as a Sleep Modulator. Int. J. Mol. Sci.2017, 18 (11). https://doi.org/10.3390/ijms18112334.

(79) Prakash, A.; Bharti, K.; Majeed, A. B. A. Zinc: Indications in Brain Disorders. Fundam. Clin. Pharmacol.2015, 29 (2), 131–149. https://doi.org/10.1111/fcp.12110.

(80) Rouault, T. A. How Mammals Acquire and Distribute Iron Needed for Oxygen-Based Metabolism. PLoS Biol.2003, 1 (3). https://doi.org/10.1371/journal.pbio.0000079.

(81) Iron https://lpi.oregonstate.edu/mic/minerals/iron (accessed May 17, 2021).

(82) Office of Dietary Supplements - Magnesium https://ods.od.nih.gov/factsheets/magnesium-HealthProfessional/ (accessed May 17, 2021).

(83) Long, S.; Romani, A. M. Role of Cellular Magnesium in Human Diseases. Austin J. Nutr. Food Sci.2014, 2 (10).

(84) de Baaij, J. H. F.; Hoenderop, J. G. J.; Bindels, R. J. M. Magnesium in Man: Implications for Health and Disease. Physiol. Rev.2015, 95 (1), 1–46. https://doi.org/10.1152/physrev.00012.2014.

(85) Calcium https://lpi.oregonstate.edu/mic/minerals/calcium (accessed May 17, 2021).

(86) Office of Dietary Supplements - Calcium https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/ (accessed May 17, 2021).

(87) Bailey, R. L.; Dodd, K. W.; Goldman, J. A.; Gahche, J. J.; Dwyer, J. T.; Moshfegh, A. J.; Sempos, C. T.; Picciano, M. F. Estimation of Total Usual Calcium and Vitamin D Intakes in the United States. J. Nutr.2010, 140 (4), 817–822. https://doi.org/10.3945/jn.109.118539.

(88) Clark, S. F. Iron Deficiency Anemia. Nutr. Clin. Pract. Off. Publ. Am. Soc. Parenter. Enter. Nutr.2008, 23 (2), 128–141. https://doi.org/10.1177/0884533608314536.

(89) WHO | Assessing the iron status of populations http://www.who.int/nutrition/publications/micronutrients/anaemia_iron_deficiency/9789241596107/en/ (accessed May 17, 2021).

(90) McLean, E.; Cogswell, M.; Egli, I.; Wojdyla, D.; de Benoist, B. Worldwide Prevalence of Anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr.2009, 12 (4), 444–454. https://doi.org/10.1017/S1368980008002401.

(91) Rosanoff, A.; Weaver, C. M.; Rude, R. K. Suboptimal Magnesium Status in the United States: Are the Health Consequences Underestimated? Nutr. Rev.2012, 70 (3), 153–164. https://doi.org/10.1111/j.1753-4887.2011.00465.x.

(92) Jamison JR. Mineral Deficiency: A Dietary Dilemma? J. Nutr. Environ. Med.1999, 9 (2), 149–158. https://doi.org/10.1080/13590849961744.

(93) Nutrient Reference Values for Australia and New Zealand https://www.health.govt.nz/publication/nutrient-reference-values-australia-and-new-zealand (accessed May 23, 2021).

You have successfully subscribed!
This email has been registered