Vitafoods Asia 2019



25-26 September 2019  




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Xanthines : theobromine and caffeine.


Methylxanthines are derived from a purine base (xanthine) found in most body tissues and fluids and in other organisms.


The two major methylxanthines found in plants are Caffeine (in coffee, guarana, mate and tea) and Theobromine (in cocoa and mate). Theophylline is also naturally found in tea as traces (~1 mg/l).


Coffee, tea and cocoa are ancient beverages with traditional use. Coffee and tea are well known as mild stimulants drunk all over the world whereas cocoa is more famous for its hedonic and behavourial effects.


Everybody knows that caffeine is the active ingredients of coffee and tea. But for cocoa derivate products, the determination of the psychostimulant active ingredients was unclear. The scientists hesitated between polyphenols, anandamine, different amines as salsolinol, or xanthines. Smit [1] demonstrated in 2004 that the therapeutically active molecules of cocoa were the methylxanthines.



Pharmacology of Xanthines


The psychostimulant properties of xanthines are due to their ability to interact with the neurotransmission in different regions of the brain, thereby promoting behavioural functions, such as vigilance, attention, mood and arousal [2].


It is now well established that under normal physiological conditions, the effects exerted in the brain by methylxanthines depend on their ability to act as an antagonist at different adenosine receptors [3].


Adenosine is a ubiquitous neuromodulator that acts at four G-protein-coupled receptors (A1, A2A, A2B and A3). The major adenosine receptors implicated in arousal performances are A1 and A2A.


Pharmacological studies indicate that the CNS effects of methylxanthines are mediated particularly by their antagonistic actions at the A1 and A2A subtypes of the adenosine receptors [4].


Xanthines action on brain receptors.


The methylxanthines interact also with other central receptors as β1-Adrenergic (cortex), β2-adrenergic (cerebellum), 5-HT1 serotonin (cortex), 5-HT2 serotonin (cortex), muscarinic (cortex), nicotinic (cortex), GABA A (cortex), Ca2+ channel (cortex) [5]. The action of xanthines is central but also peripheral; they modulate calcium in the skeletal muscle during fatigue [6].


During the fatigue the leakage and the recapture of calcium is attenuated within the muscle fibers. Cognityl, herbal supplement for concentration, due to its content in methylxanthines, reinforce the normal contraction of skeletal muscle by potentialising twitch tension.

Xanthines exert their action on the sarcoplasmic reticulum, releasing Ca2+ from it by increasing the open probability of Ryanodine Receptor 1 (RyR1) (Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum, an essential step in muscle contraction). This effect is due to both an increase in
open time constants and a decreased in closed time constants. In addition, the number of open events was increased, transferring the channel into a highly activated state.
By this way, xanthines enhance the muscular force of contraction too.


Methylxanthines have behavioural and stimulant effects. The difference of affinity of their receptors implies different therapeutic activities. The challenge is to get the good amount and ratio of theobromine and caffeine to deliver the optimal effect.




[1] Smit HJ, Gaffan EA, Rogers PJ. Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology. 2004; 176: 412-419.


[2] Fisone G, Borgkvist A, Usiello A. Caffeine as a psychomotor stimulant: mechanism of action. Cell. Mol. Life Sci. 2004; 61: 857-872.


[3] Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau E. Actions of Caffeine in the Brain with Special Referece to Factors That Contribute to Its Widespread Use. Pharmacol. Rev. 1999; 51: 83-133.


[4] Lorist MM, Tops M. Caffeine, fatigue, and cognition. Brain Cogn. 2003; 53: 82-94.


[5] Shi D, Daly JW. Chronic Effects of Xanthines on Levels of Central receptors in Mice. Cell. Mol. Neurobiol. 1999; 19: 719-732.


[6] Hawke TJ, Allen DG, Lindinger MI. Paraxanthine, a caffeine metabolite, dose dependently increases [Ca2+]i in skeletal muscle. J. Appl. Physiol. 2000; 89: 2312-2317.