THEOBROMINE (COCOA EXTRACT)
Theobromine is mainly produced from cocoa husks as a by-product of chocolate manufacture. Unlike caffeine, it is a very mild CNS stimulant (1), and it has antioxidant characteristics (2). Of all structurally related purine alkaloids (methylxanthines), theobromine is the predominant member present in chocolate (3). Therefore, chocolate and other cocoa products are the main sources of theobromine in our Western diet. However, it can also be found in small quantities in tea (Camilla sinensis; 4), guarana , mate (Ilex paraguariensis; 5) and cola nut (6,7), whilst its presence in coffee is negligible at a mere 10% of that in tea.
A relatively recently discovered tea variety, Camellia ptilophylla, is naturally free of caffeine, but contains high levels of theobromine instead around 15 18 times the level in of green tea (8), hence its familiar name “cocoa tea”. Likewise, cocoa bean varieties differ in their theobromine content, with Forastero varieties generally containing the highest amounts (9). Whilst the cocoa beans are being processed (fermentation, roasting, etc.), the theobromine content changes mainly during the fermentation stage. During this stage methylxanthines migrate from the bean into the shell, causing a decrease in cocoa bean theobromine content of around 25% (9).
Following oral administration in man, theobromine absorption from the digestive tract is slow, especially compared with caffeine, with an estimated peak plasma time of 2.5 h (compared with 0.5 h for caffeine) (10). In humans, methylxanthines are metabolised by demethylation (removal of methyl side groups) by the enzyme cytochrome P450 (CYP). (11). However, theobromine does not metabolise into other dimethylxanthines (i.e. theophylline or paraxanthine), nor does it “upgrade” to caffeine (10. However, humans are exposed to theobromine though demethylation of caffeine, in addition to the ingestion of theobromine.
The main mechanism of action for methylxanthines has long been established as an inhibition of adenosine receptors (12,13). However, caffeine and theobromine show differential affinities for different adenosine receptor subtypes. Daly et al. (14) found that theobromine is 2-3 times less active than caffeine as an adenosine A1 receptor antagonist, but at least 10 times less active than caffeine as an A2 receptor antagonist.
It has been concluded that caffeine and theobromine were the only likely substances to play a role in the psychopharmacological activity of chocolate. This idea was confirmed when the same authors (15) showed that the combination of caffeine (19 mg) and theobromine (250 mg) contained in a 2-oz bar (approximately 50 g) of dark chocolate has significant effects on energetic arousal, reaction time and information processing. Subsequent work reported that the same combination of methylxanthines increased the liking for the flavour of a ‘novel’ drink when combined with the (encapsulated) active substances compared with an encapsulated ‘placebo’ (16). These results show a role for chocolate methylxanthines in our liking for chocolate.
Only a very few early publications have reported individual and combined effects of caffeine and theobromine. Dorfman and Jarvik (17) gave volunteers 300 mg caffeine and/or 300 mg theobromine before the volunteers retired for the evening. Those in the caffeine and caffeine + theobromine condition showed a longer sleep latency and lower sleep quality than those in the theobromine condition.
Additional data confirmed that sleep latency increases were related to caffeine dose and not to theobromine. Finally, they did not find any interactive effects of the two methylxanthines. In a study of a more exploratory nature, Mumford et al. (1) provided some valuable insights into the comparative effects of caffeine and theobromine on mood and cognition by investigating their subjective effects. Despite the small sample size, and the use of relatively high doses of methylxanthines, this study presented some very interesting and important findings. First of all, it shows how theobromine possesses caffeine-like qualities by means subjective effect descriptions such as: “Energy”, “Motivation to work”, “Alert”, “Sleepy” (decreased). The discrimination threshold phase of the study showed a wide range of reliable discrimination thresholds amongst the volunteers.
Further evidence for caffeine-like effects of theobromine, was provided by Ott (18), who replaced a dietary caffeine intake with a daily dose of 600 mg theobromine (200 mg in the morning, afternoon and evening) for 7 days. Acute theobromine deprivation resulted in “tension headache, muscle tension in the shoulders and neck, and extreme lethargy” within 16 h. These symptoms were reversed within 60 min of the consumption of another 200-mg dose of theobromine, suggesting that the symptoms were that of theobromine withdrawal.
More recently, Mitchell et al (19) examined the potential synergistic and singular effects of theobromine and caffeine. They administered capsules of theobromine, caffeine, a combination of both, or placebo (microcrystalline cellulose) to 24 healthy female subjects. Aspects of participants’ mood and psychomotor performance were measured using the Bond–Lader visual analog scale and the Digit Symbol Substitution Test (DSST), respectively. Blood pressure was also measured at baseline and at 1 h, 2 h, and 3 h after administration. Relative to placebo, theobromine alone decreased self-reported calmness at 3 h post ingestion and lowered blood pressure at 1 h. Caffeine increased self-reported alertness at all post-administration time points but was also associated with elevated blood pressure at 1 h. The combination of caffeine and theobromine had effects similar to those of caffeine alone on mood, except for the absence of blood pressure effects. It was tentatively concluded that caffeine may have more central-nervous-system mediated effects on alertness, while theobromine may be acting primarily via peripheral physiological mechanisms.
Other authors reported theobromine showed differential effects on mood depending on dose (20). This suggests that theobromine at normal intake levels, as can be found in a standard 40-g bar of dark chocolate, may contribute to the positive effects of chocolate.
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20. Matthew J. Baggott & Emma Childs & Amy B. Hart & Eveline de Bruin & Abraham A. Palmer & Joy E. Wilkinson & Harriet de Wit Psychopharmacology of theobromine in healthy volunteers Psychopharmacology DOI 10.1007/s00213-013-3021-0