Table 3. Summary of the characteristics and outcomes of the cocoa bioavailability and chronic studies.

Reference	Characteristics of the study	Number of volunteers and criteria	Cocoa product and dose	Main cocoa metabolites*	Health effects
Gómez-Juaristi et al. (2019)	Polyphenol bioavailability study Randomized and crossover, 8 h long carried out on two separated days	13 Healthy subjects	Day 1: 15 g of conventional cocoa (CC)—19.80 mg of flavanols/day Day 2: 25 g of cocoa rich in methylxanthines and phenols (MPC)—68.25 mg of flavanols/day	Plasma: epicatechin and its phase II derivatives: 3′-Methyl-epicatechin-5-sulfate, epicatechin-3′-sulfate, 4′-methyl-epicatechin-5-sulfate, epicatechin-3′-glucuronide, among others. 5-(3′,4′-Dihydroxyphenyl)-γ-valerolactone (DHPVL) and its phase II derivatives (HPVL-3′-glucuronide, HPVL-3′-sulfate, PVL-methyl-glucuronide). Urine: phase II derivatives of epicatechin, approximately 33% of total. The majority were phase II derivatives of 5-(4′-hydroxyphenyl)-γ-valerolactone (HPVL) and 4-hydroxy-5-(4′-hydroxyphenyl)valeric acid (HHPVA): HPVL-3′-sulfate followed by HHPVA-sulfate, PVL-sulfate and HPVL-3′-glucuronide, among others Dose-dependent response	No changes in blood pressure along the 8 h. No changes in antioxidant capacity in blood along the 8 h, except 1 h (ABTS) and 2 and 8 h (FRAP)
Martínez-López et al. (2014a)	Methylxanthine bioavailability study Randomized and crossover, 8 h long carried out on two separated days	13 Healthy subjects	Day 1: 15 g of conventional cocoa (CC)—84.45 mg of theobromine (TB) and 9.9 mg of caffeine (CF)/day Day 2: 25 g of cocoa rich in methylxanthines and phenols (MPC)—177 mg TB, 75.75 mg CF and 3.25 mg theophylline (TP)/day	Plasma: TB, CF, TP and paraxanthine (PX) together with two monomethylxanthines (3-methylxanthine (MX) and 7-MX) Urine: TB, CF, TP and PX, along with monomethylxanthines (1-MX, 3-MX and 7-MX) and different mono-, di- and tri- methyluric (MU) acids (1-MU, 1,3-MU, 1,7-MU, 3,7-MU and 1,3,7-MU). 7-MX as the most abundant metabolite followed by TB and 3-MX Dose-dependent response	No changes in blood pressure along the 8 h. No changes in antioxidant capacity in blood along the 8 h, except 1 h (ABTS) and 2 and 8 h (FRAP)
Sarriá et al. (2014)	Randomized, controlled and crossover chronic study. Cocoa and control interventions were four weeks long	44 healthy subjects (n = 24) and moderately hypercholesterolemic (n = 20)	30 g/day (2 doses of 15 g of cocoa rich in dietary fibre (DFC)) 34.8 mg of flavanols/day 153.3 mg of TB and 15.3 mg of CF/day 6.6 g total dietary fibre (DF) 0.5 g soluble DF/day 6.1 g insoluble DF/day	Phenol metabolites according to Gómez-Juaristi et al. (2019): Epicatechin and phase II derivatives of epicatechin Phase II derivatives of hydroxyphenyl-γ-valerolactones and valeric acid Methylxanthine metabolites according to Martínez-López et al. (2014a): TB, CF, TP and paraxanthine (PX) together with monomethylxanthines (1-MX, 3-MX and 7-MX) and mono-, di- and tri-MU acids (1-MU, 1,3-MU, 1,7-MU, 3,7-MU and 1,3,7-MU) Dietary fibre according to Sarriá et al. (2014).	↑HDL-cholesterol ↓Blood glucose ↑IL-1β ↓IL-10
Martínez-López et al. (2014b)	Randomized, controlled and crossover-chronic study. Cocoa and control interventions were four weeks long	44 healthy subjects (n = 24) and moderately hypercholesterolemic (n = 20)	15 g/day (two doses of 7.5 g) of cocoa rich in cocoa (PC) 45.3 mg of flavanols/day 96.45 mg of TB and 13.2 mg of CF/day 2.3 g total dietary fibre (DF) 0.5 g soluble DF/day 1.8 g insoluble DF/day	Phenol metabolites according to Gómez-Juaristi et al. (2019): Epicatechin and phase II derivatives of epicatechin Phase II derivatives of hydroxyphenyl-γ-valerolactones and valeric acid Methylxanthine metabolites according to Martínez-López et al. (2014a): TB, CF, TP and PX together with monomethylxanthines and different mono-, di- and tri-MU acids Dietary	↑HDL-cholesterol

Note:

^*5-(3′,4′-dihydroxyphenyl)-γ-valerolactone (DHPVL); 5-(4′-hydroxyphenyl)-γ-valerolactone (HPVL); 5-phenyl-γ-valerolactone (PVL); 4-hydroxy-5-(3′,4′-dihydroxyphenyl)valeric acid (HDHPVA) and 4-hydroxy-5-(hydroxyphenyl)valeric acid (HHPVA).