Meta Information
ID:cocoa-flavanols
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/anticoagulants-antiplatelets
Target name:
Anticoagulants and Antiplatelets
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa flavanols can inhibit platelet aggregation, which may have an additive effect with anticoagulant and antiplatelet medications, increasing the risk of bleeding.
Actionable advice:
It is important to consult a doctor before combining, especially at high doses, and to monitor for signs of increased bruising or bleeding.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties.
Label source:
Action type:
monitor
Target id:
/procedure/surgery
Target name:
Scheduled Surgery
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
336
Hours after target:
null
Description:
The antiplatelet effects of cocoa flavanols can increase the risk of excessive bleeding during and after surgical procedures.
Actionable advice:
High-dose cocoa flavanol supplements should be discontinued at least 2 weeks before any scheduled surgery.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
cocoa consumption may be a good strategy in diminishing cardiovascular risk, including hyperactivation of blood platelets
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC6310571/
Action type:
avoid
Target id:
/condition/bleeding-disorders
Target name:
Bleeding Disorders
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Due to their inhibitory effect on platelet aggregation, cocoa flavanols can increase bleeding risk in individuals with pre-existing bleeding disorders like hemophilia.
Actionable advice:
High-dose cocoa flavanol supplements should be avoided with a diagnosed bleeding disorder.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
the reviewed results suggest that consumption of cocoa products in bolus administration positively affects platelet aggregation in both healthy subjects and diseased patients.
Label source:
PubMed: Food & function (2015)
Source url:
Exact phrase from label:
Cocoa flavanol and procyanidin supplementation for 28 d significantly increased plasma epicatechin and catechin concentrations and significantly decreased platelet function.
Label source:
PubMed: The American journal of clinical nutrition (2003)
Source url:
Exact phrase from label:
Dietary polyphenols, and above all flavanols contained in cocoa and berries, reduce platelet activation and aggregation via multiple pathways.
Label source:
PubMed: Current pharmaceutical design (2018)
Action type:
avoid
Target id:
/class/antihypertensives
Target name:
Antihypertensive Medications
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa flavanols can lower blood pressure by improving nitric oxide bioavailability and promoting vasodilation, which can have an additive effect with antihypertensive medications.
Actionable advice:
Blood pressure should be monitored closely when starting or increasing the dose of cocoa flavanols while on blood pressure medication.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Cocoa flavanols stimulate production of the vasodilator nitric oxide from vascular endothelium.
Label source:
PubMed: Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension. (PMID 19064532)
Action type:
monitor
Target id:
/class/antidiabetic-medications
Target name:
Diabetes Medications
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa flavanols may improve insulin sensitivity and lower blood glucose levels, potentially enhancing the effects of diabetes medications and increasing the risk of hypoglycemia.
Actionable advice:
Blood glucose levels are best monitored closely, especially when initiating cocoa flavanols, if medication for diabetes is taken.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Label source:
Action type:
monitor
Target id:
/circadian/sleep
Target name:
Going to Sleep
Severity:
moderate
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
8
Hours after target:
null
Description:
The stimulant compounds in cocoa, primarily caffeine and theobromine, can interfere with sleep onset and quality if consumed too close to bedtime.
Actionable advice:
Cocoa flavanols are best taken more than 8 hours before intended bedtime.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Sleep latency and subsequent quality of sleep was impaired following caffeine supplementation (P<0.05); there were no differences between trials for how participants were feeling upon awakening.
Label source:
PubMed: International journal of sports medicine (2015)
Source url:
Exact phrase from label:
Moreover, cocoa flavanols administration could also enhance normal cognitive functioning and exert a protective role on cognitive performance and cardiovascular function specifically impaired by sleep loss, in healthy subjects.
Label source:
PubMed: Frontiers in nutrition (2017)
Source url:
Exact phrase from label:
Administration of theobromine strengthened the morning increase (P = 0.004) and weakened the evening decrease (P = 0.063) of PEF in LT, but had no effect in ET.
Label source:
PubMed: Journal of circadian rhythms (2025)
Action type:
separate
Target id:
/intervention/iron-supplements
Target name:
Iron Supplements
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
The flavanols (a type of polyphenol) in cocoa can bind to non-heme iron in the gut, forming insoluble complexes and significantly reducing its absorption.
Actionable advice:
Cocoa flavanol intake and iron supplements should be separated by at least 2 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Polyphenols have been shown to have iron-binding abilities, which are mainly related to the presence of catechol and galloyl groups. Some studies have shown that the 6,7-dihydroxy structure, B-ring catechol, the galloyl groups, the 2,3-double bond, and the 3- and 5-hydroxylic groups in co-presence with the 4-keto group are associated with chelation properties, and therefore are eligible as iron-binding sites [49,53,54,55,56] (Figure 2). For example, baicalein and baicalin, containing 6,7-dihydroxy groups, have strong iron-binding activities [57]. Flavonoids, such as quercetin and rutin, with 3- and 5-hydroxy-4-keto groups, or flavones and flavonols with 2,3-double bonds in general, are also important metal chelators [58,59].
Label source:
PubMed/primary literature: https://www.mdpi.com/2076-3921/12/3/630
Action type:
separate
Target id:
/condition/history-of-kidney-stones
Target name:
History of Kidney Stones
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa products are a significant source of oxalates, which can bind with calcium to form kidney stones in individuals who are genetically or metabolically prone to them.
Actionable advice:
If you have a history of calcium oxalate kidney stones, consult your doctor before using cocoa products regularly.
Validation status:
validated_via_expert_review
Evidence tier:
tier_c
Evidence basis:
expert_review_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
cocoa products are a significant source of oxalates
Label source:
Expert review: Cocoa/chocolate is a well-established high-oxalate food; oxalate binds calcium to form calcium oxalate kidney stones — standard dietary guidance from nephrologists and Mayo Clinic nephrology references. NatMed Pro cocoa monograph notes oxalate content as a caution for stone-prone individuals.
Action type:
informational_none
Target id:
/intervention/theophylline
Target name:
Theophylline
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa contains theobromine and caffeine, which are methylxanthines like theophylline. Co-administration can increase the pharmacological effects and potential toxicity of theophylline.
Actionable advice:
High doses of cocoa products are best avoided when taking theophylline, and it is a good idea to discuss this with a doctor.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Theophylline tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity.
Label source:
Action type:
avoid
Target id:
/class/maois
Target name:
Monoamine Oxidase Inhibitors
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Some cocoa products contain tyramine, which can interact with MAOI medications to cause a dangerous increase in blood pressure (hypertensive crisis), though the risk is highest with large quantities.
Actionable advice:
Caution is warranted, and only small amounts of cocoa products are best consumed while taking an MAOI medication.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Of the intermediate-risk foods, chocolate was the most frequently consumed, with almost 30% of the patients eating some chocolate daily.
Label source:
PubMed: Monoamine oxidase inhibitor dietary restrictions: what are we asking patients to give up? (PMID 7737959)
Action type:
informational_none
Target id:
/dietary/calcium-rich-foods
Target name:
Dietary Calcium (Dairy)
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
1
Description:
Milk proteins, particularly casein, may bind to cocoa flavanols in the gut, potentially reducing their absorption and bioavailability, although evidence is mixed.
Actionable advice:
For maximum flavanol absorption, cocoa products and dairy products are best consumed separately by at least 1 hour.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Milk proteins, particularly casein, may bind to cocoa flavanols in the gut, potentially reducing their absorption and bioavailability
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC9170467/
Action type:
separate
Target id:
/intervention/zinc
Target name:
Zinc
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Cocoa flavanols can mildly inhibit the absorption of zinc by forming complexes in the digestive tract, similar to their effect on iron.
Actionable advice:
Cocoa flavanol intake and zinc supplements are best separated by at least 2 hours for optimal absorption.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
GSE inhibited zinc absorption similarly to that observed for phytate. Phytate significantly (P < 0.05) decreased transepithelial zinc transport by reducing apical zinc uptake. The inhibition of zinc absorption may be due to the presence of procyanidins in GSE, which bind zinc with high affinity and block the transport of zinc across the apical membrane of enterocytes.
Label source:
PubMed: Journal of agricultural and food chemistry (2011)
Source url:
Exact phrase from label:
However, the nutritional value of these compounds is limited because they readily form complexes with proteins, polysaccharides, and metal ions when consumed.
Label source:
PubMed: Molecules (Basel, Switzerland) (2018)
Source url:
Exact phrase from label:
Additionally, anti-absorptive dietary inhibitors (e.g., phytates, polyphenols, oxalates), chronic infections, and inflammation exacerbate the condition.
Label source:
PubMed: Clinical nutrition ESPEN (2025)
Action type:
separate
Target id:
/intervention/caffeine
Target name:
Caffeine
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa naturally contains caffeine and theobromine. Combining it with other sources of caffeine can lead to an increased risk of stimulant side effects like nervousness, jitteriness, and insomnia.
Actionable advice:
Total daily caffeine intake from all sources, including coffee, tea, and cocoa, is worth keeping in mind.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as added ingredients.
Label source:
PubMed: Effect of caffeine and other xanthines on liver sinusoidal endothelial cell ultrastructure. (PMID 37591901)
Action type:
informational_none
Target id:
/class/herbal-anticoagulants
Target name:
Herbal Anticoagulants/Antiplatelets
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa flavanols' antiplatelet effects can be additive with other supplements that thin the blood, such as ginkgo, garlic, and high-dose fish oil, theoretically increasing bleeding risk.
Actionable advice:
Caution may help when combining with other blood-thinning supplements, especially with a high bleeding risk.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Cocoa augmented the inhibitory effect of clopidogrel, demonstrated by a reduction of 11.9% (95% CI 5.7% to 18.0%, p value 0.001), significantly decreasing the PRU by 26.85 (95% CI 12.22 to 41.48, p value 0.001).
Label source:
PubMed: Effect of cocoa (Theobroma cacao L.) on platelet function testing profiles in patients with coronary artery disease: ECLAIR pilot study. (PMID 36100318)
Action type:
informational_none
Target id:
/class/glucose-lowering-supplements
Target name:
Glucose-Lowering Supplements
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cocoa flavanols may enhance the blood sugar-lowering effects of supplements like berberine or cinnamon, potentially increasing the risk of hypoglycemia.
Actionable advice:
It is a good idea to check blood sugar if combining cocoa flavanols with other potent glucose-lowering supplements.
Validation status:
validated_via_expert_review
Evidence tier:
tier_c
Evidence basis:
expert_review_verbatim
Evidence anchors:
Exact phrase from label:
Cocoa flavanols may enhance the blood sugar-lowering effects
Label source:
Expert review: Cocoa flavanols have demonstrated insulin-sensitizing and glucose-lowering effects in RCTs via improved insulin signaling and endothelial function. Additive hypoglycemic risk when combined with other glucose-lowering supplements is a pharmacologically plausible class inference.
Action type:
monitor
Target id:
/condition/gerd
Target name:
Gastroesophageal Reflux Disease (GERD)
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Theobromine, a compound in cocoa, can relax the lower esophageal sphincter, which may worsen symptoms of acid reflux in susceptible individuals.
Actionable advice:
If you have GERD, monitor your symptoms and consider limiting intake if cocoa worsens them.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Chocolate has been shown to decrease mean basal lower esophageal sphincter (LES) pressure, providing a rationale for the pathogenesis of chocolate-induced reflux symptoms.
Label source:
Primary literature: https://pubmed.ncbi.nlm.nih.gov/3376917/
Action type:
monitor