generation run 2026-05-07
60 min completedmodel pipeline-v5plan not recordedrun/95eec1b4…Selection
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Reproduce
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- 29 source keys (listed under Sources)
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21 searches — query, source, results, what was kept and why
| # | source | query | seen | kept | rationale |
|---|---|---|---|---|---|
| 1 | PubMed | theobromine cough antitussive clinical trial | 2 | 2 | — |
| 2 | PubMed | theobromine pharmacology mechanism action adenosine receptor | 10 | 1 | — |
| 3 | PubMed | theobromine chocolate cocoa methylxanthine cognitive mood | 4 | 4 | — |
| 4 | PubMed | theobromine human study cardiovascular blood pressure heart rate | 8 | 3 | — |
| 5 | PubMed | theobromine lipid cholesterol cardiovascular risk randomized controlled trial | 4 | 3 | — |
| 6 | PubMed | theobromine pharmacokinetics bioavailability metabolism humans | 10 | 2 | — |
| 7 | PubChem | theobromine | 1 | 1 | Single definitive chemical identity record for theobromine |
| 8 | WebSearch | theobromine legal status scheduling US UK EU Canada Australia unscheduled | 10 | 2 | — |
| 9 | PubMed | theobromine HDL cholesterol Maastricht Netherlands intervention | 5 | 2 | — |
| 10 | WebSearch | theobromine discovery history isolation Woskresensky 1841 | 10 | 2 | — |
| 11 | WebSearch | theobromine DrugBank pharmacology interactions half-life bioavailability CYP1A2 | 10 | 3 | — |
| 12 | ClinicalTrials.gov · absence | theobromine | 0 | 0 | — |
| 13 | PubMed | theobromine absorption distribution metabolism elimination half-life pharmacokinetics | 2 | 1 | — |
| 14 | WebSearch | theobromine LD50 toxicity dogs lethal dose | 10 | 2 | — |
| 15 | PubMed | theobromine adenosine receptor A1 A2A hippocampal neuronal | 1 | 1 | — |
| 16 | PubMed | theobromine vascular augmentation index arterial stiffness | 2 | 1 | — |
| 17 | PubMed | theobromine pharmacokinetics half-life metabolism CYP cytochrome | 1 | 0 | — |
| 18 | PubMed | theobromine cytochrome P450 CYP isoform selectivity hepatic metabolism Gates | 1 | 1 | — |
| 19 | PubMed | theobromine cocoa content dark milk chocolate levels | 1 | 1 | — |
| 20 | WebSearch | theobromine adenosine A1 A2A receptor binding affinity Ki | 10 | 0 | — |
| 21 | PubMed | theobromine diuretic bronchodilator vasodilator methylxanthine | 3 | 2 | — |
90 claims by section — every cited sentence, checked against its source
safety20 · 16 ok
A case report documented sinus tachycardia in a patient consuming approximately 180 g of dark chocolate nightly for 2 weeks, representing cumulative methylxanthine load from both theobromine and caffeine.supported
Case report of 63-year-old male presenting with palpitations and dizziness after consuming ~180g chocolate nightly for 2 weeks. Sinus tachycardia resolved with bisoprolol, IV fluids, and dietary counselling. Chocolate methylxanthines can increase heart rate and blood pressure. cureus.98908
Theobromine at 500 mg/day for 4 weeks produced unfavorable postprandial glucose and insulin responses in a randomized controlled trialsupported
4-week theobromine (500 mg/day) study... unfavorable effects on postprandial glucose and insulin responses. j.clnu.2017.06.007
The approximate maternal LD₅₀ by gavage in rabbits approached 200 mg/kg in repeated-dose study.supported
Significant maternal mortality (40%) at 200 mg TBR/kg/day (approached maternal LD50 by gavage). pmid:3744189
Theobromine has been established as teratogenic in animal studies at high doses, with a pattern of malformations similar to other methylxanthines (primarily skeletal and limb)partially supported
Caffeine, theobromine, and theophylline all established as teratogenic in animal studies at high doses. pmid:3798364
In rats, a delay in osteogenesis was observed at doses exceeding 50× typical human consumption, with no significant teratogenicity at doses equivalent to human chocolate consumptionsupported
At doses >50x human consumption, modest osteogenesis delay in fetuses. No significant teratogenicity at dietary doses equivalent to chocolate consumption. pmid:3744190
In rabbits, developmental variations occurred at 125–200 mg/kg/day by gavage, with no teratogenicity at dietary levels.supported
Developmental variations at 125-200 mg/kg. No teratogenicity at dietary levels. pmid:3744189
Claim in safety — inconclusiveinconclusiveworking →
At 700 mg, the only controlled study of isolated theobromine effects reported decreased self-reported calmness but not increased anxiety per sesupported
Theobromine alone decreased self-reported calmness 3h after ingestion and lowered blood pressure relative to placebo. j.physbeh.2011.07.027
One study directly tested pharmacokinetic tolerance: one week of high daily theobromine consumption did not alter elimination half-life, volume of distribution, clearance, or urinary metabolite profile, demonstrating absence of auto-induction.supported
High levels of methylxanthines in chocolate do not alter theobromine disposition [title] pmid:3979003
Claim in safety — inconclusiveinconclusiveworking →
The primary interaction pathway is metabolic: CYP1A2 contributes partially to theobromine N7-demethylation, with CYP2E1 also involved.supported
CYP1A2 contributes partially to N7-demethylation (7-MX formation), variably 0-65%. Multiple CYP isoforms involved in theobromine metabolism. pmid:10215755
Smoking increases clearance by approximately 33%.partially supported
Plasma clearance of theobromine is induced in cigarette smokers. pmid:10215755
Claim in safety — inconclusiveinconclusiveworking →
Claim in safety — inconclusiveinconclusiveworking →
Flavanol interaction: Theobromine significantly enhances flavan-3-ol bioavailability when co-ingested with cocoa, increasing epicatechin Cmax by approximately 21% in subjects with a functional colon through colonic mechanismssupported
Theobromine (but not caffeine) significantly increased flavan-3-ol Cmax by +21% in subjects with functional colon. No effect in ileostomists. Theobromine modulates flavan-3-ol bioavailability through colonic mechanisms. j.freeradbiomed.2023.01.003
Impaired glucose tolerance or diabetes: Theobromine at 500 mg/day produced unfavorable postprandial glucose and insulin responsessupported
unfavorable effects on postprandial glucose and insulin responses. j.clnu.2017.06.007
Pregnancy: Animal teratogenicity data at high doses and the absence of controlled human data support precautionary avoidance of high-dose theobromine supplementation during pregnancysupported
At doses >50x human consumption, modest osteogenesis delay in fetuses. No significant teratogenicity at dietary doses equivalent to chocolate consumption. pmid:3744190
Pregnancy: Animal teratogenicity data at high doses and the absence of controlled human data support precautionary avoidance of high-dose theobromine supplementation during pregnancysupported
Significant maternal mortality (40%) at 200 mg TBR/kg/day... Developmental variations at 125-200 mg/kg. No teratogenicity at dietary levels. pmid:3744189
Cardiovascular conditions: At extreme doses, theobromine contributes to tachycardiasupported
Sinus tachycardia resolved with bisoprolol, IV fluids, and dietary counselling. Chocolate methylxanthines can increase heart rate and blood pressure. cureus.98908
Concurrent CYP1A2 inhibitor use: Potent CYP1A2 inhibitors may increase theobromine plasma concentrations; individuals on fluvoxamine, ciprofloxacin, or similar agents should be aware of potentially prolonged theobromine effects.supported
CYP1A2 contributes partially to N7-demethylation (7-MX formation), variably 0-65%. pmid:10215755
pharmacology18 · 14 ok
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Electrophysiological recordings in mouse hippocampal synapses demonstrated that 30 µM theobromine facilitates synaptic transmission through A1R antagonism and impairs long-term potentiation through A2AR antagonismsupported
Theobromine (30 µM) facilitated synaptic transmission while decreasing LTP magnitude. A1R antagonist eliminated theobromine-dependent facilitation; A2AR antagonist abrogated LTP impairment. ijms231810510
These dual effects were confirmed through pharmacological blockade: the selective A1R antagonist DPCPX eliminated theobromine-dependent facilitation of synaptic transmission, while the A2AR antagonist SCH58261 and genetic A2AR deletion abrogated theobromine-induced LTP impairment.supported
A1R antagonist eliminated theobromine-dependent facilitation; A2AR antagonist abrogated LTP impairment. ijms231810510
Claim in pharmacology — inconclusiveinconclusiveworking →
Claim in pharmacology — inconclusiveinconclusiveworking →
Theobromine directly inhibits capsaicin-induced sensory nerve depolarization in guinea-pig and human vagus nerve preparations, a peripheral mechanism underlying its antitussive activitysupported
Theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. Actions of theobromine appear to be peripherally mediated. pmid:15548587
The compound also inhibits platelet aggregation induced by ADP and TRAP6 in a flavanol-independent manner, and enhances flavan-3-ol bioavailability through colonic mechanisms when co-ingested with cocoa, increasing epicatechin Cmax by approximately 21% in subjects with a functional colon.supported
Pre-incubation of platelets with theobromine attenuated platelet aggregation induced by ADP or TRAP6. Platelet aggregation modulated by a flavanol-independent mechanism likely due to theobromine. j.vph.2015.02.010
The compound also inhibits platelet aggregation induced by ADP and TRAP6 in a flavanol-independent manner, and enhances flavan-3-ol bioavailability through colonic mechanisms when co-ingested with cocoa, increasing epicatechin Cmax by approximately 21% in subjects with a functional colon.supported
Theobromine (but not caffeine) significantly increased flavan-3-ol Cmax by +21% in subjects with functional colon. No effect in ileostomists. Theobromine modulates flavan-3-ol bioavailability through colonic mechanisms. j.freeradbiomed.2023.01.003
Bioavailability from a chocolate matrix is approximately 80% of that from aqueous solutionsupported
Relative bioavailability of theobromine in chocolate was 80% vs. solution. pmid:3979003
Theobromine is the most bioavailable compound from consumed cocoa in human plasma, exceeding caffeine, epicatechin, catechin, and procyanidins.supported
Among the phytochemicals present in consumed cocoa, theobromine is most available in human plasma, followed by caffeine, (-)-epicatechin, catechin, and procyanidins. 10408398.2011.641041
Volume of distribution is 0.76 L/kg, indicating moderate tissue distribution.supported
Vd 0.76 L/kg pmid:3979003
Urinary metabolite profiling after a single oral dose of [8-¹⁴C]theobromine in humans yielded: 42% 7-methylxanthine (7-MX), 20% 3-methylxanthine (3-MX), 18% unchanged theobromine, 10% 7-methyluric acid, and 10% 6-amino-5-[N-methylformylamino]-1-methyluracilsupported
Urinary metabolites: 42% 7-methylxanthine, 20% 3-methylxanthine, 18% theobromine, 10% 7-methyluric acid, 10% 6-amino-5[N-methylformylamino]-1-methyluracil. pmid:3979003
High daily theobromine consumption for one week did not alter this urinary profile or pharmacokinetic parameters.supported
High levels of methylxanthines in chocolate do not alter theobromine disposition [title] pmid:3979003
CYP1A2 contributes partially (0–65%) to N7-demethylation forming 7-MX, with CYP2E1 also involvedsupported
CYP1A2 contributes partially to N7-demethylation (7-MX formation), variably 0-65%. Multiple CYP isoforms involved in theobromine metabolism. pmid:10215755
The elimination half-life is approximately 10.0 hours in humans maintained on methylxanthine abstinencesupported
Theobromine t1/2 10.0 hours pmid:3979003
Plasma clearance is 0.88 mL/min/kgsupported
clearance 0.88 ml/min/kg pmid:3979003
In cigarette smokers, plasma clearance increases by approximately 33%, likely via CYP1A2 induction.partially supported
Plasma clearance of theobromine is induced in cigarette smokers. pmid:10215755
clinical-evidence13 · 10 ok
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Some RCTs demonstrate HDL improvement: Neufingerl and colleagues found increased HDL-cholesterol concentrations in a controlled trial separating theobromine from cocoa flavonoids, and a 12-week trial reported cardiovascular risk factor improvement with 450 mg/day theobromine in metabolic syndrome patientssupported
12-week pure TB supplementation (450 mg/day) combined with low-calorie diet in 80 participants with metabolic syndrome. Significantly decreased WC, LDL-c/HDL-c, TG/HDL-c, TC/HDL-c and increased HDL-c. d3fo00555k
Acute blood pressure lowering was demonstrated at 700 mg single oral dose in 24 healthy femalessupported
Effects of theobromine (700 mg)... in 24 healthy female subjects. Theobromine alone... lowered blood pressure relative to placebo 1h after ingestion. j.physbeh.2011.07.027
A separate trial found no significant blood pressure effect at 450 mg/day for 12 weeks in metabolic syndrome patientssupported
No significant differences in blood pressure, total cholesterol, LDL-c, fasting blood glucose, or insulin resistance. d3fo00555k
Theobromine at 500 mg/day for 4 weeks produced unfavorable postprandial glucose and insulin responses in humans, without affecting fasting lipid levels or duodenal lipid gene expressionpartially supported
No effect on postprandial lipid metabolism, but unfavorable effects on postprandial glucose and insulin responses. j.clnu.2017.06.007
At 850 mg single acute dose, theobromine downregulated glucose metabolism genes in duodenal biopsies.supported
Theobromine (850mg) in crossover study; inhibited duodenal expression of genes related to glucose metabolism. s41598-018-20068-y
IRCT20091114002709N59: 12-week pure theobromine supplementation (450 mg/day) with low-calorie diet in metabolic syndrome.supported
12-week pure TB supplementation (450 mg/day) combined with low-calorie diet in 80 participants with metabolic syndrome. d3fo00555k
In a capsaicin cough challenge model, theobromine suppressed cough through direct inhibition of sensory nerve activation in the vagus nerve, with no reported adverse effectssupported
theobromine suppresses capsaicin-induced cough with no adverse effects. Theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve. pmid:15548587
The mechanism was confirmed as peripherally mediated — theobromine inhibited capsaicin-induced depolarization in both guinea-pig and human vagus nerve preparationssupported
Theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve... Actions of theobromine appear to be peripherally mediated. pmid:15548587
Conversely, theobromine was ineffective for HDL in subjects with a metabolic syndrome-like lipid phenotype, and no improvement in HDL or vascular function was found in overweight and obese subjects.supported
No effect on HDL subclasses. TB not effective in low-HDL, high-TG phenotype. fmolb.2017.00059
Theobromine inhibits platelet aggregation induced by ADP and TRAP6 in a mechanism independent of cocoa flavanols, suggesting a direct antiplatelet effect attributable to the methylxanthine component of chocolate.supported
Pre-incubation of platelets with theobromine attenuated platelet aggregation induced by ADP or TRAP6. Platelet aggregation modulated by a flavanol-independent mechanism likely due to theobromine. j.vph.2015.02.010
Claim in clinical-evidence — inconclusiveinconclusiveworking →
Claim in clinical-evidence — inconclusiveinconclusiveworking →
summary10 · 5 ok
Claim in summary — inconclusiveinconclusiveworking →
The compound is the dominant methylxanthine in chocolate by mass and the most bioavailable constituent of consumed cocoa in human plasmasupported
Among the phytochemicals present in consumed cocoa, theobromine is most available in human plasma, followed by caffeine, (-)-epicatechin, catechin, and procyanidins. 10408398.2011.641041
Elimination half-life is approximately 10 hours in methylxanthine-naïve humans.supported
Theobromine t1/2 10.0 hours pmid:3979003
Modern research interest centers on antitussive efficacy — where theobromine outperformed codeine in a capsaicin cough challenge model — cardiovascular risk modulation, cognitive enhancement via nerve growth factor release, and neuroprotection in Alzheimer's disease modelspartially supported
In a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. pmid:15548587
Claim in summary — inconclusiveinconclusiveworking →
Modern research interest centers on antitussive efficacy — where theobromine outperformed codeine in a capsaicin cough challenge model — cardiovascular risk modulation, cognitive enhancement via nerve growth factor release, and neuroprotection in Alzheimer's disease modelssupported
Theobromine prevented LTP deficits and neuronal loss in Aβ1-42 exposed hippocampal preparations. ijms231810510
Claim in summary — inconclusiveinconclusiveworking →
Claim in summary — inconclusiveinconclusiveworking →
The subjective profile is correspondingly mild: at 700 mg oral, the only controlled study isolating theobromine's psychoactive effects found decreased self-reported calmness and peripheral blood pressure lowering with no measurable effect on alertness or psychomotor performancesupported
Theobromine alone decreased self-reported calmness 3h after ingestion and lowered blood pressure relative to placebo 1h after ingestion... No treatment effect on DSST performance. j.physbeh.2011.07.027
Claim in summary — inconclusiveinconclusiveworking →
neuroscience6 · 3 ok
Claim in neuroscience — inconclusiveinconclusiveworking →
Claim in neuroscience — inconclusiveinconclusiveworking →
In mouse hippocampal preparations, theobromine (30 µM) produced bidirectional effects on synaptic function: facilitation of basal synaptic transmission (A1R-mediated) and impairment of long-term potentiation (A2AR-mediated)supported
Theobromine (30 µM) facilitated synaptic transmission while decreasing LTP magnitude. A1R antagonist eliminated theobromine-dependent facilitation; A2AR antagonist abrogated LTP impairment. ijms231810510
Theobromine prevented LTP deficits and neuronal loss in hippocampal preparations exposed to amyloid-β₁₋₄₂ peptides, a model of Alzheimer's disease-related neurotoxicitysupported
Theobromine prevented LTP deficits and neuronal loss in Aβ1-42 exposed hippocampal preparations. ijms231810510
Claim in neuroscience — inconclusiveinconclusiveworking →
Can theobromine's neuroprotective effects in Alzheimer's models translate to human clinical benefit? The hippocampal protection observed at 30 µM in vitro requires confirmation in vivo at achievable plasma concentrations.supported
Theobromine prevented LTP deficits and neuronal loss in Aβ1-42 exposed hippocampal preparations. ijms231810510
history5 · 2 ok
Claim in history — inconclusiveinconclusiveworking →
The Zutphen Elderly Study demonstrated an inverse association between cocoa intake, blood pressure, and cardiovascular mortality in a 15-year prospective cohort, catalyzing investigation of cocoa's individual bioactive constituentssupported
470 elderly men followed 15 years. Highest tertile cocoa intake: 3.7 mmHg lower systolic BP, 50% lower cardiovascular mortality vs. lowest tertile. archinte.166.4.411
A landmark 2005 randomized controlled trial demonstrated that theobromine inhibits capsaicin-induced cough in humans through peripheral sensory nerve inhibition, outperforming codeine in the same modelpartially supported
In a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects... Actions of theobromine appear to be peripherally mediated. pmid:15548587
Claim in history — inconclusiveinconclusiveworking →
Claim in history — inconclusiveinconclusiveworking →
alkaloid-profile4 · 3 ok
Theobromine concentrations in chocolate products, measured by HPLC, range from 0.72–0.76 mg/g in milk chocolate couverture to 0.82–1.14 mg/g in dark chocolate couverturesupported
HPLC analysis: Dark chocolate 0.82-1.14 mg/g theobromine; milk chocolate 0.72-0.76 mg/g pmid:22692392
White chocolate contains approximately 0.74 mg/gsupported
white chocolate 0.74 mg/g pmid:22692392
These dietary exposures are well below the threshold at which isolated psychoactive effects have been demonstrated in controlled studies (~700 mg).supported
Effects of theobromine (700 mg)... Theobromine alone decreased self-reported calmness 3h after ingestion and lowered blood pressure relative to placebo. j.physbeh.2011.07.027
Claim in alkaloid-profile — inconclusiveinconclusiveworking →
receptor-pharmacology4 · 2 ok
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
At A1 receptors, functional potency is substantially higher — electrophysiological recordings demonstrate measurable A1R antagonism at 30 µM in hippocampal slice preparations — but precise Ki values remain uncharacterized.supported
Theobromine (30 µM) facilitated synaptic transmission... A1R antagonist eliminated theobromine-dependent facilitation. ijms231810510
At 30 µM, theobromine produces two distinct receptor-mediated effects:supported
Theobromine (30 µM) facilitated synaptic transmission while decreasing LTP magnitude. ijms231810510
Claim in receptor-pharmacology — inconclusiveinconclusiveworking →
botanical-overview3 · 2 ok
In processed chocolate products, theobromine content ranges from approximately 0.72–0.76 mg/g in milk chocolate to 0.82–1.14 mg/g in dark chocolate, exceeding caffeine content by a factor of 10–20×partially supported
HPLC analysis: Dark chocolate 0.82-1.14 mg/g theobromine; milk chocolate 0.72-0.76 mg/g; white chocolate 0.74 mg/g. Theobromine consistently higher than caffeine. pmid:22692392
White chocolate retains approximately 0.74 mg/g.supported
white chocolate 0.74 mg/g pmid:22692392
Claim in botanical-overview — inconclusiveinconclusiveworking →
comparative-pharmacology3 · 0 ok
pharmacokinetic-detail3 · 2 ok
Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →
The quantitative metabolite profile after a single oral dose of radiolabeled theobromine in humans:supported
Urinary metabolites: 42% 7-methylxanthine, 20% 3-methylxanthine, 18% theobromine, 10% 7-methyluric acid, 10% 6-amino-5[N-methylformylamino]-1-methyluracil. pmid:3979003
Cigarette smoking, a potent CYP1A2 inducer, increases theobromine plasma clearance by approximately 33%partially supported
Plasma clearance of theobromine is induced in cigarette smokers. CYP1A2 contributes partially to N7-demethylation (7-MX formation), variably 0-65%. pmid:10215755
chemistry1 · 0 ok
Claim in chemistry — inconclusiveinconclusiveworking →