Caffeine

evidence_span

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experimental_model

Concurrent caffeine interaction study

exposure

6 mg melatonin alone or with three 200 mg caffeine doses

limitations

Caffeine schedule and amount were study-specific. CYP1A2 inhibition was the proposed mechanism; higher melatonin exposure does not imply better sleep while using caffeine.

nutrient_topic

Melatonin research collection; topical membership is not evidence of a direct dietary effect. · Melatonin

organism

Twelve humans, six smokers and six nonsmokers

plain_language

One substance can promote wakefulness while increasing blood exposure to another substance.

primary_references

[melatonin-p14616429] Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. (2003). https://pubmed.ncbi.nlm.nih.gov/14616429/ DOI: 10.1046/j.1365-2125.2003.01933.x

tissue_or_cell_type

Oral melatonin pharmacokinetics

Melatonin: synthesis, receptors, circadian timing and nutrient interactions (2026-09-17) · lines 708–719

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Concurrent caffeine interaction study · source_derived_draft · unverified_draft

### melatonin-caffeine-exposure Concurrent caffeine raised melatonin peak concentration by 142% and AUC by 120% on average. Condition category: normal nutrient_topic: Melatonin research collection; topical membership is not evidence of a direct dietary effect. plain_language: One substance can promote wakefulness while increasing blood exposure to another substance. organism: Twelve humans, six smokers and six nonsmokers tissue_or_cell_type: Oral melatonin pharmacokinetics experimental_model: Concurrent caffeine interaction study limitations: Caffeine schedule and amount were study-specific. CYP1A2 inhibition was the proposed mechanism; higher melatonin exposure does not imply better sleep while using caffeine. exposure: 6 mg melatonin alone or with three 200 mg caffeine doses evidence_span: {"source_cache": "artifacts/melatonin-research/14616429.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6a8b06b9e1bcb570dca49735b73c2c7360a77381ae6fa25744bcccee7ceb52d8", "start_char": 0, "end_char": 1070, "text_sha256": "6a8b06b9e1bcb570dca49735b73c2c7360a77381ae6fa25744bcccee7ceb52d8"} [melatonin-p14616429] Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. (2003). https://pubmed.ncbi.nlm.nih.gov/14616429/ DOI: 10.1046/j.1365-2125.2003.01933.x

evidence_access

Primary abstract

experimental_model

Engineered human receptor construct; crystallographic comparison with XAC and ZM241385.

limitations

Engineered inactive-state structure, not a measurement of native receptor signaling in a person.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A receptor structure shows where caffeine binds.

primary_references

Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21885291/ · DOI 10.1016/j.str.2011.06.014

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 28–34

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Engineered human receptor construct; crystallographic comparison with XAC and ZM241385. · source_derived_draft · unverified_draft

## caf-a2a-structure A receptor structure shows where caffeine binds. Crystallography resolved caffeine in a thermostabilized A2A receptor with an inactive-state conformation. Model: Engineered human receptor construct; crystallographic comparison with XAC and ZM241385. Limitations: Engineered inactive-state structure, not a measurement of native receptor signaling in a person. Evidence access: Primary abstract Structure of the adenosine A(2A) receptor in complex with ZM241385 and the xanthines XAC and caffeine. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21885291/ · DOI 10.1016/j.str.2011.06.014

evidence_access

Primary abstract

experimental_model

Kinase assays and irradiated A549 tumor-cell experiments.

limitations

Pharmacological radiosensitization context; no claim that dietary caffeine inhibits human DNA repair or treats cancer.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine also has a laboratory DNA-damage-response target.

primary_references

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 412–418

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Kinase assays and irradiated A549 tumor-cell experiments. · source_derived_draft · unverified_draft

## caf-atm Caffeine also has a laboratory DNA-damage-response target. Caffeine inhibited the checkpoint kinase at concentrations associated with experimental radiosensitization. Model: Kinase assays and irradiated A549 tumor-cell experiments. Limitations: Pharmacological radiosensitization context; no claim that dietary caffeine inhibits human DNA repair or treats cancer. Evidence access: Primary abstract Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

evidence_access

Primary abstract

experimental_model

Kinase assays and irradiated A549 tumor-cell experiments.

limitations

Pharmacological radiosensitization context; no claim that dietary caffeine inhibits human DNA repair or treats cancer.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine also has a laboratory DNA-damage-response target.

primary_references

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 420–426

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Kinase assays and irradiated A549 tumor-cell experiments. · source_derived_draft · unverified_draft

## caf-atr Caffeine also has a laboratory DNA-damage-response target. Caffeine inhibited the checkpoint kinase at concentrations associated with experimental radiosensitization. Model: Kinase assays and irradiated A549 tumor-cell experiments. Limitations: Pharmacological radiosensitization context; no claim that dietary caffeine inhibits human DNA repair or treats cancer. Evidence access: Primary abstract Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

evidence_access

Primary abstract

experimental_model

17 adults; controlled diet; two 3 mg/kg lean-body-mass doses on day two of a before/after metabolic-ward trial.

limitations

Two-day urinary balance is not total body mineral balance or a long-term deficiency diagnosis.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Later compensation reduced, but did not erase, the measured daily loss.

primary_references

Effect of caffeine on circadian excretion of urinary calcium and magnesium. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7836625/ · DOI 10.1080/07315724.1994.10718436

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 340–346

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 17 adults; controlled diet; two 3 mg/kg lean-body-mass doses on day two of a before/after metabolic-ward trial. · source_derived_draft · unverified_draft

## caf-ca24 Later compensation reduced, but did not erase, the measured daily loss. Later nighttime conservation did not fully offset earlier loss; net 24-hour urinary excretion increased by 0.32 mmol. Model: 17 adults; controlled diet; two 3 mg/kg lean-body-mass doses on day two of a before/after metabolic-ward trial. Limitations: Two-day urinary balance is not total body mineral balance or a long-term deficiency diagnosis. Evidence access: Primary abstract Effect of caffeine on circadian excretion of urinary calcium and magnesium. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7836625/ · DOI 10.1080/07315724.1994.10718436

evidence_access

Primary abstract

experimental_model

Irradiated cultured A549 lung carcinoma cells.

limitations

These findings are not a demonstrated clinical caffeine–radiotherapy benefit.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The cancer-cell experiment measured altered checkpoint behavior.

primary_references

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 428–434

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Irradiated cultured A549 lung carcinoma cells. · source_derived_draft · unverified_draft

## caf-checkpoint The cancer-cell experiment measured altered checkpoint behavior. Caffeine-treated irradiated A549 cells failed G2 arrest and showed radioresistant DNA synthesis after S-phase irradiation. Model: Irradiated cultured A549 lung carcinoma cells. Limitations: These findings are not a demonstrated clinical caffeine–radiotherapy benefit. Evidence access: Primary abstract Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

evidence_access

Primary abstract

experimental_model

U2OS cAMP biosensor and pathway perturbations.

limitations

Does not exclude high-concentration PDE or calcium-channel effects in other systems.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The clock experiment identified a receptor-linked signaling route.

primary_references

Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 92–98

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · U2OS cAMP biosensor and pathway perturbations. · source_derived_draft · unverified_draft

## caf-clock-camp The clock experiment identified a receptor-linked signaling route. A cAMP biosensor detected increased cAMP; pharmacological and knockdown experiments supported adenosine-receptor signaling rather than RyR or PDE perturbation as sufficient to explain the clock effect. Model: U2OS cAMP biosensor and pathway perturbations. Limitations: Does not exclude high-concentration PDE or calcium-channel effects in other systems. Evidence access: Primary abstract Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

evidence_access

Primary abstract

experimental_model

Human osteosarcoma cells with clock-gene luciferase reporters.

limitations

Cell period is not identical to human sleep duration.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The effect also reached a cellular clock model.

primary_references

Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 84–90

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human osteosarcoma cells with clock-gene luciferase reporters. · source_derived_draft · unverified_draft

## caf-clock-cell The effect also reached a cellular clock model. Caffeine lengthened the circadian reporter period dose-dependently in U2OS cells. Model: Human osteosarcoma cells with clock-gene luciferase reporters. Limitations: Cell period is not identical to human sleep duration. Evidence access: Primary abstract Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

evidence_access

Primary abstract

experimental_model

Double-blind within-subject circadian experiment lasting about 49 days.

limitations

A study-specific phase shift, not a fixed effect in every person; endogenous timing differs from clearance of a melatonin supplement.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine shifted internal timing as well as wakefulness.

primary_references

Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 76–82

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Double-blind within-subject circadian experiment lasting about 49 days. · source_derived_draft · unverified_draft

## caf-clock-human Caffeine shifted internal timing as well as wakefulness. Caffeine three hours before habitual bedtime delayed the human melatonin rhythm by approximately 40 minutes. Model: Double-blind within-subject circadian experiment lasting about 49 days. Limitations: A study-specific phase shift, not a fixed effect in every person; endogenous timing differs from clearance of a melatonin supplement. Evidence access: Primary abstract Effects of caffeine on the human circadian clock in vivo and in vitro. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26378246/ · DOI 10.1126/scitranslmed.aac5125

evidence_access

Primary abstract

experimental_model

12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550.

limitations

Small healthy-volunteer study; patient effect size and toxicity cannot be inferred for an individual.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine changed exposure to a drug sharing its metabolic pathway.

primary_references

Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 268–274

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550. · source_derived_draft · unverified_draft

## caf-clozapine-auc Caffeine changed exposure to a drug sharing its metabolic pathway. Caffeine coadministration increased mean clozapine AUC by 19% in the crossover experiment. Model: 12 nonsmoking healthy men; single 12.5 mg clozapine; caffeine 400–1000 mg/day, mean 550. Limitations: Small healthy-volunteer study; patient effect size and toxicity cannot be inferred for an individual. Evidence access: Primary abstract Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

evidence_access

Primary abstract

experimental_model

Same randomized open-label crossover.

limitations

Not a medication-adjustment rule.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The pharmacokinetic pattern supported reduced drug metabolism.

primary_references

Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 276–282

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same randomized open-label crossover. · source_derived_draft · unverified_draft

## caf-clozapine-clear The pharmacokinetic pattern supported reduced drug metabolism. Mean clozapine oral clearance fell 14%; metabolite-to-parent ratios also fell during caffeine exposure. Model: Same randomized open-label crossover. Limitations: Not a medication-adjustment rule. Evidence access: Primary abstract Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10606838/ · DOI 10.1046/j.1365-2125.2000.00111.x

evidence_access

Primary abstract

experimental_model

Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing.

limitations

Small protocol-specific trial. Creatine accumulation and performance were separate endpoints.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The same stored-energy increase did not guarantee the same performance response.

primary_references

Caffeine counteracts the ergogenic action of muscle creatine loading. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8929583/ · DOI 10.1152/jappl.1996.80.2.452

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 452–458

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing. · source_derived_draft · unverified_draft

## caf-creatine-torque The same stored-energy increase did not guarantee the same performance response. Creatine increased dynamic torque by 10–23%, whereas the creatine-plus-caffeine regimen did not improve torque. Model: Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing. Limitations: Small protocol-specific trial. Creatine accumulation and performance were separate endpoints. Evidence access: Primary abstract Caffeine counteracts the ergogenic action of muscle creatine loading. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8929583/ · DOI 10.1152/jappl.1996.80.2.452

evidence_access

Primary abstract

experimental_model

Human raclopride PET, caffeine versus placebo.

limitations

Availability can reflect receptor levels or affinity. The direction did not support a simple increase in striatal dopamine release; receptor upregulation was an interpretation.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine changed a dopamine-receptor measurement in selected brain regions.

primary_references

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25871974/ · DOI 10.1038/tp.2015.46

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 68–74

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human raclopride PET, caffeine versus placebo. · source_derived_draft · unverified_draft

## caf-dopamine-pet Caffeine changed a dopamine-receptor measurement in selected brain regions. Caffeine 300 mg increased D2/D3 PET availability in putamen and ventral striatum, but not caudate, in 20 healthy participants. Model: Human raclopride PET, caffeine versus placebo. Limitations: Availability can reflect receptor levels or affinity. The direction did not support a simple increase in striatal dopamine release; receptor upregulation was an interpretation. Evidence access: Primary abstract Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25871974/ · DOI 10.1038/tp.2015.46

evidence_access

Primary abstract

experimental_model

Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test.

limitations

Small acute experiment. Beta blockade supports an adrenergic contribution, not proof that it is the only mechanism or that a blocker should be used to counter caffeine.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine changed an adrenergic hormone measurement.

primary_references

Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12015346/ · DOI 10.1152/japplphysiol.01229.2001

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 484–490

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test. · source_derived_draft · unverified_draft

## caf-epinephrine Caffeine changed an adrenergic hormone measurement. Caffeine increased plasma epinephrine with or without propranolol. Model: Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test. Limitations: Small acute experiment. Beta blockade supports an adrenergic contribution, not proof that it is the only mechanism or that a blocker should be used to counter caffeine. Evidence access: Primary abstract Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12015346/ · DOI 10.1152/japplphysiol.01229.2001

evidence_access

Primary abstract

experimental_model

Double-blind study, 12 caffeine and 12 placebo participants over six hours.

limitations

Proximal sodium-reabsorption inhibition was proposed from correlations, not directly measured; no osteoporosis outcome.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

High repeated exposure changed renal calcium clearance.

primary_references

The effect of high-dose, short-term caffeine intake on the renal clearance of calcium, sodium and creatinine in healthy adults. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852164/ · DOI 10.1111/bcp.14856

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 356–362

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Double-blind study, 12 caffeine and 12 placebo participants over six hours. · source_derived_draft · unverified_draft

## caf-high-calcium High repeated exposure changed renal calcium clearance. An 800 mg total caffeine gum regimen increased renal calcium clearance by 77%; changes correlated with sodium clearance and urine volume. Model: Double-blind study, 12 caffeine and 12 placebo participants over six hours. Limitations: Proximal sodium-reabsorption inhibition was proposed from correlations, not directly measured; no osteoporosis outcome. Evidence access: Primary abstract The effect of high-dose, short-term caffeine intake on the renal clearance of calcium, sodium and creatinine in healthy adults. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33852164/ · DOI 10.1111/bcp.14856

evidence_access

Primary abstract

experimental_model

15 adults; 0.5–4.3 mg/kg intravenous caffeine after at least 36 hours abstinence; one vehicle subject.

limitations

PET occupancy does not establish that A1 alone mediates wakefulness or a universal oral-dose threshold.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine reached and occupied adenosine receptors in the human brain.

primary_references

Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22966134/ · DOI 10.2967/jnumed.112.105114

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 20–26

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 15 adults; 0.5–4.3 mg/kg intravenous caffeine after at least 36 hours abstinence; one vehicle subject. · source_derived_draft · unverified_draft

## caf-human-a1 Caffeine reached and occupied adenosine receptors in the human brain. Caffeine displaced 5–44% of the A1 PET ligand signal; modeled half-maximal displacement corresponded to plasma caffeine of 67 micromolar. Model: 15 adults; 0.5–4.3 mg/kg intravenous caffeine after at least 36 hours abstinence; one vehicle subject. Limitations: PET occupancy does not establish that A1 alone mediates wakefulness or a universal oral-dose threshold. Evidence access: Primary abstract Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22966134/ · DOI 10.2967/jnumed.112.105114

evidence_access

Primary abstract

experimental_model

Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test.

limitations

Small acute experiment. Beta blockade supports an adrenergic contribution, not proof that it is the only mechanism or that a blocker should be used to counter caffeine.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

More insulin was measured without a corresponding glucose difference.

primary_references

Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12015346/ · DOI 10.1152/japplphysiol.01229.2001

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 492–498

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test. · source_derived_draft · unverified_draft

## caf-insulin More insulin was measured without a corresponding glucose difference. Insulin and C-peptide areas were 42% and 39% greater with caffeine, while blood glucose was similar among trials. Model: Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test. Limitations: Small acute experiment. Beta blockade supports an adrenergic contribution, not proof that it is the only mechanism or that a blocker should be used to counter caffeine. Evidence access: Primary abstract Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12015346/ · DOI 10.1152/japplphysiol.01229.2001

evidence_access

Primary abstract

experimental_model

Canine cerebellar channels in planar lipid bilayers.

limitations

Millimolar concentrations; opposite channel effects are distinct targets, not a scientific contradiction.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine can inhibit one calcium-release channel while activating another.

primary_references

Caffeine-induced inhibition of inositol(1,4,5)-trisphosphate-gated calcium channels from cerebellum. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8186468/ · DOI 10.1091/mbc.5.1.97

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 388–394

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Canine cerebellar channels in planar lipid bilayers. · source_derived_draft · unverified_draft

## caf-ip3 Caffeine can inhibit one calcium-release channel while activating another. Caffeine inhibited IP3-gated channels with half-inhibition at 1.64 mM; 5 mM reduced opening frequency more than threefold without changing conductance. Model: Canine cerebellar channels in planar lipid bilayers. Limitations: Millimolar concentrations; opposite channel effects are distinct targets, not a scientific contradiction. Evidence access: Primary abstract Caffeine-induced inhibition of inositol(1,4,5)-trisphosphate-gated calcium channels from cerebellum. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8186468/ · DOI 10.1091/mbc.5.1.97

evidence_access

Primary abstract

experimental_model

Same canine channel preparation.

limitations

No human brain outcome or dietary inositol rescue was demonstrated.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The functional block did not simply displace the measured ligand binding.

primary_references

Caffeine-induced inhibition of inositol(1,4,5)-trisphosphate-gated calcium channels from cerebellum. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8186468/ · DOI 10.1091/mbc.5.1.97

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 396–402

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same canine channel preparation. · source_derived_draft · unverified_draft

## caf-ip3-rescue The functional block did not simply displace the measured ligand binding. Increasing IP3 overcame inhibition, but caffeine did not reduce specific IP3 binding to the receptor. Model: Same canine channel preparation. Limitations: No human brain outcome or dietary inositol rescue was demonstrated. Evidence access: Primary abstract Caffeine-induced inhibition of inositol(1,4,5)-trisphosphate-gated calcium channels from cerebellum. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8186468/ · DOI 10.1091/mbc.5.1.97

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

CYP1A2 is the principal demethylating route; minor routes and individual clearance vary.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine produces a distinct metabolite that needs its own record.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-met-px Caffeine produces a distinct metabolite that needs its own record. Caffeine N3-demethylation produced the specified dimethylxanthine; fluvoxamine reduced its formation clearance. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: CYP1A2 is the principal demethylating route; minor routes and individual clearance vary. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

CYP1A2 is the principal demethylating route; minor routes and individual clearance vary.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine produces a distinct metabolite that needs its own record.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-met-tb Caffeine produces a distinct metabolite that needs its own record. Caffeine N1-demethylation produced the specified dimethylxanthine; fluvoxamine reduced its formation clearance. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: CYP1A2 is the principal demethylating route; minor routes and individual clearance vary. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

CYP1A2 is the principal demethylating route; minor routes and individual clearance vary.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine produces a distinct metabolite that needs its own record.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 188–194

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-met-tp Caffeine produces a distinct metabolite that needs its own record. Caffeine N7-demethylation produced the specified dimethylxanthine; fluvoxamine reduced its formation clearance. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: CYP1A2 is the principal demethylating route; minor routes and individual clearance vary. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

17 adults; controlled diet; two 3 mg/kg lean-body-mass doses on day two of a before/after metabolic-ward trial.

limitations

Two-day urinary balance is not total body mineral balance or a long-term deficiency diagnosis.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Later compensation reduced, but did not erase, the measured daily loss.

primary_references

Effect of caffeine on circadian excretion of urinary calcium and magnesium. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7836625/ · DOI 10.1080/07315724.1994.10718436

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 17 adults; controlled diet; two 3 mg/kg lean-body-mass doses on day two of a before/after metabolic-ward trial. · source_derived_draft · unverified_draft

## caf-mg24 Later compensation reduced, but did not erase, the measured daily loss. Later nighttime conservation did not fully offset earlier loss; net 24-hour urinary excretion increased by 0.16 mmol. Model: 17 adults; controlled diet; two 3 mg/kg lean-body-mass doses on day two of a before/after metabolic-ward trial. Limitations: Two-day urinary balance is not total body mineral balance or a long-term deficiency diagnosis. Evidence access: Primary abstract Effect of caffeine on circadian excretion of urinary calcium and magnesium. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7836625/ · DOI 10.1080/07315724.1994.10718436

evidence_access

Primary abstract

experimental_model

Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges.

limitations

Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The adapted cells responded more strongly to an adenosine agonist.

primary_references

Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. · source_derived_draft · unverified_draft

## caf-neutrophil-camp The adapted cells responded more strongly to an adenosine agonist. After caffeine exposure, NECA stimulation produced greater cAMP accumulation. Model: Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. Limitations: Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial. Evidence access: Primary abstract Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

evidence_access

Primary abstract

experimental_model

Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges.

limitations

Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Repeated exposure changed receptor abundance in immune cells.

primary_references

Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. · source_derived_draft · unverified_draft

## caf-neutrophil-density Repeated exposure changed receptor abundance in immune cells. Repeated caffeine exposure increased neutrophil A2A receptor binding density. Model: Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. Limitations: Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial. Evidence access: Primary abstract Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

evidence_access

Primary abstract

experimental_model

Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges.

limitations

Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The immune-cell response was reversible and depended on the agonist challenge.

primary_references

Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. · source_derived_draft · unverified_draft

## caf-neutrophil-superoxide The immune-cell response was reversible and depended on the agonist challenge. NECA-stimulated adapted neutrophils showed lower superoxide production; binding and functional changes returned to baseline after 48 hours withdrawal. Model: Human neutrophils after 400 or 600 mg/day for one week, or 400 mg/day for two weeks; ex-vivo binding and NECA challenges. Limitations: Adapted cells were challenged with an agonist; this is not the same as an immediate effect of caffeine, nor a clinical anti-inflammatory trial. Evidence access: Primary abstract Caffeine intake induces an alteration in human neutrophil A2A adenosine receptors. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16143823/ · DOI 10.1007/s00018-005-5312-z

evidence_access

Primary abstract

experimental_model

A1, A2A and double-knockout mouse comparison.

limitations

Not evidence of durable weight loss in humans.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Receptor status changed the animal metabolic response.

primary_references

Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19218506/ · DOI 10.1152/ajpheart.00754.2008

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · A1, A2A and double-knockout mouse comparison. · source_derived_draft · unverified_draft

## caf-oxygen Receptor status changed the animal metabolic response. Caffeine ingestion increased oxygen consumption in wild-type mice, with smaller responses in receptor-knockout groups. Model: A1, A2A and double-knockout mouse comparison. Limitations: Not evidence of durable weight loss in humans. Evidence access: Primary abstract Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19218506/ · DOI 10.1152/ajpheart.00754.2008

evidence_access

Primary abstract

experimental_model

Kinase and radiation-response assays.

limitations

Do not infer identical activity against all DNA-damage kinases.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The response was selective across the tested kinase pathways.

primary_references

Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Kinase and radiation-response assays. · source_derived_draft · unverified_draft

## caf-p53 The response was selective across the tested kinase pathways. Caffeine reduced radiation-induced p53 Ser15 phosphorylation; DNA-PK was resistant and Chk1 only marginally inhibited in the comparison. Model: Kinase and radiation-response assays. Limitations: Do not infer identical activity against all DNA-damage kinases. Evidence access: Primary abstract Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. · 1999 · https://pubmed.ncbi.nlm.nih.gov/10485486/

evidence_access

Full-text methods 2.14 and results 3.2, Figure 3B; Europe PMC PMC5750604

experimental_model

LXFL529L cytosolic preparation, predominantly PDE4; radioactive cAMP assay.

limitations

Mixed preparation, not a pure PDE isoform or evidence of equivalent inhibition after a normal beverage.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A high-concentration enzyme effect is separate from receptor antagonism.

primary_references

Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29113064/ · DOI 10.3390/medicines4040080

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · LXFL529L cytosolic preparation, predominantly PDE4; radioactive cAMP assay. · source_derived_draft · unverified_draft

## caf-pde A high-concentration enzyme effect is separate from receptor antagonism. Caffeine inhibited measured cAMP-PDE activity by up to about 40% at 250–500 micrograms/mL in the reported assay. Model: LXFL529L cytosolic preparation, predominantly PDE4; radioactive cAMP assay. Limitations: Mixed preparation, not a pure PDE isoform or evidence of equivalent inhibition after a normal beverage. Evidence access: Full-text methods 2.14 and results 3.2, Figure 3B; Europe PMC PMC5750604 Inhibition of Cyclic Adenosine Monophosphate-Specific Phosphodiesterase by Various Food Plant-Derived Phytotherapeutic Agents. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29113064/ · DOI 10.3390/medicines4040080

evidence_access

Primary abstract

experimental_model

12 active men; creatine 0.3 g/kg/day followed by caffeine 6 mg/kg; six 10-second sprints.

limitations

Different sequence, task and outcomes from repeated coadministration; not evidence of synergy across all sprints or users.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A different sequence produced better performance in selected sprints.

primary_references

Effect of caffeine ingestion after creatine supplementation on intermittent high-intensity sprint performance. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21207054/ · DOI 10.1007/s00421-010-1792-0

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 12 active men; creatine 0.3 g/kg/day followed by caffeine 6 mg/kg; six 10-second sprints. · source_derived_draft · unverified_draft

## caf-postload-caffeine A different sequence produced better performance in selected sprints. A single caffeine dose after five days of creatine loading increased mean and peak cycling power over creatine-plus-placebo during sprints 1 and 2. Model: 12 active men; creatine 0.3 g/kg/day followed by caffeine 6 mg/kg; six 10-second sprints. Limitations: Different sequence, task and outcomes from repeated coadministration; not evidence of synergy across all sprints or users. Evidence access: Primary abstract Effect of caffeine ingestion after creatine supplementation on intermittent high-intensity sprint performance. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21207054/ · DOI 10.1007/s00421-010-1792-0

evidence_access

Primary abstract

experimental_model

Women sampled once during a trimester, within one hour of a beverage containing 30–95 mg caffeine.

limitations

Sparse, between-person sampling; not full individual clearance curves or evidence establishing fetal safety.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Pregnancy changed caffeine and metabolite exposure.

primary_references

Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26358647/ · DOI 10.1002/jcph.632

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Women sampled once during a trimester, within one hour of a beverage containing 30–95 mg caffeine. · source_derived_draft · unverified_draft

## caf-pregnancy Pregnancy changed caffeine and metabolite exposure. Dose-normalized serum caffeine rose between first and third trimester in a 59-woman study; theophylline concentrations also rose. Model: Women sampled once during a trimester, within one hour of a beverage containing 30–95 mg caffeine. Limitations: Sparse, between-person sampling; not full individual clearance curves or evidence establishing fetal safety. Evidence access: Primary abstract Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26358647/ · DOI 10.1002/jcph.632

evidence_access

Primary abstract

experimental_model

Same ten-man muscle-stimulation experiment.

limitations

Relaxation is a candidate explanation for performance differences, not proof of a universal creatine interaction.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Repeated and single-dose caffeine did not have the same measured effect.

primary_references

Opposite actions of caffeine and creatine on muscle relaxation time in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11796658/ · DOI 10.1152/japplphysiol.00255.2001

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Same ten-man muscle-stimulation experiment. · source_derived_draft · unverified_draft

## caf-relax-caffeine Repeated and single-dose caffeine did not have the same measured effect. Three days of caffeine 5 mg/kg/day prolonged relaxation time by about 10%; acute caffeine and the creatine/caffeine combination did not significantly change it. Model: Same ten-man muscle-stimulation experiment. Limitations: Relaxation is a candidate explanation for performance differences, not proof of a universal creatine interaction. Evidence access: Primary abstract Opposite actions of caffeine and creatine on muscle relaxation time in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11796658/ · DOI 10.1152/japplphysiol.00255.2001

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The kidneys retained a smaller fraction of the filtered mineral.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-renal-ca The kidneys retained a smaller fraction of the filtered mineral. Calcium reabsorption fell from 98.6% to 97.5%, with no significant change in filtered calcium load. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The kidneys retained a smaller fraction of the filtered mineral.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-renal-mg The kidneys retained a smaller fraction of the filtered mineral. Magnesium reabsorption fell from 97.0% to 94.2%, with no significant change in filtered magnesium load. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_access

Primary abstract

experimental_model

Rabbit skeletal-muscle sarcoplasmic-reticulum vesicles; structure–activity comparison.

limitations

Millimolar preparation effects must not be presented as the mechanism of every ordinary caffeinated drink.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

At high experimental concentrations caffeine affects calcium-release machinery.

primary_references

Structure-activity relationship of xanthines and skeletal muscle ryanodine receptor/Ca2+ release channel. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9127436/ · DOI 10.1159/000139480

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Rabbit skeletal-muscle sarcoplasmic-reticulum vesicles; structure–activity comparison. · source_derived_draft · unverified_draft

## caf-ryr At high experimental concentrations caffeine affects calcium-release machinery. Millimolar caffeine activated the skeletal-muscle ryanodine-receptor system; xanthine substitution altered ryanodine binding. Model: Rabbit skeletal-muscle sarcoplasmic-reticulum vesicles; structure–activity comparison. Limitations: Millimolar preparation effects must not be presented as the mechanism of every ordinary caffeinated drink. Evidence access: Primary abstract Structure-activity relationship of xanthines and skeletal muscle ryanodine receptor/Ca2+ release channel. · 1997 · https://pubmed.ncbi.nlm.nih.gov/9127436/ · DOI 10.1159/000139480

evidence_access

Primary abstract

experimental_model

Home crossover study with subjective reports and a portable sleep monitor.

limitations

This experiment does not define an individualized cutoff for every dose or metabolism rate.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine disrupted sleep even when taken well before bedtime.

primary_references

Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24235903/ · DOI 10.5664/jcsm.3170

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Home crossover study with subjective reports and a portable sleep monitor. · source_derived_draft · unverified_draft

## caf-sleep Caffeine disrupted sleep even when taken well before bedtime. A fixed 400 mg dose at bedtime, three hours before, or six hours before increased sleep disturbance relative to placebo. Model: Home crossover study with subjective reports and a portable sleep monitor. Limitations: This experiment does not define an individualized cutoff for every dose or metabolism rate. Evidence access: Primary abstract Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. · 2013 · https://pubmed.ncbi.nlm.nih.gov/24235903/ · DOI 10.5664/jcsm.3170

evidence_access

Primary abstract

experimental_model

Mouse high-dose injection experiment.

limitations

The additional molecular target was not identified.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A higher dose produced effects that the two main receptors did not explain.

primary_references

Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19218506/ · DOI 10.1152/ajpheart.00754.2008

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 60–66

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mouse high-dose injection experiment. · source_derived_draft · unverified_draft

## caf-temperature A higher dose produced effects that the two main receptors did not explain. Injected caffeine at 30 mg/kg lowered body temperature, especially in receptor-knockout mice, suggesting an effect beyond A1/A2A blockade. Model: Mouse high-dose injection experiment. Limitations: The additional molecular target was not identified. Evidence access: Primary abstract Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19218506/ · DOI 10.1152/ajpheart.00754.2008

evidence_access

Primary abstract

experimental_model

16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges.

limitations

No universal claim that caffeine never benefits performance; these results concern the selected outcomes and schedule.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Feeling tolerant did not mean every measured response had disappeared.

primary_references

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. · source_derived_draft · unverified_draft

## caf-tolerance Feeling tolerant did not mean every measured response had disappeared. Tolerance occurred on subjective measures but not the measured physiological endpoints; chronic effects remained mainly on EEG beta-2 power. Model: 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. Limitations: No universal claim that caffeine never benefits performance; these results concern the selected outcomes and schedule. Evidence access: Primary abstract Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The acute urine measurement increased.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-urine-ca The acute urine measurement increased. Urinary calcium/creatinine rose from 120 to 200 mg/g. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The acute urine measurement increased.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 324–330

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-urine-cl The acute urine measurement increased. Urinary chloride/creatinine rose from 9200 to 14800 mg/g. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

The abstract did not report a significant potassium/creatinine ratio change; total output must not be confused with selective potassium wasting.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Potassium output also changed in the short collection.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 332–338

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-urine-k Potassium output also changed in the short collection. Total potassium output increased over the two-hour post-caffeine collection. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: The abstract did not report a significant potassium/creatinine ratio change; total output must not be confused with selective potassium wasting. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The acute urine measurement increased.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 308–314

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-urine-mg The acute urine measurement increased. Urinary magnesium/creatinine rose from 70 to 110 mg/g. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_access

Primary abstract

experimental_model

37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection.

limitations

Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The acute urine measurement increased.

primary_references

Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 316–322

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. · source_derived_draft · unverified_draft

## caf-urine-na The acute urine measurement increased. Urinary sodium/creatinine rose from 3800 to 6200 mg/g. Model: 37 women, age 31–78; decaffeinated beverage with or without caffeine 6 mg/kg lean body mass; two-hour urine collection. Limitations: Acute renal handling. The exact tubular mechanism was unresolved; no long-term deficiency, bone loss or replacement requirement measured. Evidence access: Primary abstract Effects of dietary caffeine on renal handling of minerals in adult women. · 1990 · https://pubmed.ncbi.nlm.nih.gov/2402180/ · DOI 10.1016/0024-3205(90)90616-y

evidence_span

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experimental_model

Repeated caffeine phenotyping after smoking cessation

exposure

Abrupt cessation after run-in; repeated 148-mg caffeine probe doses

limitations

Smoking-cessation kinetics cannot be assigned to starting or stopping DIM. Clinical dose management requires drug-specific monitoring.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

12 heavy smokers

plain_language

Caffeine provides a measurable probe of enzyme activity.

primary_references

[dim-p15289794] Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. (2004). https://pubmed.ncbi.nlm.nih.gov/15289794/ DOI: 10.1016/j.clpt.2004.04.003

tissue_or_cell_type

CYP1A2 activity and caffeine clearance

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 831–842

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Repeated caffeine phenotyping after smoking cessation · source_derived_draft · unverified_draft

### dim-caffeine-1a2 The paraxanthine-to-caffeine ratio was used to phenotype CYP1A2 during smoking cessation. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Caffeine provides a measurable probe of enzyme activity. organism: 12 heavy smokers tissue_or_cell_type: CYP1A2 activity and caffeine clearance experimental_model: Repeated caffeine phenotyping after smoking cessation limitations: Smoking-cessation kinetics cannot be assigned to starting or stopping DIM. Clinical dose management requires drug-specific monitoring. exposure: Abrupt cessation after run-in; repeated 148-mg caffeine probe doses evidence_span: {"source_cache": "artifacts/dim-research/15289794.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2", "start_char": 0, "end_char": 1753, "text_sha256": "90eb96e72afdbbb53c322c2be9a34e5aa523c27f2fd0995a8eb224e2ec6e35e2"} [dim-p15289794] Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. (2004). https://pubmed.ncbi.nlm.nih.gov/15289794/ DOI: 10.1016/j.clpt.2004.04.003

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/36501092.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b", "start_char": 0, "end_char": 1425, "text_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b"}

experimental_model

Randomized crossover beverage intervention in 11 men

exposure

Three weeks: 620 mg green tea catechins plus 373 mg CGAs plus 119 mg caffeine; control 119 mg caffeine

limitations

A multi-ingredient formulation with a small sample. Effects cannot be assigned to CGA alone or treated as a contradiction of an acute isolated-CGA experiment.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human

plain_language

Different incretins responded in different directions.

primary_references

[chlorogenic_acid-p36501092] Effects of Ingesting Both Catechins and Chlorogenic Acids on Glucose, Incretin, and Insulin Sensitivity in Healthy Men: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial. (2022). https://pubmed.ncbi.nlm.nih.gov/36501092/ DOI: 10.3390/nu14235063

tissue_or_cell_type

Postprandial glucose, insulin and incretin measurements

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 1075–1086

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover beverage intervention in 11 men · source_derived_draft · unverified_draft

### chlorogenic_acid-mixture-gip The combined beverage reduced postprandial GIP. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different incretins responded in different directions. organism: Human tissue_or_cell_type: Postprandial glucose, insulin and incretin measurements experimental_model: Randomized crossover beverage intervention in 11 men limitations: A multi-ingredient formulation with a small sample. Effects cannot be assigned to CGA alone or treated as a contradiction of an acute isolated-CGA experiment. exposure: Three weeks: 620 mg green tea catechins plus 373 mg CGAs plus 119 mg caffeine; control 119 mg caffeine evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/36501092.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b", "start_char": 0, "end_char": 1425, "text_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b"} [chlorogenic_acid-p36501092] Effects of Ingesting Both Catechins and Chlorogenic Acids on Glucose, Incretin, and Insulin Sensitivity in Healthy Men: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial. (2022). https://pubmed.ncbi.nlm.nih.gov/36501092/ DOI: 10.3390/nu14235063

evidence_span

{"source_cache": "artifacts/chlorogenic_acid-research/36501092.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b", "start_char": 0, "end_char": 1425, "text_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b"}

experimental_model

Randomized crossover beverage intervention in 11 men

exposure

Three weeks: 620 mg green tea catechins plus 373 mg CGAs plus 119 mg caffeine; control 119 mg caffeine

limitations

A multi-ingredient formulation with a small sample. Effects cannot be assigned to CGA alone or treated as a contradiction of an acute isolated-CGA experiment.

nutrient_topic

Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid

organism

Human

plain_language

The complete tested combination is the exposure.

primary_references

[chlorogenic_acid-p36501092] Effects of Ingesting Both Catechins and Chlorogenic Acids on Glucose, Incretin, and Insulin Sensitivity in Healthy Men: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial. (2022). https://pubmed.ncbi.nlm.nih.gov/36501092/ DOI: 10.3390/nu14235063

tissue_or_cell_type

Postprandial glucose, insulin and incretin measurements

Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 1062–1073

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized crossover beverage intervention in 11 men · source_derived_draft · unverified_draft

### chlorogenic_acid-mixture-glp1 The combined beverage increased postprandial GLP-1 relative to its caffeine control. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The complete tested combination is the exposure. organism: Human tissue_or_cell_type: Postprandial glucose, insulin and incretin measurements experimental_model: Randomized crossover beverage intervention in 11 men limitations: A multi-ingredient formulation with a small sample. Effects cannot be assigned to CGA alone or treated as a contradiction of an acute isolated-CGA experiment. exposure: Three weeks: 620 mg green tea catechins plus 373 mg CGAs plus 119 mg caffeine; control 119 mg caffeine evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/36501092.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b", "start_char": 0, "end_char": 1425, "text_sha256": "dcd5f0afb16bd6f9c61c91be9220e18751e0e34c8eac1aeeb5613649ed2d001b"} [chlorogenic_acid-p36501092] Effects of Ingesting Both Catechins and Chlorogenic Acids on Glucose, Incretin, and Insulin Sensitivity in Healthy Men: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial. (2022). https://pubmed.ncbi.nlm.nih.gov/36501092/ DOI: 10.3390/nu14235063

evidence_span

{"source_cache": "artifacts/dim-research/7893591.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545", "start_char": 0, "end_char": 849, "text_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545"}

experimental_model

Clinical caffeine phenotyping and prior clozapine exposure

exposure

Caffeine test related to single-dose clozapine kinetics

limitations

Correlation supports enzyme relevance; no DIM administration or prediction of an individual clinical effect.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

14 healthy adults

plain_language

Enzyme activity was linked to drug handling in people, separately from any DIM exposure.

primary_references

[dim-p7893591] Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. (1994). https://pubmed.ncbi.nlm.nih.gov/7893591/ DOI: 10.1111/j.1365-2125.1994.tb04385.x

tissue_or_cell_type

CYP1A2 phenotype and clozapine disposition

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 688–699

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical caffeine phenotyping and prior clozapine exposure · source_derived_draft · unverified_draft

### dim-clozapine-phenotype Caffeine-derived CYP1A2 indices correlated with clozapine clearance in the 14-person study. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Enzyme activity was linked to drug handling in people, separately from any DIM exposure. organism: 14 healthy adults tissue_or_cell_type: CYP1A2 phenotype and clozapine disposition experimental_model: Clinical caffeine phenotyping and prior clozapine exposure limitations: Correlation supports enzyme relevance; no DIM administration or prediction of an individual clinical effect. exposure: Caffeine test related to single-dose clozapine kinetics evidence_span: {"source_cache": "artifacts/dim-research/7893591.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545", "start_char": 0, "end_char": 849, "text_sha256": "d568c4f2cdf1fc2d58f2ea22e395a7d7813cef2b1433fe25da51a2c40df5c545"} [dim-p7893591] Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. (1994). https://pubmed.ncbi.nlm.nih.gov/7893591/ DOI: 10.1111/j.1365-2125.1994.tb04385.x

evidence_span

{"source_cache": "artifacts/dim-research/16103443.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4", "start_char": 0, "end_char": 1706, "text_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4"}

experimental_model

Phase I placebo run-in and dose escalation

exposure

I3C 400 mg/day then 800 mg/day for four weeks each

limitations

The administered compound was I3C, not DIM. Multiple acid-condensation products and nonrandomized sequential periods prevent assigning the observed fold change specifically to DIM.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

17 women at elevated breast-cancer risk

plain_language

There is human evidence for the precursor, but it must not be silently relabeled as a DIM trial.

primary_references

[dim-p16103443] A phase I study of indole-3-carbinol in women: tolerability and effects. (2005). https://pubmed.ncbi.nlm.nih.gov/16103443/ DOI: 10.1158/1055-9965.epi-05-0121

tissue_or_cell_type

Caffeine CYP1A2 phenotype and estrogen metabolites

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 1026–1037

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phase I placebo run-in and dose escalation · source_derived_draft · unverified_draft

### dim-i3c-human-1a2 I3C increased caffeine-probed CYP1A2 activity in 94% of participants in the phase I study. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: There is human evidence for the precursor, but it must not be silently relabeled as a DIM trial. organism: 17 women at elevated breast-cancer risk tissue_or_cell_type: Caffeine CYP1A2 phenotype and estrogen metabolites experimental_model: Phase I placebo run-in and dose escalation limitations: The administered compound was I3C, not DIM. Multiple acid-condensation products and nonrandomized sequential periods prevent assigning the observed fold change specifically to DIM. exposure: I3C 400 mg/day then 800 mg/day for four weeks each evidence_span: {"source_cache": "artifacts/dim-research/16103443.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4", "start_char": 0, "end_char": 1706, "text_sha256": "ece0ac1a0c31053cdc1ec3eefbf9c78887018e0eddf2db36c3a1a07c998e15c4"} [dim-p16103443] A phase I study of indole-3-carbinol in women: tolerability and effects. (2005). https://pubmed.ncbi.nlm.nih.gov/16103443/ DOI: 10.1158/1055-9965.epi-05-0121

dose

Seven days of simple, enteric-coated or placebo preparation

duration

7 days

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Nineteen overweight or obese men in a randomized three-way crossover trial

limitations

This is a mixture and formulation result, not an isolated-capsaicin estimate; the simple-versus-enteric comparison was P=0.09.

nutrient_topic

Capsaicin chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Capsaicin

organism

Nineteen overweight or obese men in a randomized three-way crossover trial

plain_language

A non-enteric capsaicin/green-tea/caffeine/tyrosine/calcium mixture increased 24-hour energy expenditure by 160 kJ/day versus placebo; the enteric version did not.

primary_references

Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation. (2005). https://pubmed.ncbi.nlm.nih.gov/15870822/ DOI: 10.1038/sj.ejcn.1602121

route

Oral multi-ingredient supplement

tissue

Respiration-chamber energy expenditure

Capsaicin: mechanism of action and interactions (2026-09-20) · lines 132–141

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Nineteen overweight or obese men in a randomized three-way crossover trial · source_derived_draft · unverified_draft

## capsaicin-multi-ingredient-energy A non-enteric capsaicin/green-tea/caffeine/tyrosine/calcium mixture increased 24-hour energy expenditure by 160 kJ/day versus placebo; the enteric version did not. Model/species: Nineteen overweight or obese men in a randomized three-way crossover trial Tissue/system: Respiration-chamber energy expenditure Exposure: Seven days of simple, enteric-coated or placebo preparation Route: Oral multi-ingredient supplement Duration: 7 days Limits: This is a mixture and formulation result, not an isolated-capsaicin estimate; the simple-versus-enteric comparison was P=0.09. Primary reference: Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation. (2005). https://pubmed.ncbi.nlm.nih.gov/15870822/ DOI: 10.1038/sj.ejcn.1602121 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_access

Primary full text

experimental_model

42 initiated; enzyme activities assessed in 40; before/after pharmacological-dose study.

limitations

Probe indices are not proof of transcriptional induction or a quantified interaction with every substrate; no medication adjustment follows.

nutrient_topic

Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Resveratrol

plain_language

A human drug-metabolism interaction was measured with a specific probe.

primary_references

Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20716633/ · DOI 10.1158/1940-6207.CAPR-09-0155

Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19) · lines 414–420

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 42 initiated; enzyme activities assessed in 40; before/after pharmacological-dose study. · source_derived_draft · unverified_draft

## resveratrol-human-cyp1a2 A human drug-metabolism interaction was measured with a specific probe. After 1 g/day resveratrol for four weeks, the healthy-volunteer study found increased CYP1A2 phenotypic activity using caffeine as the probe. Model: 42 initiated; enzyme activities assessed in 40; before/after pharmacological-dose study. Limitations: Probe indices are not proof of transcriptional induction or a quantified interaction with every substrate; no medication adjustment follows. Evidence access: Primary full text Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20716633/ · DOI 10.1158/1940-6207.CAPR-09-0155

evidence_span

{"source_cache": "artifacts/berberine-research/21870106.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5", "start_char": 0, "end_char": 1817, "text_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5"}

experimental_model

Two-phase randomized crossover enzyme-phenotyping study

exposure

Berberine 300 mg three times daily for 14 days versus placebo

limitations

Small short-term study. Probe metabolic ratios are not percentage inhibition of every substrate. No universal dose-adjustment rule; no statistically significant effect is not equivalence.

nutrient_topic

Berberine research collection; topical membership is not evidence of a direct dietary effect. · Berberine

organism

Healthy human male volunteers; 17 completed

plain_language

This study did not show a CYP1A2 effect matching the effects on three other enzymes.

primary_references

[berberine-p21870106] Repeated administration of berberine inhibits cytochromes P450 in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/21870106/ DOI: 10.1007/s00228-011-1108-2

tissue_or_cell_type

Oral probe pharmacokinetics and urinary metabolite ratios

Berberine: metabolism, nutrient connections and drug interactions (2026-09-17) · lines 675–686

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two-phase randomized crossover enzyme-phenotyping study · source_derived_draft · unverified_draft

### berberine-human-cyp-1a2-null No statistically significant change in caffeine probe pharmacokinetics was found after berberine. Condition category: normal nutrient_topic: Berberine research collection; topical membership is not evidence of a direct dietary effect. plain_language: This study did not show a CYP1A2 effect matching the effects on three other enzymes. organism: Healthy human male volunteers; 17 completed tissue_or_cell_type: Oral probe pharmacokinetics and urinary metabolite ratios experimental_model: Two-phase randomized crossover enzyme-phenotyping study limitations: Small short-term study. Probe metabolic ratios are not percentage inhibition of every substrate. No universal dose-adjustment rule; no statistically significant effect is not equivalence. exposure: Berberine 300 mg three times daily for 14 days versus placebo evidence_span: {"source_cache": "artifacts/berberine-research/21870106.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5", "start_char": 0, "end_char": 1817, "text_sha256": "12e465c3c0a8ce995697a6fb9bf77c079e38b413e82c8b4f2a82e45a3dbf8ae5"} [berberine-p21870106] Repeated administration of berberine inhibits cytochromes P450 in humans. (2012). https://pubmed.ncbi.nlm.nih.gov/21870106/ DOI: 10.1007/s00228-011-1108-2

evidence_span

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experimental_model

Randomized double-blind caffeine interaction experiment

exposure

250 mg caffeine with or without 200 mg theanine

limitations

Acute caffeine exposure; no basis for treating chronic hypertension or assuming caffeine adverse effects are all prevented.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

48 healthy humans

plain_language

The blood-pressure result cannot be generalized to every subjective effect.

primary_references

[theanine-p17891480] Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. (2008). https://pubmed.ncbi.nlm.nih.gov/17891480/ DOI: 10.1007/s00213-007-0938-1

tissue_or_cell_type

Blood pressure, mood and visual attention

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 1017–1028

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind caffeine interaction experiment · source_derived_draft · unverified_draft

### theanine-caffeine-jitteriness-null Theanine did not significantly reduce caffeine-associated jitteriness in the same experiment. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The blood-pressure result cannot be generalized to every subjective effect. organism: 48 healthy humans tissue_or_cell_type: Blood pressure, mood and visual attention experimental_model: Randomized double-blind caffeine interaction experiment limitations: Acute caffeine exposure; no basis for treating chronic hypertension or assuming caffeine adverse effects are all prevented. exposure: 250 mg caffeine with or without 200 mg theanine evidence_span: {"source_cache": "artifacts/theanine-research/17891480.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd12cbd6fb30feee591192380733184f9928be3c146e39a4debc121a05b8815", "start_char": 0, "end_char": 1581, "text_sha256": "dcd12cbd6fb30feee591192380733184f9928be3c146e39a4debc121a05b8815"} [theanine-p17891480] Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. (2008). https://pubmed.ncbi.nlm.nih.gov/17891480/ DOI: 10.1007/s00213-007-0938-1

evidence_span

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experimental_model

Five-way crossover visual discrimination experiment

exposure

200 mg theanine, 160 mg caffeine, combination, tea and placebo

limitations

Small acute study. Larger combination effects were interpreted as additive; statistical interaction was not significant.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

20 healthy men

plain_language

A stronger combined response does not by itself prove synergy.

primary_references

[theanine-p26869148] Acute effects of theanine, caffeine and theanine-caffeine combination on attention. (2017). https://pubmed.ncbi.nlm.nih.gov/26869148/ DOI: 10.1080/1028415x.2016.1144845

tissue_or_cell_type

Reaction time and event-related potentials

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 978–989

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five-way crossover visual discrimination experiment · source_derived_draft · unverified_draft

### theanine-caffeine-n2-p300 The combination produced greater N2-P300 amplitude than either single ingredient in the experiment. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A stronger combined response does not by itself prove synergy. organism: 20 healthy men tissue_or_cell_type: Reaction time and event-related potentials experimental_model: Five-way crossover visual discrimination experiment limitations: Small acute study. Larger combination effects were interpreted as additive; statistical interaction was not significant. exposure: 200 mg theanine, 160 mg caffeine, combination, tea and placebo evidence_span: {"source_cache": "artifacts/theanine-research/26869148.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9e57a4cbb05f109037735324857cc3fc4ac55dd8cb76f50979e820a1da52bd60", "start_char": 0, "end_char": 1813, "text_sha256": "9e57a4cbb05f109037735324857cc3fc4ac55dd8cb76f50979e820a1da52bd60"} [theanine-p26869148] Acute effects of theanine, caffeine and theanine-caffeine combination on attention. (2017). https://pubmed.ncbi.nlm.nih.gov/26869148/ DOI: 10.1080/1028415x.2016.1144845

evidence_span

{"source_cache": "artifacts/theanine-research/17891480.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd12cbd6fb30feee591192380733184f9928be3c146e39a4debc121a05b8815", "start_char": 0, "end_char": 1581, "text_sha256": "dcd12cbd6fb30feee591192380733184f9928be3c146e39a4debc121a05b8815"}

experimental_model

Randomized double-blind caffeine interaction experiment

exposure

250 mg caffeine with or without 200 mg theanine

limitations

Acute caffeine exposure; no basis for treating chronic hypertension or assuming caffeine adverse effects are all prevented.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

48 healthy humans

plain_language

One caffeine response was reduced; that does not make caffeine physiologically inactive.

primary_references

[theanine-p17891480] Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. (2008). https://pubmed.ncbi.nlm.nih.gov/17891480/ DOI: 10.1007/s00213-007-0938-1

tissue_or_cell_type

Blood pressure, mood and visual attention

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 1004–1015

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind caffeine interaction experiment · source_derived_draft · unverified_draft

### theanine-caffeine-pressure Theanine attenuated the caffeine-associated blood-pressure response in the experiment. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: One caffeine response was reduced; that does not make caffeine physiologically inactive. organism: 48 healthy humans tissue_or_cell_type: Blood pressure, mood and visual attention experimental_model: Randomized double-blind caffeine interaction experiment limitations: Acute caffeine exposure; no basis for treating chronic hypertension or assuming caffeine adverse effects are all prevented. exposure: 250 mg caffeine with or without 200 mg theanine evidence_span: {"source_cache": "artifacts/theanine-research/17891480.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dcd12cbd6fb30feee591192380733184f9928be3c146e39a4debc121a05b8815", "start_char": 0, "end_char": 1581, "text_sha256": "dcd12cbd6fb30feee591192380733184f9928be3c146e39a4debc121a05b8815"} [theanine-p17891480] Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. (2008). https://pubmed.ncbi.nlm.nih.gov/17891480/ DOI: 10.1007/s00213-007-0938-1

evidence_span

{"source_cache": "artifacts/theanine-research/18006208.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "387d341f5aec1fb42bed06021ceb14cc8b49bfdf0f5502284a98806ca732cbdf", "start_char": 0, "end_char": 1386, "text_sha256": "387d341f5aec1fb42bed06021ceb14cc8b49bfdf0f5502284a98806ca732cbdf"}

experimental_model

Randomized double-blind balanced crossover experiment

exposure

250 mg theanine, 150 mg caffeine, combination and placebo

limitations

Acute effects depend on task and treatment. Benefits of the mixture do not establish synergy for all outcomes or neutralization of caffeine.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Healthy adults

plain_language

A specific test result is more precise than a claim of globally improved intelligence.

primary_references

[theanine-p18006208] The effects of L-theanine, caffeine and their combination on cognition and mood. (2008). https://pubmed.ncbi.nlm.nih.gov/18006208/ DOI: 10.1016/j.biopsycho.2007.09.008

tissue_or_cell_type

Cognition and subjective state

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 939–950

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind balanced crossover experiment · source_derived_draft · unverified_draft

### theanine-caffeine-simple-reaction The theanine-caffeine combination improved simple reaction time in the acute crossover experiment. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A specific test result is more precise than a claim of globally improved intelligence. organism: Healthy adults tissue_or_cell_type: Cognition and subjective state experimental_model: Randomized double-blind balanced crossover experiment limitations: Acute effects depend on task and treatment. Benefits of the mixture do not establish synergy for all outcomes or neutralization of caffeine. exposure: 250 mg theanine, 150 mg caffeine, combination and placebo evidence_span: {"source_cache": "artifacts/theanine-research/18006208.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "387d341f5aec1fb42bed06021ceb14cc8b49bfdf0f5502284a98806ca732cbdf", "start_char": 0, "end_char": 1386, "text_sha256": "387d341f5aec1fb42bed06021ceb14cc8b49bfdf0f5502284a98806ca732cbdf"} [theanine-p18006208] The effects of L-theanine, caffeine and their combination on cognition and mood. (2008). https://pubmed.ncbi.nlm.nih.gov/18006208/ DOI: 10.1016/j.biopsycho.2007.09.008

evidence_access

Primary abstract

experimental_model

Mechanically skinned human muscle fibers.

limitations

Enhanced calcium-induced release was inferred; no demonstrated oral caffeine-carnosine synergy.

nutrient_topic

Carnosine collection; isomer, preparation, species, exposure and manipulation remain explicit. · L-Carnosine / beta-alanyl-L-histidine

plain_language

Calcium release may contribute in one fiber type.

primary_references

Effects of carnosine on contractile apparatus Ca²⁺ sensitivity and sarcoplasmic reticulum Ca²⁺ release in human skeletal muscle fibers. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22174397/ · DOI 10.1152/japplphysiol.01331.2011

Carnosine: synthesis, transport, carbonyl chemistry and nutrient interactions (2026-09-19) · lines 196–202

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mechanically skinned human muscle fibers. · source_derived_draft · unverified_draft

## carnosine-caffeine-response Calcium release may contribute in one fiber type. Adding 8 mM carnosine increased caffeine-evoked force; type I potentiation exceeded that explained by measured calcium sensitization alone. Model: Mechanically skinned human muscle fibers. Limitations: Enhanced calcium-induced release was inferred; no demonstrated oral caffeine-carnosine synergy. Evidence access: Primary abstract Effects of carnosine on contractile apparatus Ca²⁺ sensitivity and sarcoplasmic reticulum Ca²⁺ release in human skeletal muscle fibers. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22174397/ · DOI 10.1152/japplphysiol.01331.2011

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Receptor-knockout mouse comparison.

limitations

Species and endpoint specific; this does not contradict human A1 binding or exclude other A1 functions.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Removing A2A receptors removed the wakefulness response in mice.

primary_references

Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15965471/ · DOI 10.1038/nn1491

trigger_kind

machinery_impairment Imported condition classification; unverified.

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 36–42

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Receptor-knockout mouse comparison. · source_derived_draft · unverified_draft

## caf-a2a-wake Removing A2A receptors removed the wakefulness response in mice. Caffeine at 5, 10 and 15 mg/kg increased wakefulness in wild-type and A1-knockout mice, but not A2A-knockout mice. Model: Receptor-knockout mouse comparison. Limitations: Species and endpoint specific; this does not contradict human A1 binding or exclude other A1 functions. Evidence access: Primary abstract Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15965471/ · DOI 10.1038/nn1491

evidence_access

Primary abstract

experimental_model

Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test.

limitations

Small acute experiment. Beta blockade supports an adrenergic contribution, not proof that it is the only mechanism or that a blocker should be used to counter caffeine.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Blocking beta-adrenergic signaling removed the response in this test.

primary_references

Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12015346/ · DOI 10.1152/japplphysiol.01229.2001

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 500–506

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test. · source_derived_draft · unverified_draft

## caf-beta-block Blocking beta-adrenergic signaling removed the response in this test. With propranolol, caffeine-associated insulin and C-peptide responses resembled placebo. Model: Seven healthy men; 5 mg/kg caffeine, 80 mg propranolol, combination or placebo before an oral glucose tolerance test. Limitations: Small acute experiment. Beta blockade supports an adrenergic contribution, not proof that it is the only mechanism or that a blocker should be used to counter caffeine. Evidence access: Primary abstract Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12015346/ · DOI 10.1152/japplphysiol.01229.2001

evidence_access

Primary abstract

experimental_model

Three-day crossover; four 200 mL servings supplying 4 mg/kg/day caffeine versus equal water.

limitations

Whole coffee plus fluid in habituated men, not dry caffeine or an acute bolus in nonusers.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

An acute diuretic effect does not mean habitual coffee drinking always dehydrates.

primary_references

No evidence of dehydration with moderate daily coffee intake: a counterbalanced cross-over study in a free-living population. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24416202/ · DOI 10.1371/journal.pone.0084154

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 372–378

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Three-day crossover; four 200 mL servings supplying 4 mg/kg/day caffeine versus equal water. · source_derived_draft · unverified_draft

## caf-coffee-water An acute diuretic effect does not mean habitual coffee drinking always dehydrates. In 50 habitual male coffee drinkers, coffee and water produced no significant difference in total body water or 24-hour urine volume. Model: Three-day crossover; four 200 mL servings supplying 4 mg/kg/day caffeine versus equal water. Limitations: Whole coffee plus fluid in habituated men, not dry caffeine or an acute bolus in nonusers. Evidence access: Primary abstract No evidence of dehydration with moderate daily coffee intake: a counterbalanced cross-over study in a free-living population. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24416202/ · DOI 10.1371/journal.pone.0084154

evidence_access

Primary abstract

experimental_model

250 mg caffeine; nine women per female group and 13 men; historical formulations.

limitations

Between-group study and formulation-specific context; no universal effect size for all contraceptives.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Hormonal medication changed caffeine persistence.

primary_references

Impaired elimination of caffeine by oral contraceptive steroids. · 1980 · https://pubmed.ncbi.nlm.nih.gov/7359014/

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 252–258

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 250 mg caffeine; nine women per female group and 13 men; historical formulations. · source_derived_draft · unverified_draft

## caf-contraceptive Hormonal medication changed caffeine persistence. Women using oral contraceptives had caffeine half-life 10.7 versus 6.2 hours and lower clearance than women not using them. Model: 250 mg caffeine; nine women per female group and 13 men; historical formulations. Limitations: Between-group study and formulation-specific context; no universal effect size for all contraceptives. Evidence access: Primary abstract Impaired elimination of caffeine by oral contraceptive steroids. · 1980 · https://pubmed.ncbi.nlm.nih.gov/7359014/

evidence_access

Primary abstract

experimental_model

Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing.

limitations

Small protocol-specific trial. Creatine accumulation and performance were separate endpoints.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Caffeine did not block the measured phosphocreatine increase.

primary_references

Caffeine counteracts the ergogenic action of muscle creatine loading. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8929583/ · DOI 10.1152/jappl.1996.80.2.452

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 444–450

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing. · source_derived_draft · unverified_draft

## caf-creatine-pcr Caffeine did not block the measured phosphocreatine increase. Creatine alone and creatine plus caffeine each increased muscle phosphocreatine by 4–6%; measured ATP stayed constant. Model: Nine healthy men; six-day creatine loading 0.5 g/kg/day, with or without caffeine 5 mg/kg/day; intermittent knee-extensor testing. Limitations: Small protocol-specific trial. Creatine accumulation and performance were separate endpoints. Evidence access: Primary abstract Caffeine counteracts the ergogenic action of muscle creatine loading. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8929583/ · DOI 10.1152/jappl.1996.80.2.452

evidence_access

Primary abstract

experimental_model

Human liver microsomes; metabolite HPLC.

limitations

Not all three demethylations are exclusively CYP1A2-dependent.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

An enzyme experiment supports the observed clearance interaction.

primary_references

Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9868741/ · DOI 10.1111/j.1600-0773.1998.tb01476.x

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 212–218

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes; metabolite HPLC. · source_derived_draft · unverified_draft

## caf-cyp1a2-inhibition An enzyme experiment supports the observed clearance interaction. In human liver microsomes, fluvoxamine inhibited caffeine demethylated-metabolite formation with Ki values of 0.08–0.28 micromolar. Model: Human liver microsomes; metabolite HPLC. Limitations: Not all three demethylations are exclusively CYP1A2-dependent. Evidence access: Primary abstract Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9868741/ · DOI 10.1111/j.1600-0773.1998.tb01476.x

evidence_access

Primary abstract

experimental_model

Human liver microsomes with ketoconazole and bromocriptine.

limitations

Enzyme attribution was pharmacological, not a single-enzyme knockout.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A minor oxidative branch differs from demethylation.

primary_references

Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9868741/ · DOI 10.1111/j.1600-0773.1998.tb01476.x

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 220–226

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human liver microsomes with ketoconazole and bromocriptine. · source_derived_draft · unverified_draft

## caf-cyp3a4 A minor oxidative branch differs from demethylation. Inhibitor experiments supported CYP3A4 involvement in caffeine 8-hydroxylation to trimethyluric acid. Model: Human liver microsomes with ketoconazole and bromocriptine. Limitations: Enzyme attribution was pharmacological, not a single-enzyme knockout. Evidence access: Primary abstract Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9868741/ · DOI 10.1111/j.1600-0773.1998.tb01476.x

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

Study used 200 mg caffeine and repeated fluvoxamine; not a prediction of the same effect size for every CYP1A2 inhibitor.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Inhibiting the metabolic pathway slowed caffeine removal.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 196–202

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-fluvox-clear Inhibiting the metabolic pathway slowed caffeine removal. Median caffeine clearance fell from 107 to 21 mL/min during fluvoxamine treatment. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: Study used 200 mg caffeine and repeated fluvoxamine; not a prediction of the same effect size for every CYP1A2 inhibitor. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers.

limitations

Reported median under this regimen, not a universal caffeine half-life.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The same dose remained in the body much longer.

primary_references

A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 204–210

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. · source_derived_draft · unverified_draft

## caf-fluvox-half The same dose remained in the body much longer. Caffeine half-life increased from five to 31 hours in the fluvoxamine crossover experiment. Model: Human caffeine/fluvoxamine crossover and metabolite measurements; eight healthy volunteers. Limitations: Reported median under this regimen, not a universal caffeine half-life. Evidence access: Primary abstract A fluvoxamine-caffeine interaction study. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8807660/ · DOI 10.1097/00008571-199606000-00003

evidence_access

Primary abstract

experimental_model

Awake receptor-knockout mice; telemetry and respirometry.

limitations

Sex and route mattered; locomotion is not a direct measure of human focus.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The activity response depended on this receptor in the mouse experiment.

primary_references

Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19218506/ · DOI 10.1152/ajpheart.00754.2008

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 44–50

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Awake receptor-knockout mice; telemetry and respirometry. · source_derived_draft · unverified_draft

## caf-locomotion The activity response depended on this receptor in the mouse experiment. Injected caffeine increased locomotion only in mice expressing A2A receptors; ingestion also produced an A2A-dependent increase in males. Model: Awake receptor-knockout mice; telemetry and respirometry. Limitations: Sex and route mattered; locomotion is not a direct measure of human focus. Evidence access: Primary abstract Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19218506/ · DOI 10.1152/ajpheart.00754.2008

evidence_access

Primary abstract

experimental_model

CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo.

limitations

Death, ultrasound brain-injury signs and necrotizing enterocolitis did not differ significantly in this report.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

The benefit records retain the measured growth tradeoff.

primary_references

Caffeine therapy for apnea of prematurity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16707748/ · DOI 10.1056/nejmoa054065

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 524–530

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo. · source_derived_draft · unverified_draft

## caf-preterm-growth The benefit records retain the measured growth tradeoff. Weight gain was temporarily lower, with the greatest mean difference −23 g at two weeks. Model: CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo. Limitations: Death, ultrasound brain-injury signs and necrotizing enterocolitis did not differ significantly in this report. Evidence access: Primary abstract Caffeine therapy for apnea of prematurity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16707748/ · DOI 10.1056/nejmoa054065

evidence_access

Primary abstract

experimental_model

CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo.

limitations

Specialist neonatal treatment, not dietary caffeine. Clinical outcomes do not isolate one receptor or prove benefit in other populations.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Clinical caffeine treatment reduced an important neonatal respiratory outcome.

primary_references

Caffeine therapy for apnea of prematurity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16707748/ · DOI 10.1056/nejmoa054065

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 508–514

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo. · source_derived_draft · unverified_draft

## caf-preterm-oxygen Clinical caffeine treatment reduced an important neonatal respiratory outcome. At 36 weeks postmenstrual age, 36% of surviving caffeine-group infants required oxygen versus 47% with placebo; adjusted odds ratio 0.63. Model: CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo. Limitations: Specialist neonatal treatment, not dietary caffeine. Clinical outcomes do not isolate one receptor or prove benefit in other populations. Evidence access: Primary abstract Caffeine therapy for apnea of prematurity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16707748/ · DOI 10.1056/nejmoa054065

evidence_access

Primary abstract

experimental_model

CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo.

limitations

Specialist neonatal treatment, not dietary caffeine. Clinical outcomes do not isolate one receptor or prove benefit in other populations.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Respiratory support stopped earlier in the treatment group.

primary_references

Caffeine therapy for apnea of prematurity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16707748/ · DOI 10.1056/nejmoa054065

Caffeine: receptors, metabolism, nutrient interactions, adaptation and discovery questions (2026-09-18) · lines 516–522

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo. · source_derived_draft · unverified_draft

## caf-preterm-pressure Respiratory support stopped earlier in the treatment group. Positive airway pressure ended at median 31 weeks postmenstrual age versus 32 weeks with placebo. Model: CAP randomized trial, 2006 infants weighing 500–1250 g at birth; clinical caffeine-citrate therapy versus placebo. Limitations: Specialist neonatal treatment, not dietary caffeine. Clinical outcomes do not isolate one receptor or prove benefit in other populations. Evidence access: Primary abstract Caffeine therapy for apnea of prematurity. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16707748/ · DOI 10.1056/nejmoa054065

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Awake mice; oral gavage and three-hour collection.

limitations

Evidence of receptor dependence, not a directly demonstrated human tubular segment.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Removing A1 receptors removed the renal response in this animal model.

primary_references

Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15590766/ · DOI 10.1124/jpet.104.080432

trigger_kind

machinery_impairment Imported condition classification; unverified.

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Awake mice; oral gavage and three-hour collection. · source_derived_draft · unverified_draft

## caf-renal-a1 Removing A1 receptors removed the renal response in this animal model. Caffeine 45 mg/kg caused diuresis and natriuresis in wild-type but not A1-knockout mice. Model: Awake mice; oral gavage and three-hour collection. Limitations: Evidence of receptor dependence, not a directly demonstrated human tubular segment. Evidence access: Primary abstract Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15590766/ · DOI 10.1124/jpet.104.080432

evidence_access

Primary abstract

experimental_model

16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges.

limitations

Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Stopping after repeated use produced a measurable response.

primary_references

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. · source_derived_draft · unverified_draft

## caf-withdraw-beta Stopping after repeated use produced a measurable response. Acute withdrawal decreased EEG beta-2 power. Model: 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. Limitations: Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion. Evidence access: Primary abstract Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

evidence_access

Primary abstract

experimental_model

16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges.

limitations

Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Stopping after repeated use produced a measurable response.

primary_references

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. · source_derived_draft · unverified_draft

## caf-withdraw-fatigue Stopping after repeated use produced a measurable response. Withdrawal increased tiredness/fatigue ratings and decreased energy/vigor ratings. Model: 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. Limitations: Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion. Evidence access: Primary abstract Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

evidence_access

Primary abstract

experimental_model

16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges.

limitations

Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Stopping after repeated use produced a measurable response.

primary_references

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. · source_derived_draft · unverified_draft

## caf-withdraw-flow Stopping after repeated use produced a measurable response. At 24 hours after placebo substitution, withdrawal increased middle- and anterior-cerebral arterial flow velocities. Model: 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. Limitations: Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion. Evidence access: Primary abstract Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

evidence_access

Primary abstract

experimental_model

16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges.

limitations

Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

Stopping after repeated use produced a measurable response.

primary_references

Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. · source_derived_draft · unverified_draft

## caf-withdraw-theta Stopping after repeated use produced a measurable response. Acute withdrawal increased EEG theta power. Model: 16 regular users; double-blind within-subject study; at least 14 days on 400 mg/day or placebo, with acute challenges. Limitations: Withdrawal is adaptation to repeated exposure, not an essential-nutrient deficiency. Blood-flow velocity is not absolute cerebral perfusion. Evidence access: Primary abstract Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19241060/ · DOI 10.1007/s00213-009-1489-4

evidence_access

Primary abstract

experimental_model

Two healthy nonsmokers; caffeine 5 mg/kg before/during allopurinol 300 or 600 mg/day.

limitations

Very small human mechanistic study; not proof that dietary molybdenum controls parent-caffeine clearance.

nutrient_topic

Caffeine collection; salts, coffee, species and coexposure contexts retain their identities. · Caffeine

plain_language

A later caffeine metabolite uses the xanthine-oxidoreductase pathway.

primary_references

Effect of allopurinol on caffeine disposition in man. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3754760/ · DOI 10.1111/j.1365-2125.1986.tb05222.x

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AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Two healthy nonsmokers; caffeine 5 mg/kg before/during allopurinol 300 or 600 mg/day. · source_derived_draft · unverified_draft

## caf-xor-product A later caffeine metabolite uses the xanthine-oxidoreductase pathway. Allopurinol specifically and dose-dependently inhibited conversion of caffeine-derived 1-methylxanthine to 1-methyluric acid. Model: Two healthy nonsmokers; caffeine 5 mg/kg before/during allopurinol 300 or 600 mg/day. Limitations: Very small human mechanistic study; not proof that dietary molybdenum controls parent-caffeine clearance. Evidence access: Primary abstract Effect of allopurinol on caffeine disposition in man. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3754760/ · DOI 10.1111/j.1365-2125.1986.tb05222.x