Meta Information
ID:caffeine
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/circadian/sleep
Target name:
Going to Sleep
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
8
Hours after target:
null
Description:
Caffeine blocks adenosine receptors in the brain, which are crucial for promoting sleepiness, thereby delaying sleep onset and reducing sleep quality.
Actionable advice:
Caffeine should not be consumed for at least 8 hours before the intended bedtime.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Caffeine and theophylline stimulate the secretion of renin by inhibition of adenosine receptors and removal of the general inhibitory brake function of endogenous adenosine.
Label source:
PubMed: Methylxanthines and the kidney. (PMID 20859805)
Action type:
separate
Target id:
/class/fluoroquinolones
Target name:
Quinolone Antibiotics (e.g., Ciprofloxacin)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Certain quinolone antibiotics strongly inhibit the CYP1A2 enzyme, which is responsible for metabolizing caffeine, leading to dangerously high caffeine levels, anxiety, and palpitations.
Actionable advice:
Caffeine should be avoided completely while taking quinolone antibiotics like ciprofloxacin.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
All drugs competitively inhibited the activity of 3-demethylation, the major pathway of caffeine metabolism. Enoxacin, ciprofloxacin, and pipemidic acid were strong inhibitors exhibiting Ki values between 0.1 and 0.2 mM.
Label source:
PubMed: Drug metabolism and disposition: the biological fate of chemicals (1990)
Source url:
Exact phrase from label:
many clinical drugs such as theophylline, fluvoxamine, quinolone antibiotics, verapamil, cimetidine, and oral contraceptives can inhibit CYP1A2 activity.
Label source:
PubMed: Current drug metabolism (2021)
Source url:
Exact phrase from label:
The inhibitory effects of ciprofloxacin and other quinolone derivatives on the hepatic cytochrome P450-dependent metabolism of caffeine have been investigated in humans.
Label source:
PubMed: The American journal of medicine (1989)
Action type:
avoid
Target id:
/intervention/fluvoxamine
Target name:
Fluvoxamine (Luvox)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Fluvoxamine is a potent inhibitor of the CYP1A2 enzyme, drastically slowing caffeine metabolism and increasing its concentration and side effects.
Actionable advice:
Caffeine should be avoided completely while taking fluvoxamine.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6.
Label source:
PubMed: Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series. (PMID 34234701)
Action type:
avoid
Target id:
/intervention/clozapine
Target name:
Clozapine
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine inhibits the metabolism of clozapine via the CYP1A2 enzyme, which can lead to a toxic buildup of the medication.
Actionable advice:
Caffeine intake should be avoided or strictly limited when taking clozapine, and it is important to consult a doctor.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
CONCLUSIONS: These results suggest that caffeine in daily doses of 400-1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.
Label source:
PubMed: Effect of caffeine on clozapine pharmacokinetics in healthy volunteers. (PMID 10606838)
Action type:
avoid
Target id:
/intervention/tizanidine
Target name:
Tizanidine (Zanaflex)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine inhibits the CYP1A2 enzyme, which can increase tizanidine levels by over 10-fold, leading to severe low blood pressure and sedation.
Actionable advice:
Caffeine should be avoided completely while taking tizanidine.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Concomitant use of tizanidine with strong cytochrome P450 1A2 (CYP1A2) inhibitors (e.g., fluvoxamine, ciprofloxacin) is contraindicated.
Label source:
FDA label: Tizanidine (Zanaflex)
Action type:
avoid
Target id:
/class/stimulants
Target name:
Sympathomimetic Stimulants (e.g., Ephedrine, Pseudoephedrine)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Combining caffeine with other stimulants like ephedrine can cause excessive nervous system stimulation, leading to dangerously high blood pressure, rapid heart rate, and increased risk of stroke.
Actionable advice:
Caffeine should not be combined with stimulant medications like ephedrine or pseudoephedrine.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Ephedrine and pseudoephedrine may also cause hypertension, as well as tachyarrhythmias due to beta-adrenergic stimulation. Toxic reactions from caffeine are characterized by agitation, seizures, tachyarrhythmias, and hypotension.
Label source:
PubMed: JAMA (1984)
Source url:
Exact phrase from label:
Mean systolic blood pressure increased significantly to a maximum of 14 mm Hg above baseline at 90 minutes after ingestion (P <.001). There was a lag in the mean heart rate response that reached a maximum change of 15 beats/min above baseline at 6 hours after ingestion (P <.001).
Label source:
PubMed: Clinical pharmacology and therapeutics (2002)
Source url:
Exact phrase from label:
a relatively consistent cardiovascular manifestation of the latter preparation is an increase in heart rate, in addition to that caused by exercise alone.
Label source:
PubMed: Sports medicine (Auckland, N.Z.) (2004)
Action type:
avoid
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
High caffeine intake during pregnancy is associated with an increased risk of miscarriage, low birth weight, and other developmental issues as it crosses the placenta.
Actionable advice:
Strictly limit caffeine intake to less than 200 mg per day, or avoid completely, during pregnancy.
Validation status:
anecdotal
Evidence tier:
tier_d
Evidence basis:
anecdotal_summary
Evidence anchors:
Exact phrase from label:
Some studies suggest that the chance of miscarriage might be increased when people consume moderate (200-300 mg) or high (more than 300 mg) levels of caffeine.
Label source:
Anecdotal: MotherToBaby
Action type:
avoid
Target id:
/dietary/alcohol-acute
Target name:
Alcohol (Acute Consumption)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine masks the sedative effects of alcohol, creating a 'wide-awake drunk' state that can lead to overconsumption, impaired judgment, and increased risk-taking behaviors.
Actionable advice:
Caffeine and alcohol should not be consumed together, especially in mixed drinks.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
no evidence of alcohol-induced sedation was observed in co-consumption groups that instead demonstrated a highly stimulated state similar to that of caffeine alone. The addition of caffeine was also found to mitigate alcohol-induced ataxia.
Label source:
PubMed: Alcoholism, clinical and experimental research (2014)
Source url:
Exact phrase from label:
The increase in alcohol consumption when combined with caffeine has led to the idea that the stimulant effects of caffeine may mask the depressant effects of alcohol, and this may contribute to increased binge drinking as the individual feels more awake and stimulated.
Label source:
PubMed: Pharmacology, biochemistry, and behavior (2024)
Source url:
Exact phrase from label:
recent literature suggests that this combination conducts to feel less intoxicated but still impaired. The goal of the present article is to review cognitive impact and subjective awareness in case of caffeinated alcoholic beverage (CAB) intoxication.
Label source:
PubMed: Progress in neuro-psychopharmacology & biological psychiatry (2017)
Action type:
avoid
Target id:
/procedure/cardiac-stress-test
Target name:
Pharmacologic Cardiac Stress Test (Adenosine, Dipyridamole)
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
24
Hours after target:
null
Description:
Caffeine blocks adenosine receptors, directly interfering with the action of drugs like adenosine and dipyridamole used to simulate exercise during a cardiac stress test, making the test inaccurate.
Actionable advice:
All caffeine should be avoided for at least 24 hours before a scheduled pharmacologic cardiac stress test.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Patients scheduled for (201)Tl myocardial perfusion using pharmacologic stress with dipyridamole or adenosine are advised to abstain from caffeine for 24 h before the test.
Label source:
PubMed: Serum caffeine levels after 24-hour abstention: clinical implications on dipyridamole (201)Tl myocardial perfusion imaging. (PMID 12186961)
Action type:
separate
Target id:
/intervention/levothyroxine
Target name:
Levothyroxine
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
1
Description:
Consuming coffee or other caffeinated beverages at the same time as levothyroxine can significantly reduce its absorption from the gut, lowering its effectiveness.
Actionable advice:
Levothyroxine should be taken at least 60 minutes before or after consuming caffeine.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine.
Label source:
FDA label: Levothyroxine (Synthroid)
Action type:
separate
Target id:
/intervention/bisphosphonates
Target name:
Bisphosphonates (e.g., Alendronate)
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
Caffeine, particularly in coffee, can drastically reduce the absorption of oral bisphosphonates used for osteoporosis, rendering them ineffective.
Actionable advice:
Bisphosphonate doses and caffeine consumption should be separated by at least 2 hours.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
even dosing with orange juice or coffee has been shown to markedly reduce the absorption of FOSAMAX
Label source:
FDA label: Alendronate Sodium (Fosamax)
Action type:
separate
Target id:
/condition/anxiety-disorder
Target name:
Anxiety or Panic Disorders
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine's stimulant properties can mimic or worsen symptoms of anxiety, such as palpitations, nervousness, and restlessness, and may trigger panic attacks in susceptible individuals.
Actionable advice:
Caffeine should be avoided with an anxiety or panic disorder.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
In this context caffeine has been shown to increase anxiety and impair sleep.
Label source:
PubMed: Effects of caffeine on human behavior. (PMID 12204388)
Action type:
avoid
Target id:
/condition/hepatic-impairment
Target name:
Hepatic Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The liver is the primary site of caffeine metabolism; severe liver disease significantly prolongs caffeine's half-life, increasing the risk of toxicity and side effects.
Actionable advice:
Caffeine should be avoided with significant liver impairment.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The mean serum caffeine half-life for the healthy subjects was 5.7 hours. One patient, a 35-year-old man who had alcoholic hepatic disease, had a serum half-life of 60 hours. The other patient, a 49-year-old woman having alcoholic hepatic disease had a serum half-life of 168 hours. The prolonged serum half-lives for the two patients are explained on the basis of compromised liver function.
Label source:
PubMed: American journal of clinical pathology (1980)
Source url:
Exact phrase from label:
Mean plasma clearance of caffeine in patients with no liver disease (1.30 +/- 0.79 ml/kg/min) was significantly higher than in patients with liver disease (0.39 +/- 0.23 ml/kg/min). Mean half-life of caffeine in patients with liver disease (23.96 +/- 12.19 h) was significantly higher than in patients with no liver disease (7.25 +/- 3.04 h).
Label source:
PubMed: Journal of clinical pharmacy and therapeutics (1995)
Source url:
Exact phrase from label:
Caffeine is almost exclusively metabolized in the liver by the cytochrome P-450 enzyme system to the main product paraxanthine and the additional products theobromine and theophylline.
Label source:
PubMed: Frontiers in pharmacology (2021)
Action type:
avoid
Target id:
/intervention/theophylline
Target name:
Theophylline
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine and theophylline are both methylxanthines; taking them together results in additive effects and increased risk of toxicity, including nausea, vomiting, and rapid heart rate.
Actionable advice:
Caffeine intake is best avoided or strictly limited while taking theophylline.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Caffeine, theophylline and theobromine are methylxanthines, a class of alkaloids present in coffee, tea and cocoa and therefore widely consumed all around the world.
Label source:
PubMed: Efficient aqueous solubilization of methylxanthines via complexation with natural polyphenolate salts. (PMID 42040972)
Action type:
avoid
Target id:
/class/maois
Target name:
Monoamine Oxidase Inhibitors
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine can have a mild pressor effect (increasing blood pressure), which can be dangerously potentiated when combined with MAOIs, increasing the risk of a hypertensive crisis.
Actionable advice:
Caffeine is best used with extreme caution, or avoided completely, while taking an MAOI.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
We propose that the association of cigarette smoking with accelerated hypertension may reflect an extreme pressor effect of combined smoking and caffeine use in some patients.
Label source:
PubMed: Effect of coffee and cigarette smoking on the blood pressure of patients with accelerated (malignant) hypertension. (PMID 7752180)
Action type:
avoid
Target id:
/class/benzodiazepines
Target name:
Benzodiazepines
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine's central nervous system stimulant effects directly oppose the sedative and anxiolytic effects of benzodiazepines, potentially reducing their therapeutic efficacy.
Actionable advice:
Caffeine is best avoided when using benzodiazepines for sedation or anxiety relief.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
It has anxiolytic, hypnotic, sedative and muscle-relaxant properties and is used for the short-term treatment of anxiety and panic attacks. The purine alkaloid caffeine, conversely, is the most widely used central nervous system stimulant.
Label source:
PubMed: The adulterated XANAX pill: a fatal intoxication with etizolam and caffeine. (PMID 32607751)
Action type:
avoid
Target id:
/intervention/lithium
Target name:
Lithium
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine has a diuretic effect that increases the renal clearance of lithium, which can lower lithium levels in the blood and reduce its effectiveness for managing bipolar disorder.
Actionable advice:
A consistent daily caffeine intake is best maintained, and it is important to consult a doctor before changing it.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
An associated reduction in renal lithium clearance resulting in increased serum lithium level is thought to be the mechanism.
Label source:
PubMed: Lithium tremor and caffeine intake: two cases of drinking less and shaking more. (PMID 3338980)
Action type:
informational_none
Target id:
/intervention/l-theanine
Target name:
L-Theanine
Severity:
moderate
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
L-Theanine promotes relaxation and alpha brain waves, which counteracts the jitteriness and anxiety sometimes caused by caffeine, leading to a state of calm, focused alertness.
Actionable advice:
L-Theanine is best taken at the same time as caffeine for enhanced cognitive benefits.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Some studies suggest l-theanine may increase alpha waves in the brain associated with relaxation and selective attention, reduce stress and anxiety, and improve sleep quality, though findings are often inconsistent. Potential neuroprotective and anti-seizure effects have also been reported in animal models. When combined with caffeine, l-theanine may improve cognitive performance, alertness and focus.
Label source:
PubMed: l-theanine: From tea leaf to trending supplement - does the science match the hype for brain health and relaxation? (PMID 39854799)
Action type:
informational_none
Target id:
/intervention/exercise
Target name:
Exercise
Severity:
moderate
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
null
Description:
Caffeine is a well-established ergogenic aid that can improve physical performance, increase endurance, and reduce the perception of effort during exercise.
Actionable advice:
Consume caffeine approximately 30-60 minutes before a workout for optimal performance benefits.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Conclusions: Caffeine improved aerobic endurance and neuromuscular performance in well-trained soccer players regardless of their responsiveness to caffeine at rest.
Label source:
PubMed: Caffeine Supplementation: Ergogenic in Both High and Low Caffeine Responders. (PMID 30427235)
Action type:
informational_none
Target id:
/intervention/iron-bisglycinate
Target name:
Iron Supplements
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
2
Description:
Tannins present in coffee and tea, often consumed with caffeine, can bind to non-heme iron in the gut, significantly reducing its absorption.
Actionable advice:
Iron supplement doses and coffee or tea should be separated by at least 1-2 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
A cup of coffee reduced iron absorption from a hamburger meal by 39% as compared to a 64% decrease with tea, which is known to be a potent inhibitor of iron absorption.
Label source:
PubMed: Inhibition of food iron absorption by coffee. (PMID 6402915)
Action type:
separate
Target id:
/class/estrogens
Target name:
Estrogens and Progestins (Hormonal Therapy & Contraceptives)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Estrogen-containing medications can inhibit the CYP1A2 enzyme, slowing the metabolism of caffeine and potentially increasing its effects and side effects like jitteriness.
Actionable advice:
Increased caffeine sensitivity is worth keeping in mind, and reducing intake may be warranted while on oral contraceptives.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Consistent with previous results found in younger women, these results indicate that exogenous estrogen in older women may inhibit CYP1A2-mediated caffeine metabolism.
Label source:
PubMed: Journal of clinical pharmacology (1999)
Source url:
Exact phrase from label:
Inhibition studies with caffeine, phenacetin, 17 beta-estradiol, and progesterone as inhibitors of the CYP1A1 and CYP1A2 catalyzed O-deethylation of 7-ethoxyresorufin suggest all compounds as possible substrates of CYP1A enzymes.
Label source:
PubMed: Drug metabolism and disposition: the biological fate of chemicals (1993)
Source url:
Exact phrase from label:
Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity.
Label source:
PubMed: Clinical pharmacology and therapeutics (2016)
Action type:
informational_none
Target id:
/intervention/echinacea
Target name:
Echinacea
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Echinacea can inhibit the CYP1A2 enzyme, slowing down the breakdown of caffeine and increasing the risk of side effects like nervousness and headache.
Actionable advice:
Caution is warranted, and reducing caffeine intake is worth considering, when taking echinacea supplements.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Weak effects in terms of either induction or inhibition were found for GB (presystemic/hepatic CYP3A4 induction/inhibition, CYP2C19 induction at high doses), milk thistle/silymarin (CYP2C9 inhibition), GS/berberine (CYP3A4 and CYP2D6 inhibition), Echinacea (presystemic/hepatic CYP3A4 inhibition/induction, CYP1A2 and CYP2C9 inhibition at high doses).
Label source:
PubMed: Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. (PMID 22855269)
Action type:
informational_none
Target id:
/condition/peptic-ulcer-disease
Target name:
Peptic Ulcer Disease (PUD) or GERD
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine stimulates the secretion of gastric acid, which can worsen the symptoms of peptic ulcers, gastritis, or gastroesophageal reflux disease (GERD).
Actionable advice:
Caffeine is best avoided with active PUD or severe GERD, especially on an empty stomach.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs).
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC5544304/
Action type:
separate
Target id:
/condition/cardiac-arrhythmia
Target name:
Cardiac Arrhythmias
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
As a stimulant, caffeine can increase heart rate and may trigger or worsen certain types of heart rhythm disturbances in susceptible individuals.
Actionable advice:
It is important to consult a cardiologist about safe caffeine consumption for those with a history of arrhythmias.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Chocolate contains methylxanthines, such as caffeine and related stimulants, which can increase heart rate and blood pressure, and may induce arrhythmias by stimulating the sympathetic nervous system.
Label source:
PubMed: Chocolate-Induced Sinus Tachycardia: A Sweet Surprise. (PMID 41523427)
Action type:
informational_none
Target id:
/intervention/creatine
Target name:
Creatine
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
1
Description:
Conflicting evidence suggests that co-ingestion of high-dose caffeine may blunt the ergogenic benefits of creatine loading, possibly due to opposing effects on muscle relaxation time or GI distress.
Actionable advice:
Consider separating creatine and caffeine intake by at least an hour if you notice reduced benefits.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Mechanisms that specifically enhance physical strength include increased blood flow delivery via the NO-sGC-cGMP pathway, attenuation of central nervous system fatigue through LAT1-mediated tryptophan competition, and maintenance of calcium homeostasis via the SERCA-RyR1-VDAC1-MCU axis.
Label source:
PubMed: Multimechanistic actions of functional factors in enhancing physical strength and endurance: a scoping review of nutritional basis and natural extracts. (PMID 42211549)
Action type:
informational_none
Target id:
/lifestyle/tobacco-smoking
Target name:
Tobacco Smoking
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Polycyclic aromatic hydrocarbons in tobacco smoke are potent inducers of the CYP1A2 enzyme, which can more than double the speed of caffeine metabolism, reducing its effects.
Actionable advice:
More caffeine may be needed for the same effect while smoking, and intake may need to be reduced after quitting.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1, CYP1A2 and possibly CYP2E1, CYP1A1 is primarily an extrahepatic enzyme found in lung and placenta.
Label source:
PubMed: Clinical pharmacokinetics (1999)
Source url:
Exact phrase from label:
Polycyclic aromatic hydrocarbons (PAHs) are some of the major lung carcinogens found in tobacco smoke. PAHs are potent inducers of the hepatic cytochrome P-450 (CYP) isoenzymes 1A1, 1A2, and, possibly, 2E1.
Label source:
PubMed: American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists (2007)
Source url:
Exact phrase from label:
Mean caffeine t1/2 in smokers (3.5 hr) was shorter than that in the nonsmokers (6.0 hr). The body clearance of caffeine in the smokers (155 +/- 16 ml . kg-1 . hr-1) was greater than that in the nonsmokers (94 +/- 18 ml . kg-1 . hr-1) (p less than 0.05).
Label source:
PubMed: Clinical pharmacology and therapeutics (1978)
Action type:
informational_none
Target id:
/intervention/saint-johns-wort
Target name:
Saint John's Wort
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
St. John's Wort can induce metabolic enzymes, including CYP1A2, potentially speeding up the clearance of caffeine and reducing its duration of action.
Actionable advice:
You may notice a reduced effect from caffeine when taking St. John's Wort.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein by constituent(s) in SJW.
Label source:
PubMed: St John's wort (Hypericum perforatum): drug interactions and clinical outcomes. (PMID 12392581)
Action type:
informational_none
Target id:
/intervention/calcium-citrate
Target name:
Calcium Supplements
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine can slightly increase the amount of calcium excreted in the urine, which over the long term could impact bone health if dietary calcium intake is insufficient.
Actionable advice:
Adequate daily calcium intake may help for regular high-dose caffeine consumers.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of bone loss at the spine (-8.14 +/- 2.62%) than did women with the TT genotype (-0.34 +/- 1.42%) when their caffeine intake was >300 mg/d.
Label source:
PubMed: Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes. (PMID 11684540)
Action type:
informational_none
Target id:
/intervention/magnesium
Target name:
Magnesium Supplements
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Caffeine acts as a mild diuretic and can increase the urinary excretion of magnesium, potentially contributing to lower magnesium levels over time.
Actionable advice:
Adequate daily magnesium intake may help for regular high-dose caffeine consumers.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Urinary Ca and Mg were elevated significantly (p = 0.01 and p = 0.04) for six h after the second caffeine dose.
Label source:
PubMed: Journal of the American College of Nutrition (1994)
Source url:
Exact phrase from label:
Oral doses of caffeine increase the urinary excretion of calcium, magnesium, sodium and chloride for at least 3 h after consumption.
Label source:
PubMed: The Journal of nutrition (1993)
Action type:
informational_none
Target id:
/class/anticoagulants-antiplatelets
Target name:
Anticoagulants and Antiplatelets
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
In theory, very high doses of caffeine might have a mild antiplatelet effect, which could add to the effects of anticoagulant or antiplatelet drugs, but this is not considered clinically significant at normal doses.
Actionable advice:
No specific action is needed with normal caffeine intake, but avoid excessive consumption.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Both caffeine and L2 inhibit thromboxane formation in whole blood in a dose dependent fashion.
Label source:
PubMed: A potent inhibitor of thrombin stimulated platelet thromboxane formation from unprocessed tea. (PMID 3473509)
Action type:
avoid