Meta Information
ID:folate
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/anticonvulsants
Target name:
Enzyme-Inducing Anticonvulsant Medications
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Certain anticonvulsants (e.g., phenytoin, carbamazepine) can deplete folate levels, while high-dose folate supplementation can lower the concentration of these drugs, potentially increasing seizure risk.
Actionable advice:
Folate can lower phenytoin (and some other anticonvulsant) levels, risking breakthrough seizures. Have your prescriber monitor drug levels and adjust the dose when you start or stop folate.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
7.1 Drugs that Affect Phenytoin Concentrations
Table 2 includes commonly occurring drug interactions that affect phenytoin concentrations.
Label source:
Action type:
adjust_with_prescriber
Target id:
/condition/vitamin-b12-deficiency
Target name:
Vitamin B12 Deficiency
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
High doses of folate can correct the anemia caused by vitamin B12 deficiency without addressing the deficiency itself, masking the condition and allowing potentially irreversible nerve damage to progress.
Actionable advice:
Rule out or address Vitamin B12 deficiency before starting high-dose (over 1000 mcg) folate.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression.
Label source:
PubMed: Food and nutrition bulletin (2024)
Source url:
Exact phrase from label:
However, there is concern that cobalamin deficiency and its characteristic neuropathy could be masked when hematological abnormalities in risk groups such as the elderly and vegetarians are reversed through folic acid supplementation.
Label source:
PubMed: Nutrition reviews (2009)
Source url:
Exact phrase from label:
The inappropriate administration of folic acid in the presence of vitamin B12 deficiency may lead to both neurologic and, later, hematologic relapse.
Label source:
PubMed: Handbook of clinical neurology (2014)
Action type:
informational_none
Target id:
/intervention/methotrexate-cancer
Target name:
Methotrexate (for Cancer)
Severity:
major
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Folate can counteract the mechanism of methotrexate, a folate antagonist, potentially reducing its effectiveness in cancer chemotherapy.
Actionable advice:
Folate supplements should be strictly avoided unless specifically directed by an oncologist.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases.
Label source:
Methotrexate (methotrexate sodium) FDA label, Sec. 7.1 / 5.10 Folic Acid Supplementation (Neoplastic Diseases).
Action type:
avoid
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
major
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Folate is essential for rapid cell division and growth, and adequate levels are required to prevent major birth defects of the baby's brain and spine (neural tube defects).
Actionable advice:
Women of childbearing age should ensure an intake of at least 400-800 mcg of folic acid daily.
Validation status:
anecdotal
Evidence tier:
tier_d
Evidence basis:
anecdotal_summary
Evidence anchors:
Exact phrase from label:
Due to its involvement in rapidly dividing tissues, folate is essential during periods of rapid growth, such as pregnancy and infancy.
Label source:
Anecdotal: StatPearls
Action type:
informational_none
Target id:
/intervention/vitamin-b12
Target name:
Vitamin B12
Severity:
major
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin B12 is an essential cofactor for the MTR enzyme, which uses methyl-folate to remethylate homocysteine back to methionine. They work together to control homocysteine levels.
Actionable advice:
For homocysteine management, adequate intake of Vitamin B12 alongside folate should be maintained.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Folic acid (FA) and vitamin B12, essential components of one-carbon metabolism, are especially crucial.
Label source:
PubMed: The Impact of a High Folic Acid and Low Vitamin B12 Diet on Oxidative Stress in Dams at Delivery and Young Offspring: Sex Matters. (PMID 42250594)
Action type:
informational_none
Target id:
/intervention/methotrexate-autoimmune
Target name:
Methotrexate (for Autoimmune Disease)
Severity:
moderate
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
24
Hours after target:
24
Description:
Low-dose folate is often prescribed with methotrexate for conditions like rheumatoid arthritis to reduce its side effects, but it should not be taken on the same day to avoid interfering with efficacy.
Actionable advice:
Folate is best taken as prescribed, though the dose is best skipped on the day methotrexate is taken.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid for patients with rheumatoid arthritis, pJIA, and psoriasis.
Label source:
Methotrexate (methotrexate sodium) FDA label, Sec. 5.10 Folic Acid Supplementation (Non-neoplastic Diseases). NOTE: in low-dose autoimmune use folate is co-prescribed to REDUCE methotrexate toxicity - the supplement is protective/recommended, not contraindicated.
Action type:
informational_none
Target id:
/intervention/sulfasalazine
Target name:
Sulfasalazine
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Sulfasalazine, used for inflammatory bowel disease and arthritis, can inhibit the intestinal absorption of folate, potentially leading to lower folate levels over time.
Actionable advice:
If taking sulfasalazine long-term, discuss folate supplementation with your doctor.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Both drugs inhibited the transport of [3H]folic acid with similar Ki values (1.38 and 1.32 mM for sulfasalazine and olsalazine, respectively).
Label source:
PubMed: Drug interactions in intestinal transport of folic acid and methotrexate. Further evidence for the heterogeneity of folate transport in the human small intestine. (PMID 1360212)
Action type:
informational_none
Target id:
/class/bile-acid-sequestrants
Target name:
Bile Acid Sequestrants
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
4
Description:
Bile acid sequestrants (e.g., cholestyramine) can bind to folate in the intestine, preventing its absorption into the bloodstream.
Actionable advice:
Folate is best taken at least 1 hour before or 4 hours after a bile acid sequestrant.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Because cholestyramine binds bile acids, QUESTRAN may interfere with normal fat digestion
and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and
K.
Label source:
Action type:
separate
Target id:
/condition/alcohol-chronic
Target name:
Chronic Alcohol Use (Alcohol Use Disorder)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Chronic heavy alcohol use interferes with folate absorption, metabolism, and storage, and increases its excretion, frequently leading to deficiency.
Actionable advice:
Individuals with heavy alcohol consumption should be assessed for folate deficiency and may require supplementation.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion.
Label source:
Medici & Halsted review, PMID 23136133. Directly and fully supports chronic-alcohol folate deficiency via all the stated mechanisms.
Action type:
informational_none
Target id:
/intervention/trimethoprim
Target name:
Trimethoprim
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The antibiotic trimethoprim inhibits an enzyme in the folate pathway, and its use in folate-deficient individuals can increase the risk of blood disorders like megaloblastic anemia.
Actionable advice:
It is a good idea to maintain adequate folate status before or during treatment with trimethoprim, especially if long-term.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
CONTRAINDICATIONS
Trimethoprim is contraindicated in individuals hypersensitive to trimethoprim and in those with
documented megaloblastic anemia due to folate deficiency.
Label source:
Action type:
informational_none
Target id:
/intervention/vitamin-b6
Target name:
Vitamin B6
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin B6 is a required cofactor for enzymes in the homocysteine metabolic pathway, working alongside folate and B12 to maintain healthy levels.
Actionable advice:
For homocysteine management, adequate intake of Vitamin B6 alongside folate is a good idea.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
We saw similar inverse associations between homocysteine and intakes of folate and vitamin B6, but not vitamin B12.
Label source:
PubMed: Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. (PMID 11411265)
Action type:
informational_none
Target id:
/condition/mthfr-polymorphism
Target name:
MTHFR Gene Polymorphism
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Common genetic variations in the MTHFR enzyme can impair the conversion of synthetic folic acid to its active form (L-methylfolate), potentially reducing its effectiveness.
Actionable advice:
Individuals with known MTHFR variants may benefit more from the L-methylfolate form of the supplement.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
some individuals have a genetic deficiency in the methylene tetrahydrofolate reductase (MTHFR) gene that limits conversion of folic acid to its biologically active form, L-methylfolate.
Label source:
PMID 22108397. Directly supports MTHFR variants impairing folic-acid -> L-methylfolate conversion.
Action type:
informational_none
Target id:
/biomarker/homocysteine
Target name:
Homocysteine Levels
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Folate, along with vitamins B12 and B6, is essential for the metabolic pathway that converts homocysteine to methionine, thereby lowering plasma homocysteine levels.
Actionable advice:
It is a good idea to maintain adequate folate intake to keep healthy homocysteine levels.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B12 and pyridoxal-5'-phosphate.
Label source:
PubMed: Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. (PMID 11411265)
Action type:
monitor
Target id:
/intervention/zinc
Target name:
Zinc
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
High doses of folic acid (over 1000 mcg) may form a complex with zinc in the gut, potentially reducing the absorption of zinc.
Actionable advice:
High-dose folate and zinc supplements are best separated by at least 2 hours.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
These studies show that zinc transport is significantly decreased when folate is present in the intestinal lumen. Similarly folic acid transport is significantly decreased with the presence of zinc.
Label source:
PubMed: The American journal of clinical nutrition (1986)
Source url:
Exact phrase from label:
To determine whether this intestinal inhibition is secondary to zinc and folate-forming complexes, charcoal-binding studies were performed. These studies indicate that zinc and folate from complexes at pH 2.0, but that at pH 6.0, these complexes dissolve.
Label source:
PubMed: The American journal of clinical nutrition (1986)
Source url:
Exact phrase from label:
Folic acid, IP3 and IP5 were significant influencing factors for bioavailable zinc.
Label source:
PubMed: Journal of the American College of Nutrition (2006)
Action type:
separate
Target id:
/condition/cancer-history-or-high-risk
Target name:
History of or High Risk for Cancer
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
There is a theoretical concern that high levels of unmetabolized folic acid from high-dose supplementation could accelerate the growth of existing but undiagnosed cancerous cells.
Actionable advice:
Very high doses of folic acid (over 1000 mcg) are generally best avoided unless medically indicated; methylfolate may be a preferable option.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations.
Label source:
NIH workshop review, PMID 33022704. Supports the claim ONLY as a theoretical/inconclusive concern - matching the row's hedge; do not overstate.
Action type:
avoid
Target id:
/class/nsaids
Target name:
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Chronic, long-term use of NSAIDs may interfere with folate metabolism, although the clinical significance is generally low for most people.
Actionable advice:
If you use NSAIDs daily for a prolonged period, ensure your dietary folate intake is adequate.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The long-term cardiovascular toxicity in children exposed to CELEBREX has not been
evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to
CELEBREX or other COX-2 selective and non-selective NSAIDs [see Boxed Warning,
Warnings and Precautions (5.5), and Clinical Studies (14.3)].
Label source:
Action type:
informational_none
Target id:
/intervention/green-tea-extract
Target name:
Green Tea Extract / High-Dose Green Tea
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Concentrated green tea catechins may weakly inhibit dihydrofolate reductase (DHFR), an enzyme crucial for folate metabolism, potentially reducing folate availability.
Actionable advice:
If taking high-dose green tea extract, ensure your folate intake is sufficient.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
we observed a time- and dose-dependent inhibition of DHFR activity by epigallocatechin gallate and a green tea extract. Our data suggest that regular green tea consumption is unlikely to impair folate status in healthy males, despite the DHFR inhibitory activity of GTC.
Label source:
Augustin et al., PMID 19826188. Confirms the DHFR-inhibition MECHANISM but concludes real-world green tea is UNLIKELY to impair folate status. FLAG: clinical relevance is weak - severity should be minor at most.
Action type:
informational_none
Target id:
/class/acid-suppressors
Target name:
Gastric Acid Suppressors (PPIs, H2 Blockers)
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Reduced stomach acid may slightly impair the release and absorption of folate from food sources, though the effect on supplemental folic acid is minimal.
Actionable advice:
Long-term users of acid suppressors should ensure adequate folate intake through diet or supplements.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: folate absorption is modestly pH-dependent (optimal in the acidic proximal small bowel), so chronic acid suppression can slightly reduce it. Minor, monitoring-level; supplemental folic acid is generally well absorbed regardless.
Label source:
Class inference
Action type:
informational_none