The predominant natural form in food and blood

Active, methylated form ready for immediate use

Preferred supplemental form for many people

Bypasses MTHFR genetic variations

Better absorbed than folic acid

Brands: Metafolin, Quatrefolic, L-methylfolate

Reduced form of folate

Found naturally in foods

Must be methylated to become 5-MTHF

Active coenzyme form

Natural folate form

Leucovorin in medical use

Bypasses some metabolic steps

Does not require DHFR enzyme

Good alternative to folic acid

Mixture of various polyglutamate forms

Must be converted to monoglutamate for absorption

Lower bioavailability than supplements (50-60%)

Synthetic, oxidized form not found in nature

Must be converted through multiple steps to active 5-MTHF

Requires DHFR (dihydrofolate reductase) enzyme

Can accumulate as unmetabolized folic acid (UMFA)

Most common in supplements and fortification

More stable and cheaper than natural forms

~85% bioavailable

400-800 mcg: completely safe and essential

Proven benefit: decades of safe use

No birth defects: from supplementation

Required for all pregnant women

Up to 5,000 mcg: used safely in high-risk pregnancies

Medical supervision: for very high doses

Specific indications: previous NTD, certain medications

Generally well-tolerated

No UMFA accumulation

Better tolerated at high doses

Preferred for therapeutic use

Upper limit less relevant

Main concern: B12 masking (take B12 with folate)

Natural folates: extremely safe

Folic acid: safe at reasonable doses (<1,000 mcg)

Food sources: impossible to overdose

Upper limit: conservative, set for safety margin

Measures folate in blood

Normal range: >3 ng/mL (>6.8 nmol/L)

Deficiency: <3 ng/mL

Reflects recent intake more than stores

Can fluctuate with diet

Less useful than RBC folate

Gold standard for folate status

Reflects tissue stores over 3-4 months

Normal range: >140 ng/mL (>317 nmol/L)

Optimal: >400 ng/mL for pregnancy

Less affected by recent intake

Better indicator of long-term status

Functional marker of folate (and B12, B6) status

Normal: <10-12 μmol/L

Elevated: >15 μmol/L concerning

Reflects adequacy of methylation

Also affected by B12 and B6

Cardiovascular risk marker

Megaloblastic anemia: large red blood cells

Macrocytosis: MCV >100 fL

Hypersegmented neutrophils

Low hemoglobin and hematocrit

Indicates deficiency

Distinguishes B12 from folate deficiency

Elevated only in B12 deficiency

Normal in folate deficiency

Critical test when B12 masking suspected

C677T polymorphism: most common (30-40% have one copy)

A1298C polymorphism: also common

Homozygous C677T: 10-15% of population

Commercial tests: 23andMe, specialty labs

Indicates need for 5-MTHF form

Before pregnancy: baseline folate status

Suspected deficiency: symptoms present

Megaloblastic anemia: diagnosed

Elevated homocysteine: check folate, B12, B6

Malabsorption: monitor status

Medications: on drugs that deplete folate

MTHFR testing: if family history or symptoms

Baseline: before starting high-dose folate

Follow-up: 3 months after starting

Homocysteine: if elevated, recheck after 2-3 months

Pregnancy: may test if previous deficiency

Regular monitoring: if on long-term high doses

Fatigue, weakness, pallor

Mental status: mood, cognition

Oral symptoms: tongue, mouth sores

Neurological: tingling, numbness (check B12 too)

Diet quality and variety

Alcohol consumption

Medication use

Pregnancy status or planning

Family history

Start supplementation: 400-800 mcg daily

Build folate stores before conception

Neural tube closes: 21-28 days after conception (often before pregnancy known)

Blood levels: achieve optimal RBC folate >400 ng/mL

5-MTHF preferred: if MTHFR variants or better absorption desired

Continue 600-800 mcg daily minimum

Neural tube formation: weeks 3-4 of pregnancy

Cell division rapid: folate demands highest

Brain development: critical early period

Never skip: even one day could matter

600-800 mcg daily: maintain throughout

Increased needs: placental growth, fetal development

Prevent complications: anemia, preeclampsia, preterm birth

Support maternal health: energy, mood, immunity

Continue breastfeeding: 500 mcg daily while nursing

Previous NTD: 4,000-5,000 mcg daily

Family history: of neural tube defects

Diabetes: Type 1 or Type 2

Obesity: BMI >30

Anti-epileptic drugs: especially valproate

Multiple pregnancy: twins, triplets

Medical supervision: for high-dose protocols

Cleft lip/palate: reduced risk

Congenital heart defects: lower incidence

Preterm birth: reduced risk

Low birth weight: prevention

Preeclampsia: lower risk

Autism: some studies suggest lower risk with adequate folate

Childhood cognition: better outcomes with adequate maternal folate

Heterozygous (one copy): 30-40% of population, ~30% reduced enzyme activity

Homozygous (two copies): 10-15% of population, ~70% reduced enzyme activity

Effects: reduced conversion of folic acid to 5-MTHF

May need: higher folate intake or 5-MTHF form

Heterozygous: common, mild effect

Homozygous: moderate enzyme reduction

Less impact: than C677T

Combined: compound heterozygous (C677T + A1298C)

Elevated homocysteine: especially C677T homozygous

Increased risk: cardiovascular disease, pregnancy complications

May need: 5-MTHF instead of folic acid

Higher doses: sometimes required

Not a disease: just requires different form or higher dose

5-MTHF form: 400-1,000 mcg daily (bypasses enzyme)

B12 (methylcobalamin): 500-1,000 mcg daily

B6: 25-50 mg daily

Betaine (TMG): 500-1,000 mg (alternative pathway)

B2 (Riboflavin): 50-100 mg (supports MTHFR enzyme)

Avoid high-dose folic acid: may accumulate as UMFA

MTHFR overhyped: in functional medicine circles

Not always problematic: many people do fine with folic acid

Testing useful: but not always necessary

Reasonable approach: use 5-MTHF if uncertain

Low folate: associated with depression

Deficiency common: in depressed patients (15-38%)

Predictor of response: low folate = poor antidepressant response

Supplementation: improves antidepressant effectiveness

Mechanism: methylation, neurotransmitter synthesis

Prescription form: Deplin (7.5 mg or 15 mg)

Medical food: not FDA-approved drug but regulated

Evidence: improves antidepressant response

Augmentation: added to SSRIs or SNRIs

Dosage: 7.5-15 mg daily (much higher than nutritional dose)

Responders: especially those with MTHFR variants or low folate

Lower doses: 400-1,000 mcg typical

May help: mild to moderate depression

Not replacement: for prescription medication

Adjunct therapy: alongside other treatments

Safe to try: very low risk

Check folate: baseline RBC folate and homocysteine

Check B12: always test B12 with folate

5-MTHF: 400-1,000 mcg daily (or prescription 7.5-15 mg)

B12: 1,000 mcg methylcobalamin daily

B6: 50-100 mg daily

Omega-3s: 2-3g daily (EPA-rich)

Timeline: 4-8 weeks to assess benefit

Medical supervision: especially if on medications

Schizophrenia: some benefit as adjunct

Bipolar disorder: may help depressive episodes

Anxiety: indirect benefits through neurotransmitters

Cognitive decline: prevention and slowing

Elevated levels: >10-15 μmol/L increase cardiovascular risk

Folate effective: lowers homocysteine 20-30%

Requires B12 and B6: for complete pathway

Target: <10 μmol/L optimal

Timeline: 4-8 weeks to see reduction

Folate: 400-1,000 mcg daily (5-MTHF preferred)

B12: 500-1,000 mcg (methylcobalamin)

B6: 25-50 mg

Betaine: 500-1,000 mg (additional methyl donor)

Monitor: homocysteine every 3-6 months

Stroke reduction: some studies show benefit

Heart disease: mixed results in trials

Atherosclerosis: may slow progression

Most benefit: in those with elevated homocysteine

Primary prevention: beneficial

Secondary prevention: mixed results

Elevated homocysteine (>12 μmol/L)

Family history of heart disease

MTHFR variants

Stroke prevention

Kidney disease (often elevated homocysteine)

DNA integrity: prevents chromosomal damage

DNA methylation: proper gene expression

Colorectal cancer: reduced risk with adequate folate

Other cancers: generally protective at adequate levels

Tumor promotion: may promote existing tumors

Colorectal polyps: high doses may increase advanced adenomas

Prostate cancer: some concern with high folic acid

Timing matters: protective before cancer, risky after

Adequate intake: 400-600 mcg protective

Avoid mega-doses: >1,000 mcg without medical reason

Food sources: natural folates safest

If cancer diagnosed: discuss with oncologist

Surveillance: colonoscopy if family history

U-shaped relationship: too little and too much both problematic

Sweet spot: 400-800 mcg appears optimal

Natural folates: safer than synthetic folic acid

Individual variation: genetics play a role

US, Canada: since 1998 (140 mcg per 100g enriched grain)

Many countries: worldwide adoption

Public health success: 20-50% reduction in NTDs

Flour, bread, pasta, rice: commonly fortified

Breakfast cereals: often highly fortified

NTD reduction: dramatic public health achievement

Improved folate status: in general population

Reduced deficiency: especially in vulnerable groups

Cost-effective: major prevention for small investment

UMFA accumulation: some people have high levels

B12 masking: theoretical increased risk

Cancer: mixed evidence on effects

Overconsumption: some get >1,000 mcg from fortified foods + supplements

Lack of choice: difficult to avoid if trying

Check total intake: food + supplements

Read labels: fortified foods add up

Natural sources: emphasize when possible

Appropriate supplementation: don't double up unnecessarily

Breast milk: adequate if mother folate-replete

Formula: fortified with folate

No supplementation: usually unless specific indication

Maternal status: most important

Growth: higher needs during rapid growth

Diet quality: ensure adequate vegetable/legume intake

Supplementation: usually through multivitamin

Age-appropriate: scale doses to body weight

Girls: start thinking about preconception folate

Growth spurts: increased needs

Diet often poor: may benefit from supplementation

Education: importance for future pregnancy

Women childbearing age: 400 mcg daily essential

Men: 400 mcg adequate for general health

Cardiovascular prevention: especially if elevated homocysteine

Mental health: may help with mood

Absorption decreases: with age and medications

Higher needs: due to reduced efficiency

Cognitive protection: may slow decline

B12 critical: always combine with B12

Monitor status: especially if on PPIs, H2 blockers

Dosage: 400-800 mcg daily reasonable

Not ergogenic: doesn't enhance performance directly

Adequate levels: important for red blood cell production

Energy metabolism: supports cellular energy

Recovery: cell division and repair

High cell turnover: exercise increases demands

Oxidative stress: may increase requirements

Adequate intake: 400-800 mcg ensures sufficiency

No mega-doses: needed for athletes

Exercise: acute elevation after intense exercise

Chronic elevation: if inadequate B vitamins

Cardiovascular health: important for endurance athletes

B-complex approach: folate, B12, B6 together

DNA synthesis and cell division: essential for all rapidly dividing cells

Neural tube defect prevention: 70% reduction with adequate intake

Methylation and homocysteine: works with B12 and B6 to lower cardiovascular risk

Form matters: 5-MTHF superior to folic acid for many people

Always combine with B12: prevents B12 deficiency masking

MTHFR variations common: 40-50% have at least one variant

Dose: 400-800 mcg daily (ALL women who could become pregnant)

Form: Folic acid proven effective, 5-MTHF excellent alternative

Start: BEFORE pregnancy (1-3 months preconception)

Continue: Throughout pregnancy (600-800 mcg) and breastfeeding (500 mcg)

High-risk: 4,000-5,000 mcg if previous NTD or high-risk factors

Non-negotiable: most important supplementation for this group

Dose: 400 mcg daily

Form: Either folic acid or 5-MTHF fine

Source: Multivitamin or B-complex adequate

Food: Emphasize leafy greens, legumes, fortified grains

Dose: 400-1,000 mcg daily

Form: 5-MTHF preferred

Combination: B12 (500-1,000 mcg) + B6 (25-50 mg) essential

Betaine: 500-1,000 mg for additional support

Monitor: Homocysteine every 3-6 months, target <10 μmol/L

Dose: 400-1,000 mcg daily (or prescription 7.5-15 mg L-methylfolate)

Form: 5-MTHF strongly preferred

Combination: B12 (1,000 mcg) + B6 (50-100 mg) + Omega-3s (2-3g)

Timeline: 4-8 weeks to assess benefit

Adjunct: Adds to antidepressant effectiveness

Dose: 400-1,000 mcg daily

Form: 5-MTHF ESSENTIAL (bypasses enzyme deficiency)

Combination: B12 (methylcobalamin) + B6 + B2 (50-100mg)

Betaine: 500-1,000 mg (alternative pathway)

Avoid: High-dose folic acid (may accumulate as UMFA)

Pregnancy (proven effective for NTD prevention)

Cost-effective general supplementation

No known MTHFR mutations

Standard multivitamins

Fortified foods

MTHFR genetic variations (C677T, A1298C)

Depression or mental health support

Elevated homocysteine

Concerns about UMFA accumulation

Poor response to folic acid

Optimal absorption desired

Worth extra cost for many people

Always take with B12: prevents B12 deficiency masking

Monitor B12 levels: especially elderly, vegans, on PPIs

Upper limit 1,000 mcg: from folic acid supplements

Natural folates safe: no upper limit for food folate

Pregnancy essential: but standard doses (400-800 mcg)

ALL women who could become pregnant (400-800 mcg)

Pregnant/breastfeeding women (600-800 mcg)

People with elevated homocysteine (400-1,000 mcg + B12 + B6)

Depression sufferers (5-MTHF 400-1,000 mcg or prescription doses)

MTHFR variants (5-MTHF 400-1,000 mcg)

Medication users (methotrexate, anti-epileptics, sulfasalazine)

Alcohol consumers (800-1,000 mcg minimum)

Elderly (400-800 mcg)

Malabsorption disorders (800-1,000 mcg)

Water-soluble vitamin, daily intake needed

Heat-sensitive, destroyed by cooking

Light-sensitive, degraded by UV exposure

Critical for DNA synthesis and cell division

Essential for methylation reactions

Works intimately with vitamin B12

Provides methyl groups for nucleotide synthesis

Essential for making thymine (DNA base)

Required for purine synthesis

Critical during rapid cell division

DNA repair and maintenance

Chromosome integrity

Essential for all rapidly dividing cells

Red blood cell formation

White blood cell production

Intestinal cell turnover

Skin cell regeneration

Fetal development

Converts homocysteine to methionine

Generates SAMe (S-adenosylmethionine)

Gene expression regulation

Neurotransmitter synthesis

Detoxification pathways

Epigenetic modifications

Homocysteine metabolism (with B12 and B6)

Methionine synthesis

Serine and glycine interconversion

Histidine metabolism

Serotonin synthesis (mood)

Dopamine production (motivation)

Norepinephrine (alertness)

Requires adequate folate for methylation

Prevents megaloblastic anemia

Essential for hemoglobin synthesis

Proper red blood cell maturation

Oxygen transport capacity

Prevents neural tube defects (70% reduction)

Reduces risk of cleft lip and palate

Prevents congenital heart defects

Supports placental development

Reduces preeclampsia risk

Lowers preterm birth risk

Essential for fetal brain development

Lowers homocysteine levels (heart disease marker)

Reduces stroke risk (especially with B12)

May lower blood pressure

Protects against atherosclerosis

Reduces cardiovascular mortality

Improves endothelial function

Reduces depression risk and severity

Improves antidepressant effectiveness

Supports cognitive function and memory

May slow cognitive decline in elderly

Reduces dementia risk (with B12)

Supports neurotransmitter balance

May help with schizophrenia symptoms

May reduce colorectal cancer risk (complex relationship)

Protects against chromosomal damage

Maintains DNA integrity

Effect varies by dose and timing

Too much may promote existing tumors

Adequate levels protective

Supports white blood cell production

Enhances immune response

Important for thymus function

Antibody production

Cellular immunity

Lowers homocysteine (high levels increase fracture risk)

Supports bone cell function

May reduce osteoporosis risk

Works with B12 for bone density

Male fertility: improves sperm quality and count

Female fertility: supports ovulation and implantation

Reduces miscarriage risk

Supports early embryo development

Infants 0-6 months: 65 mcg DFE

Infants 7-12 months: 80 mcg DFE

Children 1-3 years: 150 mcg DFE

Children 4-8 years: 200 mcg DFE

Children 9-13 years: 300 mcg DFE

Males 14+ years: 400 mcg DFE

Females 14+ years: 400 mcg DFE

Pregnancy: 600 mcg DFE

Breastfeeding: 500 mcg DFE

1 mcg DFE = 1 mcg food folate

1 mcg DFE = 0.6 mcg folic acid from supplements (taken with food)

1 mcg DFE = 0.5 mcg folic acid from supplements (taken on empty stomach)

Example: 400 mcg folic acid supplement = 667-800 mcg DFE

Adults: 1,000 mcg daily (from folic acid only, not natural folates)

Concern: May mask B12 deficiency

Natural folates: No established upper limit

Maintenance: 400-800 mcg daily

Multivitamin: Usually contains 400-800 mcg

Food folate equivalent: Aim for 400+ mcg DFE from all sources

Preconception: 400-800 mcg daily (start 1-3 months before)

First trimester: 600-800 mcg daily minimum

Throughout pregnancy: 600-800 mcg daily

High-risk women: 4,000-5,000 mcg daily (previous NTD, certain medications)

Preferred form: 5-MTHF or mixed folates

Homocysteine reduction: 400-1,000 mcg daily

Combined with B12 (500-1,000 mcg) and B6 (25-50 mg)

Target homocysteine: Below 10 μmol/L

Adjunct to antidepressants: 400-1,000 mcg daily

5-MTHF preferred: 7.5-15 mg for depression (prescription L-methylfolate)

Stand-alone: 400-800 mcg daily for mood support

Works best with B12 and B6

Optimal range: 400-600 mcg daily

Avoid mega-doses: >1,000 mcg may promote existing tumors

Food sources preferred: Natural folates safest

5-MTHF form: 400-1,000 mcg daily

Bypass conversion issues

Higher doses sometimes needed: Up to 5-15 mg (medical supervision)

Pregnancy and breastfeeding (highest needs)

Alcohol consumption (significant depletion)

Oral contraceptives (modest increase)

Certain medications (methotrexate, sulfasalazine, others)

Malabsorption disorders (celiac, Crohn's)

MTHFR genetic variations

Psoriasis, eczema (increased cell turnover)

Hemodialysis (removes folate)

Advanced age (reduced absorption)

Beef liver: 215 mcg per 3 oz (richest source)

Chicken liver: 654 mcg per 3 oz (extremely high)

Spinach (cooked): 263 mcg per cup

Black-eyed peas: 211 mcg per cup (cooked)

Asparagus: 268 mcg per cup (cooked)

Brussels sprouts: 157 mcg per cup (cooked)

Fortified breakfast cereals: 100-400 mcg per serving

Lentils: 358 mcg per cup (cooked)

Chickpeas: 282 mcg per cup (cooked)

Kidney beans: 131 mcg per cup (cooked)

Pinto beans: 294 mcg per cup (cooked)

Broccoli: 168 mcg per cup (cooked)

Avocado: 90 mcg per medium fruit

Romaine lettuce: 64 mcg per cup (raw)

Bread (fortified): 40 mcg per slice

White rice (fortified): 90 mcg per cup (cooked)

Pasta (fortified): 102 mcg per cup (cooked)

Eggs: 24 mcg per large egg

Orange: 29 mcg per medium orange

Orange juice: 35 mcg per cup

Banana: 24 mcg per medium fruit

Tomato juice: 49 mcg per cup

Green beans: 33 mcg per cup (cooked)

Peanuts: 88 mcg per 1/4 cup

Sunflower seeds: 76 mcg per 1/4 cup

Beets: 148 mcg per cup (cooked)

Cooking: Destroys 50-90% of folate (water-soluble, heat-sensitive)

Boiling: Worst method, leaches folate into water

Steaming: Better preservation than boiling

Microwaving: Minimal loss

Storage: Fresh vegetables lose folate over time

Light exposure: UV light degrades folate

Food processing: Significant losses during processing

Fortification: Added back to refined grains in many countries

Most common and cheapest form

Highly stable, long shelf life

Must be converted to active 5-MTHF

Requires DHFR enzyme (can be overwhelmed at high doses)

May accumulate as unmetabolized folic acid (UMFA)

85-100% bioavailable

Used in fortification programs

Proven to prevent neural tube defects

Dosage: 400-1,000 mcg daily typical

Active, methylated form (L-methylfolate)

No conversion needed, immediate use

Bypasses MTHFR genetic polymorphisms

No UMFA accumulation

Better for people with MTHFR variations

More expensive than folic acid

Brands: Metafolin (Merck), Quatrefolic (Gnosis)

May be better absorbed than folic acid

Preferred for depression treatment

Dosage: 400-1,000 mcg daily (up to 15 mg for depression)

Natural folate form

Leucovorin in medical use

Bypasses DHFR enzyme

Good alternative to folic acid

More stable than other natural forms

Used in cancer treatment protocols

Dosage: 400-800 mcg daily typical

Combination of natural folate forms

From food sources or fermentation

May include 5-MTHF, folinic acid, and others

Potentially better than folic acid alone

More expensive

General prevention and health maintenance

Cost-effective supplementation

Pregnancy (proven safe and effective)

No known MTHFR mutations

Fortified foods (standard form)

MTHFR genetic variations (C677T or A1298C)

Depression or mental health issues

Poor response to folic acid

Concerns about UMFA accumulation

Methylation support

Cardiovascular disease with homocysteine

Worth extra cost for optimization

Alternative to folic acid

MTHFR variations

When 5-MTHF too expensive

Specific medical protocols

With or without food: both effective (food may enhance absorption)

Morning preferred: may be energizing for some

Consistent daily dosing: maintains steady levels

High doses: can be split throughout day

Before pregnancy: start 1-3 months before conception

Intimately linked: B12 and folate work together in methylation

Homocysteine: Both needed to lower levels

Methylation: B12 converts 5-MTHF back to THF (methyl trap without B12)

Deficiency masking: High folate can mask B12 deficiency

Always combine: Take together for cardiovascular and neurological health

Dosage: 500-1,000 mcg B12 with 400-800 mcg folate

Homocysteine: Third member of homocysteine-lowering trio

Transsulfuration: B6 converts homocysteine to cysteine

Neurotransmitters: Both needed for synthesis

Complete pathway: All three B vitamins (B6, B9, B12) together

Dosage: 25-50 mg B6 with folate and B12

B2 (Riboflavin): Required for MTHFR enzyme function

B3 (Niacin): Methylation pathway support

Complete B-complex: Prevents imbalances

All work synergistically: Better together than alone

Alternative methyl donor pathway

Reduces folate requirements

Methylation support

Brain health synergy

Pregnancy: both critical for fetal development

Direct homocysteine to methionine conversion

Methyl donor like folate

Reduces folate needs

Liver support

Homocysteine: powerful combination with folate

Required for many folate-dependent enzymes

Methylation support

Energy metabolism

Cardiovascular health

Folate metabolism

DNA synthesis support

Immune function

Cell division

Folate: 600-800 mcg (start preconception)

Choline: 450-550 mg (critical for fetal brain)

Iron: 27 mg (if deficient)

DHA: 200-300 mg (brain development)

Iodine: 150-220 mcg (thyroid function)

Comprehensive prenatal: covers all bases

Folate: 400-1,000 mcg

B12: 500-1,000 mcg (methylcobalamin)

B6: 25-50 mg

Betaine: 500-1,000 mg (TMG)

Omega-3s: 1-2g daily (anti-inflammatory)

5-MTHF: 400-1,000 mcg (or 7.5-15 mg prescription)

B12: 1,000 mcg (methylcobalamin)

B6: 50-100 mg

SAMe: 400-800 mg (methyl donor)

Omega-3s: 2-3g daily (EPA-rich)

5-MTHF: 400-1,000 mcg (bypasses enzyme)

B12: 1,000 mcg (methylcobalamin)

B2: 50-100 mg (supports MTHFR enzyme)

Betaine: 500-1,000 mg (alternative pathway)

Folate antagonist: drug designed to block folate

DO NOT take folate: during methotrexate treatment week

Timing critical: folate given 24-48 hours after methotrexate

Leucovorin rescue: folinic acid used medically

Medical supervision: essential for coordination

Undermines treatment: folate during treatment reduces effectiveness

Inhibits folate absorption significantly

Supplementation needed: 1,000-2,000 mcg daily

Long-term use: monitor folate status

Separate timing: take folate away from medication

Reduce folate levels significantly

Supplementation needed: 400-1,000 mcg daily

Bidirectional: folate may reduce drug levels

Medical supervision: coordinate with neurologist

Monitor seizure control: adjust doses as needed

Folate antagonist properties

Short-term use: usually not problematic

Long-term use: may need folate supplementation

Separate timing: several hours apart

Modest folate depletion

Supplementation helpful: 400-800 mcg daily

Especially important: if planning pregnancy soon after stopping

Safe to combine

Cholestyramine/Colestipol: bind folate, reduce absorption

Take 4+ hours apart from folate supplements

Monitor folate status

Reduce folate absorption

H2 blockers and PPIs: may affect B vitamin absorption

Take supplements away from antacids

May interfere with folate metabolism

Usually not clinically significant

Monitor if on high-dose aspirin chronically

Many deplete folate

Medical supervision: coordinate supplementation

Timing critical: may interfere with treatment

Blocks folate absorption in intestines

Increases urinary folate excretion

Impairs folate metabolism in liver

Chronic alcoholism: major cause of deficiency

Moderate drinkers: 800 mcg daily minimum

Heavy drinkers: 1,000-2,000 mcg daily

Food sources: emphasize folate-rich foods

B-complex: all B vitamins depleted by alcohol

High folate: can correct anemia of B12 deficiency

Neurological damage: continues despite corrected anemia

Dangerous: allows B12 neuropathy to progress

Always combine: B12 with folate supplementation

Monitor B12: especially in elderly, vegans, on PPIs

Genetic variations: C677T and A1298C common

Reduced enzyme activity: can't convert folic acid efficiently

5-MTHF preferred: bypasses the issue

Not necessarily deficient: but may need active form

Testing available: 23andMe, specialty labs

All women who could become pregnant

Neural tube defects: occur in first 3-4 weeks (before most know they're pregnant)

Start preconception: 1-3 months before trying

Continue throughout pregnancy and breastfeeding

400-800 mcg daily minimum

Higher risk women: 4,000-5,000 mcg daily

Non-negotiable: most important supplementation for this group

Previous neural tube defect: 4,000-5,000 mcg daily

Family history: of NTDs

Diabetes: increased NTD risk

Obesity: higher folate needs

Anti-epileptic drugs: valproate, carbamazepine

Medical supervision: for high-dose protocols

Elevated homocysteine: >10-12 μmol/L

Heart disease: family or personal history

Stroke prevention: especially with B12 and B6

Atherosclerosis: plaque buildup

High blood pressure: may help reduce

Depression: especially treatment-resistant

Low folate levels: associated with depression

Antidepressant augmentation: improves medication response

Cognitive decline: prevention and slowing

Schizophrenia: some benefit as adjunct

Mood disorders: general mood support

C677T homozygous: 10-15% of population

A1298C: another common variant

Compound heterozygous: one of each

5-MTHF form essential: bypasses enzyme deficiency

Higher needs: may need more than standard doses

Methotrexate: folate rescue protocols (medical supervision)

Anti-epileptics: significantly depleted

Sulfasalazine: long-term IBD treatment

Oral contraceptives: modest depletion

PPIs/H2 blockers: long-term use

Aspirin: high-dose chronic use

Celiac disease: malabsorption

Crohn's disease: impaired absorption

Inflammatory bowel disease: increased needs

Chronic diarrhea: losses increased

Post-gastric bypass: reduced absorption

Alcohol consumption: even moderate depletes folate

Poor diet: inadequate vegetable/legume intake

Smoking: increases folate needs

High stress: increases metabolic demands

Elderly: reduced absorption, increased needs

Cognitive decline: prevention strategy

Reduced stomach acid: impairs absorption

Often on multiple medications: increased depletion

Psoriasis: increased cell turnover

Eczema: rapid skin cell division

Hemodialysis: removes folate

Sickle cell anemia: increased red blood cell production

Hemolytic anemia: rapid cell turnover

Low folate: increases cancer risk

Adequate folate: protective

High-dose folate: may promote existing tumors

Timing matters: protective before, potentially harmful after

Medical supervision: essential if diagnosed with cancer

Moderate doses: 400-600 mcg likely safe

Avoid mega-doses: >1,000 mcg without medical guidance

High folate masks: anemia improves but nerve damage continues

Always check B12: before high-dose folate

Combined supplementation: always take B12 with folate

Elderly at risk: reduced B12 absorption

Vegans/vegetarians: low B12 intake

Pernicious anemia: autoimmune B12 deficiency

Neurological symptoms: tingling, numbness, balance issues

High-dose folate: may reduce anti-epileptic drug levels

Medical supervision: essential for coordination

Don't avoid folate: but dose carefully

Monitor seizure control: when starting supplementation

Medication adjustment: may be needed

Folate supplementation: may increase malaria risk

Folate antagonists: used to treat malaria

Medical guidance: in malaria-endemic regions

Risk-benefit: weigh carefully

Do not take: during treatment week

Timing critical: folate 24-48 hours after methotrexate

Medical protocols: specific rescue timing

Undermines treatment: if taken incorrectly

Bidirectional interaction: affects drug and drug affects folate

Medical supervision: coordinate dosing

Monitor levels: both folate and medication

Don't stop supplementing: but coordinate timing

Folic acid fine: can convert effectively

Standard supplements: work well

No special considerations

Folic acid problematic: conversion impaired

5-MTHF preferred: bypasses enzyme

UMFA accumulation: concern with high-dose folic acid

Lower doses: if using folic acid

May mask B12 deficiency

Possible cancer promotion (if existing tumors)

May reduce natural killer cell activity

UMFA accumulation with folic acid

Monitor carefully if using high doses

Medical supervision: required

Specific indications: depression, certain genetic conditions

Prescription L-methylfolate: for depression (7.5-15 mg)

Not for general use

Heat-sensitive and destroyed by cooking

Alcohol depletes significantly

Many medications interfere

Poor diet common

Increased needs in pregnancy often unmet

Fatigue and weakness

Irritability and mood changes

Difficulty concentrating (brain fog)

Headaches

Loss of appetite

Shortness of breath with exertion

Pallor (pale skin)

Sore, red tongue (glossitis)

Mouth ulcers and sores

Loss of taste

Burning sensation in mouth

Depression and anxiety

Irritability

Cognitive difficulties

Memory problems

Insomnia

Megaloblastic anemia: large, immature red blood cells

Macrocytic anemia: enlarged red blood cells

Low red blood cell count

Low hemoglobin

Fatigue severe and progressive

Weakness and lethargy

Shortness of breath

Diarrhea

Nausea

Weight loss

Loss of appetite

Digestive disturbances

Elevated homocysteine levels

Increased cardiovascular risk

May contribute to heart disease over time

Peripheral neuropathy: tingling, numbness

Balance problems

Memory impairment

Depression worsening

Profound weakness and fatigue

Severe shortness of breath

Rapid heartbeat (tachycardia)

Pale or jaundiced appearance

Hypersegmented neutrophils (diagnostic finding)

Pancytopenia: low all blood cell types

Requires immediate medical treatment

Neural tube defects: spina bifida, anencephaly

Cleft lip and palate

Congenital heart defects

Low birth weight

Preterm birth

Placental abruption

Preeclampsia

Miscarriage and stillbirth

Fetal neural tube defects

Cognitive impairments in offspring

Behavioral problems in children

Developmental delays

Impaired immune response

Increased infection susceptibility

Reduced white blood cell function

Poor wound healing

Severe depression

Cognitive impairment

Elevated homocysteine (>15 μmol/L)

Increased cancer risk long-term

Osteoporosis risk

Infertility

Pregnant and breastfeeding women

Chronic alcoholics

People with malabsorption (celiac, Crohn's)

Elderly with poor diets

People on certain medications (methotrexate, anti-epileptics)

Dialysis patients

People with MTHFR mutations (if on folic acid)

Smokers

Individuals with eating disorders

Spina bifida: incomplete closure of spine

Anencephaly: absence of major brain portions (fatal)

Encephalocele: brain tissue protrudes through skull

21-28 days after conception

Before most women know they're pregnant

Why preconception supplementation critical

400-800 mcg daily: 70% reduction in NTDs

Must start before pregnancy

All women of childbearing age should supplement

Fortification programs: reduced NTDs by 20-50% in populations

No known toxicity

No upper limit for food folate

Excess excreted in urine

Virtually impossible to overdose from food

Corrects megaloblastic anemia from B12 deficiency

Neurological damage continues undetected

Allows irreversible nerve damage to progress

Particularly dangerous in elderly

Why upper limit set at 1,000 mcg

Accumulation: when DHFR enzyme overwhelmed (>400 mcg single dose)

Concerns: potential immune effects, cancer promotion

Research mixed: effects not fully understood

May reduce natural killer cell activity

Theoretical concern more than proven toxicity

Masks B12 deficiency (main concern)

May promote existing tumors (debated)

Possible immune effects (reduced NK cells)

Sleep disturbances (some people)

Vivid dreams or nightmares (rare)

Irritability or mood changes (rare)

Skin reactions (rare)

Gastrointestinal upset (rare)

Zinc depletion (very high doses)

Altered mental status (extremely high doses)

Seizures (in epileptic patients, rare)

Neuropathy (rare, usually other causes)