Methotrexate and Vitamin Deficiencies

Methotrexate (often abbreviated as MTX) is a medication commonly used to treat conditions like rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), psoriasis, and certain cancers.
It works by inhibiting the enzyme dihydrofolate reductase, which interferes with folate metabolism. While effective, this mechanism can lead to deficiencies in several vitamins, particularly those in the B-vitamin family and vitamin D. These deficiencies arise from direct interference (e.g., folate depletion), malabsorption caused by gastrointestinal side effects, or interactions with the drug’s antifolate properties.
Below is a summary of the key vitamin deficiencies associated with methotrexate use, based on clinical studies and expert guidelines.
Note that while folic acid supplementation is standard to counteract folate issues, other deficiencies may require monitoring and targeted supplementation under medical supervision.

Common Vitamin Deficiencies Linked to Methotrexate

Vitamin	Why It Occurs	Associated Risks/Symptoms	Management Notes
Folate (Vitamin B9)	Methotrexate directly blocks folate metabolism, leading to rapid depletion. This is the most well-established deficiency.	Megaloblastic anemia, fatigue, mouth sores, gastrointestinal upset, elevated liver enzymes, and increased infection risk.	Routine folic acid (synthetic folate) supplementation (e.g., 1–5 mg weekly, not on MTX dosing day) is recommended for non-cancer patients to reduce side effects without reducing efficacy. Food sources include leafy greens.
Vitamin B12 (Cobalamin)	MTX may impair gastrointestinal absorption (via non-celiac enteropathy), and folate supplementation can mask B12 issues. Risk is higher in older adults, those with RA comorbidities (e.g., pernicious anemia), or concurrent use of drugs like proton-pump inhibitors.	Hyperhomocysteinemia (elevated blood homocysteine, a marker of functional B12 deficiency), anemia, neurological symptoms (e.g., numbness, cognitive issues), and increased cardiovascular risk. It can exacerbate MTX toxicity, like pancytopenia.	Monitor B12 levels and homocysteine periodically, especially in RA patients on MTX. Supplementation (e.g., B12 injections or oral doses) if deficient. Not routinely supplemented unless tested low.
Vitamin D	MTX chemotherapy or long-term use is linked to reduced 25(OH)D levels, possibly due to intestinal damage, inflammation, or altered metabolism. Common in JIA and cancer patients.	Bone loss, growth impairments in children, muscle weakness, worsened RA symptoms, and increased fracture risk.	Supplementation (e.g., calcitriol or vitamin D3) may prevent MTX-induced bone loss. Monitor levels; sources include sunlight, fatty fish, or fortified foods. MTX is a significant risk factor in pediatric JIA.
Vitamin B2 (Riboflavin)	Some evidence suggests that MTX interferes with B2 absorption, although it is less studied.	Fatigue, skin issues, or anemia may compound other B-vitamin deficiencies.	Limited data; monitor if symptoms arise. Food sources: dairy, eggs, almonds. Supplementation is not standard.

Key Considerations

• Monitoring: Regular blood tests for folate, B12, homocysteine, and vitamin D are recommended, especially for long-term users or those with risk factors such as age over 65, kidney disease, or gastrointestinal issues. Untreated deficiencies can worsen MTX side effects, including severe anemia or toxicity.
• Supplementation Cautions: For cancer patients, high-dose folic acid may interfere with the efficacy of MTX; consult your oncologist. Avoid B-complex vitamins on days when taking MTX to prevent potential interactions. Always consult your doctor before taking supplements to avoid over-supplementation.
• Dietary Tips: Prioritize nutrient-rich foods (e.g., spinach for folate, salmon for B12 and D) unless restricted by your condition.
• Special Populations: Children on MTX for JIA are at higher risk for vitamin D deficiency. Older adults with RA may need B12 screening due to hyperhomocysteinemia.

This information is for educational purposes and not a substitute for professional medical advice.
If you’re taking methotrexate, speak with your healthcare provider about personalized screening and supplementation to address any deficiencies.

Below is a comprehensive, evidence-based guide to folic acid supplementation in patients taking methotrexate (MTX). It covers dosing, timing, formulations, evidence, exceptions, and practical tips for non-cancer (e.g., rheumatoid arthritis, psoriasis) and cancer patients.

1. Why Folic Acid Is Used with Methotrexate

• MTX is a folate antagonist → inhibits dihydrofolate reductase (DHFR) → depletes intracellular folate.
• Folic acid (synthetic) or folinic acid (leucovorin) bypasses this block.
• Goal: Reduce MTX toxicity (mucositis, GI upset, cytopenias, hepatotoxicity) without reducing anti-inflammatory or anti-cancer efficacy.

2. Standard Folic Acid Regimens (Non-Cancer Patients)

Regimen	Dose	Timing	Evidence / Notes
Daily low-dose	1 mg daily	Every day except MTX day	Most common in RA/psoriasis. Reduces side effects by ~70–80%.
Weekly high-dose	5 mg once weekly	24–48 h AFTER MTX dose	Preferred in UK/Europe. Same efficacy as daily. Avoids MTX day to minimize interference.
Split weekly	5 mg split into 2.5 mg on 2 days	e.g., Wed + Sun if MTX on Tue	Useful if GI upset with a single 5 mg dose.

Most guidelines recommend 5–10 mg/week total (ACR, EULAR, BSR).

3. Timing Relative to MTX Dose

MTX Schedule	Folic Acid Timing
Weekly oral MTX (e.g., Friday)	5 mg on Sunday (or 1 mg daily except Friday)
Weekly subcutaneous MTX	Same as above
Daily low-dose MTX (rare, e.g., leukemia)	Folinic acid (leucovorin) preferred

Rule of Thumb:

Never take folic acid on the same day as MTX (especially oral MTX) → may slightly reduce efficacy in RA (controversial, but avoided in practice).

4. Formulations

Form	Pros	Cons	Best For
Folic acid (tablets)	Cheap, widely available, stable	Requires conversion to active form (some patients have MTHFR mutations)	General use
L-methylfolate (Deplin, etc.)	Bypasses MTHFR issues	Expensive, limited data with MTX	Rare cases of poor response
Folinic acid (leucovorin)	Active form, bypasses DHFR	Very expensive, IV/oral	Cancer patients, high-dose MTX rescue

Folinic acid is NOT routine for low-dose weekly MTX in RA.

5. Special Populations

Group	Recommendation
Pregnancy / Planning pregnancy	STOP MTX immediately. Use 5 mg folic acid daily pre-conception & during pregnancy (teratogenicity risk).
Elderly	Use 1 mg daily or 5 mg weekly → higher risk of GI/liver side effects.
Renal impairment (CrCl <60)	Reduce folic acid dose (e.g., 1–2.5 mg/week) → MTX accumulates.
Alcoholics / Malabsorption	Check serum folate; may need higher doses or parenteral.

6. Cancer Patients (High-Dose MTX)

Scenario	Supplementation
High-dose IV MTX (>500 mg/m²)	Leucovorin rescue (not folic acid): 10–15 mg/m² q6h until MTX <0.1 µmol/L
Low-dose oral MTX (e.g., maintenance ALL)	Folic acid 1 mg daily (except MTX day) is safe
Intrathecal MTX	No routine folic acid needed

Folic acid can reduce the efficacy of high-dose MTX in cancer → only leucovorin rescue is used.

7. Monitoring & Safety

Test	Frequency	Notes
CBC	Monthly × 3, then q3 months	Watch for macrocytic anemia
Liver enzymes (ALT/AST)	Same as CBC	Folic acid reduces transaminitis
Serum folate	Only if symptoms or non-response	Usually >20 nmol/L with supplementation
Homocysteine	Optional (if B12 also checked)	Elevated if functional folate deficiency

No need to stop folic acid if labs are normal.

8. Practical Tips for Patients

1. Take folic acid with food → reduces nausea.
2. Use a pill organizer → avoid taking on MTX day.
3. Generic 1 mg tablets are fine (split 5 mg if needed).
4. Do NOT take multivitamins with >0.4 mg folic acid on MTX day.
5. If you forget: Take the missed dose as soon as remembered, unless it’s MTX day.

9. Evidence Snapshot

Study	Finding
Shea et al. (2013, Arthritis Rheum)	5 mg folic acid weekly = 79% reduction in MTX discontinuation due to toxicity
Dervieux et al. (2006)	Daily 1 mg = weekly 5 mg in efficacy
Whittle et al. (Cochrane 2013)	Folic/folinic acid reduces GI, liver, and hematologic toxicity

Bottom Line: Recommended Regimen (RA/Psoriasis)

5 mg folic acid once weekly, 24–48 hours AFTER MTX dose
(or 1 mg daily, skipping MTX day)

Always confirm with your rheumatologist or pharmacist.
Never self-adjust cancer-related MTX regimens.

Read Methotrexate and Folic Acid Patient Handout