NSTK · 01.2026Independent supplement reference
NutriStack
Edition 1.0Updated July 13, 2026

Methotrexate

Prescription ·Exploratory record · not publication-reviewed ·Updated July 13, 2026

The anchor DMARD and most widely used first-line therapy for rheumatoid arthritis, also indicated for psoriatic arthritis, psoriasis, and certain cancers. Low-dose weekly methotrexate is the cornerstone of RA treatment per ACR guidelines. Despite its antimetabolite origins, the anti-inflammatory doses used in rheumatology are far lower than oncologic doses.

Evidence tier
Strong
Indexed sources
10 2016–2025
Interactions
0
Depletes
1 nutrient
Read the sources → Compare profiles
Publication status

Exploratory record, not a reviewed medical publication.

See the editorial and medical-review policies for the publication gate.

This generated database record has not completed a claim-level review by a qualified human medical reviewer. Bibliography links and evidence labels are not approval. The page remains available for reference and is excluded from search indexing.

In short

What the research says.

A quick, data-only summary. The full evidence, dosing, and sources are below.

The anchor DMARD and most widely used first-line therapy for rheumatoid arthritis, also indicated for psoriatic arthritis, psoriasis, and certain cancers. NutriStack rates the supporting evidence as strong. Common adult dosing is RA/PsA: 7.5–25 mg once weekly (oral or subcutaneous); always supplemented with folic acid 1 mg daily (as prescribed by your physician), though a prescriber sets the actual dose. With long-term use it can deplete folate. This profile indexes 10 sources.

What it's good for
  • Disease modification in rheumatoid arthritis3,7
  • Reduction of joint inflammation and damage
  • Treatment of psoriatic arthritis3,7
  • Treatment of moderate-to-severe psoriasis
  • Improved physical function and quality of life in RA
What to watch for
  • Nausea and vomiting (common)
  • Stomatitis (mouth sores)
  • Fatigue and malaise
  • Pregnancy (Pregnancy Category X) and breastfeeding
  • Alcoholism or chronic liver disease

The bottom line

Evidence rating strong. Most-documented uses: disease modification in rheumatoid arthritis, reduction of joint inflammation and damage, treatment of psoriatic arthritis. 10 sources indexed (2016–2025), with 0 interaction records on file.

The science

How it works, mechanistically.

Core mechanism

At low (anti-inflammatory) doses, methotrexate inhibits aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, leading to intracellular accumulation of AICAR, which promotes adenosine release, a potent endogenous anti-inflammatory mediator. Adenosine binds to adenosine receptors on inflammatory cells, suppressing NF-kB activation, reducing TNF-alpha, IL-6, and other pro-inflammatory cytokines. Methotrexate also inhibits dihydrofolate reductase (DHFR), reducing de novo purine and pyrimidine synthesis and lymphocyte proliferation.5,8

Class
Disease-Modifying Antirheumatic Drug (DMARD)
Absorption
Best on an empty stomach
Dosing

Dosing & protocol.

Common range
RA/PsA: 7.5–25 mg once weekly (oral or subcutaneous); always supplemented with folic acid 1 mg daily (as prescribed by your physician)
Recommended form
Tablet (oral) or subcutaneous injection

Take on an empty stomach or with a light snack; ONCE WEEKLY dosing only, daily dosing can be fatal; supplementation with folic acid 1 mg daily (except on MTX day) reduces toxicity

Depletions

What it depletes.

Nutrients this medication can lower over time, and what to replace.

Folate

Significant

Methotrexate directly inhibits dihydrofolate reductase, lowering reduced folate pools and increasing mucosal and hematologic toxicity risk.

Replace Prescriber-directed folic acid or folinic acidMonitor CBC trend + liver enzymes; folate rescue should follow the prescriber's protocolOnset Can develop within days to weeks without folate rescue

Full Methotrexate depletion and interaction guide →

Safety

Full safety detail.

Side effects

  • Nausea and vomiting (common)
  • Stomatitis (mouth sores)
  • Fatigue and malaise
  • Hepatotoxicity (elevated LFTs, fibrosis with long-term use)
  • Bone marrow suppression (pancytopenia)
  • Pneumonitis (acute hypersensitivity lung reaction)
  • Increased infection risk
  • Alopecia

Contraindications

  • Pregnancy (Pregnancy Category X) and breastfeeding
  • Alcoholism or chronic liver disease
  • Immunodeficiency syndromes
  • Pre-existing blood dyscrasias (leukopenia, thrombocytopenia, significant anemia)
  • Severe renal impairment (CrCl <30 mL/min)
  • Active infection
Sources

Sources, by evidence tier.

Numbered references. Citations throughout the page link here.

Meta-analyses & systematic reviews

6

Reference material

4
FAQ

Common questions.

Quick answers about Methotrexate, drawn from the data on this page.

What is Methotrexate?

The anchor DMARD and most widely used first-line therapy for rheumatoid arthritis, also indicated for psoriatic arthritis, psoriasis, and certain cancers. Low-dose weekly methotrexate is the cornerstone of RA treatment per ACR guidelines. Despite its antimetabolite origins, the anti-inflammatory doses used in rheumatology are far lower than oncologic doses.

What is Methotrexate used for?

Commonly cited benefits of Methotrexate include: Disease modification in rheumatoid arthritis; Reduction of joint inflammation and damage; Treatment of psoriatic arthritis; Treatment of moderate-to-severe psoriasis; Improved physical function and quality of life in RA. NutriStack rates the overall evidence as strong.

What is a typical dose of Methotrexate?

A typical adult dose of Methotrexate is RA/PsA: 7.5–25 mg once weekly (oral or subcutaneous); always supplemented with folic acid 1 mg daily (as prescribed by your physician). The commonly recommended form is Tablet (oral) or subcutaneous injection. These are general ranges, not personalized advice; confirm the right dose with a clinician.

What are the side effects of Methotrexate?

Reported side effects include nausea and vomiting (common), stomatitis (mouth sores), fatigue and malaise, hepatotoxicity (elevated lfts, fibrosis with long-term use), bone marrow suppression (pancytopenia), pneumonitis (acute hypersensitivity lung reaction). This is educational information; check with a healthcare professional before use.

How strong is the evidence for Methotrexate?

NutriStack rates this as Strong, meaning multiple high-quality meta-analyses or systematic reviews converge on the same finding. Full tier criteria are at https://nutristackapp.com/methodology/evidence-tiers.

Use this with your stack

Methotrexate in NutriStack.

Add it to your stack, see how it interacts with everything else you take, and get a Stack Score that updates the moment it does.

Download on the App Store → Read the methodology

NutriStack is an informational and organizational tool, not a medical service, and not a substitute for professional advice. Always consult a qualified healthcare professional before starting, stopping, or changing any supplement or medication.