This page shows what was measured, who it was measured in, and what that does not settle.
What Methotrexate does in the body
Methotrexate blocks the enzyme that turns folate into the usable form, so cells that are dividing fast run out of the parts they need.
Folate is the raw material cells use to build new DNA. At the high doses used in leukaemia, that is exactly the point: the cancer cells divide fastest and die first. At the low weekly doses used in arthritis the drug is doing something else — something anti-inflammatory that is probably about adenosine release rather than about blocking DNA at all — and the official prescribing information says outright that the mechanism in rheumatoid arthritis and psoriasis is unknown.
Why people take it. Rheumatoid arthritis, juvenile arthritis, severe psoriasis, and some cancers
What happened in people
Change in DAS28 of -2.1 with triple conventional therapy against -2.3 with etanercept plus methotrexate at 48 weeks, meeting non-inferiority in 353 patients
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
The limit that matters most
That methotrexate treats rheumatoid arthritis by inhibiting dihydrofolate reductase — the label states the mechanism in rheumatoid arthritis and psoriasis is unknown
Where it acts
Dihydrofolate reductase in the cytoplasm of rapidly dividing cells; at anti-inflammatory doses the relevant site is not established
Kind of result
The kind of result is not recorded
Supervision
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
What the registries record it as
24 registered substances share the start of this name, which is why a search for it can return more than one thing.
FDA substance registry · 99ITO15X8S · read 2026-08-29
Where each sentence above came from
A person wrote this explanation into the record, with the studies named in the path below.
The recorded use, written for a reader without medical training. Not signed off.
A limit recorded against this substance. Not signed off as a reviewed claim.
The four opening statements run to 135 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
Receptor
A receptor is a part of a cell that a signal fits into.
A picture of it, and where the picture fails
A receptor is like a lock waiting for one key.
Where that stops being true. A lock either opens or does not. A receptor can be half-triggered, or worn out.
What people get wrong. Fitting a receptor is read as causing a benefit. It causes a step, and nothing more.
A protein that binds a specific ligand and converts that binding into a cellular response.
Pathway
A pathway is a chain of steps inside a cell, each one setting off the next.
A picture of it, and where the picture fails
A pathway is like a row of dominoes.
Where that stops being true. Dominoes fall one way. Pathways loop back and can switch themselves off.
What people get wrong. Changing one step is read as changing the outcome. Other steps often absorb it.
An ordered series of molecular interactions producing a defined cellular change.
What happened in people◇Read from sources, not yet reviewed
What was measured, goal by goal
One row for each goal a registered study measured something for. One column for each kind of thing that could be measured.
Registered studies list 40 outcome measures that RNAWiki could read. A registered study says what someone planned to measure. It does not say what they found. 0 of the matched studies tested this substance, and 0 posted a result.
There is no single score. A strong test result and a weak life result are different facts.
Goals down the side, kinds of measurement across the top. Each cell says what kind of thing was registered, not what was found.
Goal
Life outcome
What a body can do
How a person feels
A test result
A step in the body
Harms
How long
Who was studied
Recovery
∅Nothing in the sources checkedNo registered study lists a life outcome for this goal.
∅Nothing in the sources checkedNo registered study lists a performance measure for this goal.
∅Nothing in the sources checkedNo registered study lists a symptom measure for this goal.
∅Nothing in the sources checkedNo registered study lists a test result for this goal.
∅Nothing in the sources checkedNo registered study lists a body-step measure for this goal.
—Not recordedHarms were not a registered measure for this goal.
—Not recordedNo finished study window is recorded.
…Waiting for a reviewerWho was studied is listed further down the page.
Healthy ageing
…Waiting for a reviewer1 registered study measure of this kind. No reviewed result yet.
∅Nothing in the sources checkedNo registered study lists a performance measure for this goal.
∅Nothing in the sources checkedNo registered study lists a symptom measure for this goal.
∅Nothing in the sources checkedNo registered study lists a test result for this goal.
∅Nothing in the sources checkedNo registered study lists a body-step measure for this goal.
—Not recordedHarms were not a registered measure for this goal.
—Not recordedNo finished study window is recorded.
…Waiting for a reviewerWho was studied is listed further down the page.
Which registered measures put each goal on this table
Recovery
time to marrow recovery
Healthy ageing
who experienced transplant related mortality
Sorted by fixed word lists, version v1. A name the rules do not recognise stays unsorted rather than moving to the nearest column.
What each mark on this table means
∅ Nothing in the sources checked
No registered study lists a life outcome for this goal.
— Not recorded
Harms were not a registered measure for this goal.
… Waiting for a reviewer
Who was studied is listed further down the page.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Composite of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death, and (added before unblinding) hospitalisation for unstable angina leading to urgent revascularisation
✗ The study did not show it
Who was studied
CIRT (Ridker PM et al., N Engl J Med 2019;380:752-762; NCT01594333)
201 events against 207 (4.13 against 4.31 per 100 person-years); hazard ratio 0.96 (95% CI 0.79 to 1.16). Original composite hazard ratio 1.01 (95% CI 0.82 to 1.25)
Repeated elsewhere
Unreplicated
What this does not prove. A study that did not show an effect does not show that no effect exists anywhere.
The limits of this study, and where it came from
Main limit. Methotrexate lowered none of interleukin-1β, interleukin-6 or C-reactive protein, so the intervention did not engage the mechanism the trial was designed around. It did cause liver-enzyme elevations, lower leucocyte counts and haematocrit, and a higher incidence of non-basal-cell skin cancers than placebo. The trial was stopped early at a median 2.3 years.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet at 2.5 mg (and higher strengths), oral solution, subcutaneous auto-injector and prefilled syringe, intramuscular and intravenous injection, and preservative-free formulation for intrathecal use — dosed once weekly for arthritis and psoriasis, and on entirely different schedules in oncology
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
-2.1 with triple therapy against -2.3 with etanercept plus methotrexate (p=0.26); non-inferiority met, 95% upper confidence limit 0.41 against a margin of 0.6 (p=0.002)
Repeated elsewhere
Partially Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Twenty-seven per cent of each group required a blinded switch at 24 weeks. No significant between-group differences in radiographic progression, pain, quality of life or major adverse events.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet at 2.5 mg (and higher strengths), oral solution, subcutaneous auto-injector and prefilled syringe, intramuscular and intravenous injection, and preservative-free formulation for intrathecal use — dosed once weekly for arthritis and psoriasis, and on entirely different schedules in oncology
Interval reported. Not recorded in this summary
Written into the record, not signed off as a reviewed claim.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
Mucosal, gastrointestinal, hepatic and haematologic side effects of methotrexate with folic or folinic acid supplementation, and any effect on methotrexate efficacy
✓ The study showed what it set out to show
Who was studied
Shea B et al., Cochrane Database Syst Rev 2013;5:CD000951 (folate supplementation, 6 randomised trials)
How many people
624
Study design
Systematic review and meta-analysis of double-blind randomised placebo-controlled trials
Compared against
A dummy treatment
Kind of result
A number that stands in for health
What was found
Gastrointestinal side effects RR 0.74 (95% CI 0.59 to 0.92, p=0.008); transaminase elevation RR 0.23 (95% CI 0.15 to 0.34, p<0.00001); withdrawal for any reason RR 0.39 (95% CI 0.28 to 0.53, p<0.00001)
Repeated elsewhere
Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Stomatitis showed a non-significant trend (RR 0.72, 95% CI 0.49 to 1.06), and no meaningful conclusion could be drawn about haematologic side effects because of small event numbers and poor reporting.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Oral tablet at 2.5 mg (and higher strengths), oral solution, subcutaneous auto-injector and prefilled syringe, intramuscular and intravenous injection, and preservative-free formulation for intrathecal use — dosed once weekly for arthritis and psoriasis, and on entirely different schedules in oncology
Interval reported. 95% CI 0
Written into the record, not signed off as a reviewed claim.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
RNAWiki holds 3 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What happened in people◇Read from sources, not yet reviewed
How close this is to real life
The top step is something a person would feel or care about. The bottom is a guess from software. Filled steps are where evidence exists for this substance.
■Living longer, or avoiding a major eventEvidence recorded. Death, a heart attack, a stroke, a hospital stay.15 registered measures of this kind. 1 written-up study measured this and did not show a benefit.
□What a body can do day to dayNo evidence recorded. Walking, dressing, breathing, recovering.No registered study measures this.
□Measured performanceNo evidence recorded. How much was lifted, how far was run, how fast.No registered study measures this.
□Symptoms and quality of lifeNo evidence recorded. Pain, tiredness, mood, sleep, as the person rated it.No registered study measures this.
□A number that stands in for healthNo evidence recorded. Cholesterol, blood sugar, bone density. A stand-in, not the thing itself.No registered study measures this.
■A step measured inside a personEvidence recorded. Something measured in human tissue or human cells.A human record sits on the stored organism ladder.
■AnimalsEvidence recorded. Mice, rats, dogs. Useful for ideas, not proof about people.Stored records in Yeast, Mouse, Dog. A result in animals says what to test next. It does not say what happens in people.
■Cells in a dishEvidence recorded. Cells or chemistry on a bench, far from a whole body.Stored mechanism abstracts describe steps measured in cells or tissue.
□A guess from softwareNo evidence recorded. Nobody measured it. RNAWiki never publishes one as a finding.RNAWiki stores no prediction for this record. Software can suggest a link. RNAWiki does not publish one as a finding.
Higher on these steps means closer to something a person would feel. It does not mean better done.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Where a source records it acting
Bone and bone marrow: Actively proliferating tissues such as malignant cells and bone marrow are in general more sensitive to the antifolate effect of methotrexate
US prescribing information · 04a95db9-a124-4b97-bd71-1c37a6b3b0c8 · read 2026-08-27
Intestines: Buccal and intestinal mucosa are among the actively proliferating tissues recorded as more sensitive to the effect of methotrexate
US prescribing information · 04a95db9-a124-4b97-bd71-1c37a6b3b0c8 · read 2026-08-27
Bladder and urinary tract: Cells of the urinary bladder are among the actively proliferating tissues recorded as more sensitive to the effect of methotrexate
US prescribing information · 04a95db9-a124-4b97-bd71-1c37a6b3b0c8 · read 2026-08-27
Start
Methotrexate
What a person takes: Oral tablet at 2.5 mg (and higher strengths), oral solution, subcutaneous auto-injector and prefilled syringe, intramuscular and intravenous injection, and preservative-free formulation for intrathecal use — dosed once weekly for arthritis and psoriasis, and on entirely different schedules in oncology.
The measurement behind this step
Oral absorption is saturable, so bioavailability falls as the weekly dose rises, which is the practical reason subcutaneous presentations exist. Inside cells the drug is polyglutamated and retained far longer than its plasma half-life implies, which is why weekly dosing works and why daily dosing accumulates. Elimination is predominantly renal, so declining kidney function raises exposure. Products for intrathecal administration must be preservative-free.
Getting in
A folate with two atoms changed
Methotrexate is folic acid with two small modifications. That is enough to turn the vitamin into a blocker of the enzyme that uses it.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
A 4-amino group replaces the 4-oxo of folic acid and an N10 methyl is added. The result binds dihydrofolate reductase far more tightly than the natural substrate and is not turned over, converting a catalytic cycle into a stalled complex.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
Reaching the cell
It is carried into cells, not diffused
The drug cannot cross the cell membrane on its own. A transporter that normally imports folate brings it in.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Uptake is by the reduced folate carrier, with folate receptor-mediated uptake contributing in some tissues. Loss of the carrier is a resistance mechanism that leaves the enzyme target entirely intact, so an enzyme inhibition assay would report full sensitivity in a resistant cell.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
Reaching the cell
The cell tags it so it cannot leave
Once inside, extra glutamates are attached, which traps the drug in the cell for far longer than it stays in the blood. That is why the tablet is weekly.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Folylpolyglutamate synthase adds glutamate residues, generating polyglutamates that are poor substrates for efflux and are themselves potent inhibitors of thymidylate synthase and AICAR transformylase in addition to dihydrofolate reductase. Intracellular residence far exceeds the plasma half-life, which is the pharmacological reason daily dosing accumulates to lethality.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
The change it makes
Dividing cells run out of DNA parts
With the enzyme blocked, cells cannot make the building blocks for new DNA. The fastest-dividing cells feel it first — which is the point in leukaemia and the source of the side effects everywhere else.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
The label states that dihydrofolates must be reduced to tetrahydrofolates before they can carry one-carbon groups in purine nucleotide and thymidylate synthesis, so methotrexate interferes with DNA synthesis, repair and cellular replication, and that actively proliferating tissues — malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, bladder epithelium — are generally more sensitive.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
What it acts on
In arthritis, something else is happening
At the low weekly dose used for joints, the drug is not simply starving cells of DNA. The prescribing information says the mechanism there is unknown.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Section 12.1: "The mechanism of action in rheumatoid arthritis and in psoriasis is unknown." The leading candidate is accumulation of AICAR leading to extracellular adenosine release with anti-inflammatory signalling at adenosine receptors. The supporting observation is negative and strong: folate supplementation removes most of the toxicity without significantly reducing efficacy, which an antifolate mechanism would not predict.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
What that does for a person
Disease activity falls; the inflammation theory did not generalise
Joints improve and damage slows. When the same drug was given to prevent heart attacks on the theory that it damps inflammation generally, it lowered no inflammatory marker and prevented nothing.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
CIRT, 4,786 patients: no reduction in interleukin-1β, interleukin-6 or C-reactive protein, and a primary composite hazard ratio of 0.96 (95% CI 0.79 to 1.16). CANTOS, 10,061 patients on canakinumab, which does lower interleukin-6 and C-reactive protein: hazard ratio 0.85 (0.74 to 0.98) at 150 mg. Whatever methotrexate does in a rheumatoid joint, it is not a general suppression of the interleukin-6 axis.
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 6 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What it would be like to take◇Read from sources, not yet reviewed
Felt, measured, or meaningful
Three different things that get called the same word. Registered studies measured all three, and mixing them is how a blood test becomes a health claim.
Felt
Things a person could notice without a test.
No registered study measured anything of this kind.
Measured
Things only a test, a scale or a device shows.
No registered study measured anything of this kind.
Meaningful
Things that change how a life goes, not only a number.
overall survival
event free survival
complete remission
disease free survival
complete remission at the end of consolidation therapy
survival following consolidation
event free survival following consolidation
event free survival after first randomization
disease free survival after second and third randomization
who experienced transplant related mortality
and 5 more.
A registered study says what someone planned to measure. It does not say what they found. A number moving is not the same as a life going better. The two are shown apart here.
Felt, but not shown to help. A person notices a change. No study showed it leads anywhere good.
Measured, but not felt. A number moves. The person notices nothing. Both can be true.
Measured, but not shown to matter. A number moves in the good direction. Nobody showed that lives went better.
Matters, but takes years. The result that counts may take longer than anyone would keep watching.
Names that fit none of the three (25)
overall response
complete response
clinical response
response
response rate
feasibility of intensification
dying or residual disease during induction therapy
time to marrow recovery
frequency of toxicities including infectious complications
marrow status
blasts
maximum tolerated dose
early marrow cr plus pr rate at day 21
efficacy
toxicity
response based on blood human chorionic gonadotropin assay
complete or partial response to treatment mtx
response rates
pathological response
probability of recurring
These are harms, study-process measures, or names the rules did not recognise. They are shown rather than dropped.
What it would be like to take◇Read from sources, not yet reviewed
How long anything takes
Nine different lengths of time that get confused with each other. None of them is worked out from another.
Before anything is noticed.RNAWiki does not store this separately, and never works it out from another figure on this page.
Before a test result moves.RNAWiki does not store this separately, and never works it out from another figure on this page.
Before performance moves.RNAWiki does not store this separately, and never works it out from another figure on this page.
How long the result was watched.No finished study window is recorded for a study that tested this substance.
How long people took it.How long people actually took it is not stored. The study window is not the same thing.
How long people were followed.Follow-up length is not stored separately. It is never read off the study window, which would be a different thing.
How fast the body clears it. approximately 3 to 10 hours hours
Read from the label, which states: “The elimination half-life of methotrexate is approximately 3 to 10 hours.”
How long effects linger.RNAWiki does not store this separately, and never works it out from another figure on this page.
Beyond the studies. Nothing is recorded about the long term.
The longest finished study sets the edge of what anyone measured.
A study window is not how long people took it, and neither is how long they were followed. Where RNAWiki holds only one of the three, it shows one.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Adults with rheumatoid arthritis, children with polyarticular juvenile idiopathic arthritis, adults with severe psoriasis, and — at very different doses — people with acute lymphoblastic leukaemia and certain lymphomas.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What the label states about particular groups
On pediatric, the label states: “The safety and effectiveness of methotrexate, including Rasuvo, have not been established in pediatric patients with psoriasis.”
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-30
On older people, the label states: “Clinical studies of methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.”
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-30
On people who are pregnant, the label states: “Risk Summary Based on published reports, and methotrexate's mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1) ].”
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-30
On people who are breastfeeding, the label states: “Risk Summary Limited published literature report the presence of methotrexate in human breast milk in low amounts following oral methotrexate administration, with the highest breast milk to plasma concentration ratio reported to be 0.08:1.”
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-30
On people with reduced liver function, the label states: “The effect of hepatic impairment on methotrexate pharmacokinetics has not been studied.”
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-30
On people with reduced kidney function, the label states: “Methotrexate elimination is reduced in patients with impaired renal function.”
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-30
Where the result stopped carrying
Low-dose methotrexate did not prevent cardiovascular events and did not lower any inflammatory marker in 4,786 patients, and the trial was stopped early
Folate supplementation was expected to blunt efficacy and did not, which undermines the standard antifolate explanation for the arthritis effect
Deaths have occurred from taking a weekly regimen daily, and the boxed warning now says so explicitly
Hepatic fibrosis and cirrhosis can develop in psoriasis without symptoms or abnormal liver tests, so routine enzyme monitoring is known to have a blind spot
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied for a different goal
The studies measured something else entirely.
On this record: Some registered studies measured things that match no goal on this page.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (10)
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Given by a clinician
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Oral tablet at 2.5 mg (and higher strengths), oral solution, subcutaneous auto-injector and prefilled syringe, intramuscular and intravenous injection, and preservative-free formulation for intrathecal use — dosed once weekly for arthritis and psoriasis, and on entirely different schedules in oncology
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Suppression classes recorded: S1, S3, S4, S6.
No source is stored against this line.
What is in the pack
Oral absorption is saturable, so bioavailability falls as the weekly dose rises, which is the practical reason subcutaneous presentations exist. Inside cells the drug is polyglutamated and retained far longer than its plasma half-life implies, which is why weekly dosing works and why daily dosing accumulates. Elimination is predominantly renal, so declining kidney function raises exposure. Products for intrathecal administration must be preservative-free.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
Boxed warning for embryo-fetal toxicity including fetal death, with contraindication in pregnancy for non-neoplastic disease; for severe hypersensitivity including anaphylaxis; for death following once-daily administration of a once-weekly regimen; and for serious adverse reactions including death affecting bone marrow, gastrointestinal tract, liver, lungs, skin and kidneys. Section 5 additionally warns of severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis and fatal liver failure — which in psoriasis may occur without symptoms or abnormal liver tests, generally after a cumulative dose of 1.5 g or more; of acute or chronic interstitial pneumonitis with irreversible or fatal cases; of fatal dermatologic reactions including toxic epidermal necrolysis and Stevens-Johnson syndrome; of life-threatening or fatal bacterial and fungal infection; of secondary malignancies; of tumour lysis syndrome; and of impaired fertility. Live vaccines are not recommended. Folate supplementation is directed for the arthritis and psoriasis indications and warned against in neoplastic disease.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Where this came from
Methotrexate tablets United States prescribing information — boxed warning, Indications 1.1 to 1.4, Warnings and Precautions 5.1 to 5.16, Mechanism of Action… · a recorded source, not a stored snapshot
CIRT — Cardiovascular Inflammation Reduction Trial (NCT01594333) · a recorded source, not a stored snapshot
Reports sent to a regulator
These are reports people sent to a regulator. They do not show the medicine caused the reaction.
Nobody counted how many people took the medicine and reported nothing.
The same event can be reported more than once, and many reports are incomplete.
News coverage, lawsuits and new warnings change how often people report.
A count is not a rate and not a risk.
Methotrexate appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 78065 reaction mentions were counted. One report can name several reactions.
The recorded terms (10)
rheumatoid arthritis — 12853 reaction mentions
drug intolerance — 10270 reaction mentions
pain — 8736 reaction mentions
arthralgia — 8342 reaction mentions
drug hypersensitivity — 7820 reaction mentions
joint swelling — 7167 reaction mentions
treatment failure — 6943 reaction mentions
alopecia — 5711 reaction mentions
condition aggravated — 5557 reaction mentions
abdominal discomfort — 4666 reaction mentions
open-targets-adr · recorded 2026-06-24 · a recorded source, not a stored snapshot
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Oral tablet at 2.5 mg (and higher strengths), oral solution, subcutaneous auto-injector and prefilled syringe, intramuscular and intravenous injection, and preservative-free formulation for intrathecal use — dosed once weekly for arthritis and psoriasis, and on entirely different schedules in oncology
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
Inside cells the drug is polyglutamated and retained far longer than its plasma half-life implies, which is why weekly dosing works and why daily dosing accumulates. Elimination is predominantly renal, so declining kidney function raises exposure. Products for intrathecal administration must be preservative-free.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
91 products list this as an active ingredient in the United States drug directory. 91 of them contain it and nothing else.
FDA National Drug Code directory · 0703-3678 · read 2026-08-29
They are sold as injection, injection, powder, lyophilized, for solution, injection, solution, powder, solution and tablet, taken intra-arterial, intramuscular, intrathecal and intravenous.
FDA National Drug Code directory · 0703-3678 · read 2026-08-29
The regulator's established pharmacologic class for it is folate analog metabolic inhibitor [epc] and folic acid metabolism inhibitors [moa].
FDA National Drug Code directory · 0703-3678 · read 2026-08-29
47 published labels name it as an active ingredient. 47 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · d0075461-0e7e-4967-9c9b-d6440e912c0e · read 2026-08-29
16 marketed supplement labels list this ingredient, classed as other combinations and vitamin.
Those labels carry all other, nutrient and structure/function claims. A claim of that kind is written by the manufacturer and is not assessed by any regulator, so its presence says nothing about whether it is true.
METHOTREXATE is tablets (functional scoring) at Tablet having functional scoring: 2.5 mg, recorded as prescription product; fda label in effect 2026-05-18 in the United States.
US prescribing information · 04a95db9-a124-4b97-bd71-1c37a6b3b0c8 · read 2026-08-27
Recorded price in US: 0.15658 USD per one unit as the pricing file counts it — a tablet, capsule, patch or single item, across 17 priced products whose strengths and pack forms differ, as of 2026-08-26, paid by retail pharmacies buying the product, as surveyed by the Centers for Medicare & Medicaid Services. It is not a list price, an insurance price, or what anyone pays at a counter..
Recorded source · 2026-08-26 · read 2026-08-28
Recorded price in US: 0.702–3.1283 USD per one millilitre, across 10 priced products whose strengths and pack forms differ, as of 2026-08-26, paid by retail pharmacies buying the product, as surveyed by the Centers for Medicare & Medicaid Services. It is not a list price, an insurance price, or what anyone pays at a counter..
Recorded source · 2026-08-26 · read 2026-08-28
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
Self-experiment planning is not offered for a prescription or clinician-supervised medicine. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Methotrexate studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That methotrexate treats rheumatoid arthritis by inhibiting dihydrofolate reductase — the label states the mechanism in rheumatoid arthritis and psoriasis is unknown
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That because it is anti-inflammatory in joints it is anti-inflammatory generally — CIRT found no movement in any measured inflammatory marker
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That adding a biologic to methotrexate outperforms adding two generic tablets, which the only blinded head-to-head trial did not show
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That an old, cheap, familiar drug is therefore a mild one; the boxed warning covers fetal death, anaphylaxis, fatal dosing error and fatal organ toxicity
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Methotrexate are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
The label says the mechanism in arthritis is unknown
In plain words
Methotrexate is described everywhere as a folate blocker. Its own prescribing information says that in rheumatoid arthritis and psoriasis — its two commonest uses — the mechanism of action is unknown.
What was measured
That methotrexate treats rheumatoid arthritis by inhibiting dihydrofolate reductase — the mechanism its label describes for proliferating tissue and explicitly declines to extend to arthritis
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Section 12.1 sets out the antifolate mechanism in full: dihydrofolates must be reduced to tetrahydrofolates before they can carry one-carbon groups for purine and thymidylate synthesis, so methotrexate interferes with DNA synthesis, repair and cellular replication, and actively proliferating tissues are generally more sensitive. It then adds a single sentence: "The mechanism of action in rheumatoid arthritis and in psoriasis is unknown." The strongest evidence that the arthritis effect is not simple antifolate action comes from the drug’s own regimen: section 5.10 directs folic or folinic acid supplementation for rheumatoid arthritis, juvenile arthritis and psoriasis, and a Cochrane review of six trials in 624 patients found supplementation reduced toxicity substantially with no statistically significant effect on efficacy. If the therapeutic effect were folate depletion, replacing the folate should have removed it.
Written into the record, not signed off as a reviewed claim
CIRT: the inflammation theory was tested directly and failed
In plain words
If methotrexate works in arthritis by damping inflammation, and inflammation causes heart attacks, methotrexate should prevent heart attacks. In 4,786 patients it did not — and it did not lower any inflammatory marker either.
What was measured
Composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death, plus interleukin-1β, interleukin-6 and C-reactive protein levels
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
The Cardiovascular Inflammation Reduction Trial randomised 4,786 patients with previous myocardial infarction or multivessel coronary disease, plus type 2 diabetes or metabolic syndrome, to low-dose methotrexate at a target of 15 to 20 mg weekly or matching placebo, all with 1 mg of folate daily. It was stopped after a median 2.3 years. The final primary composite occurred in 201 patients on methotrexate against 207 on placebo (4.13 against 4.31 per 100 person-years; hazard ratio 0.96, 95% CI 0.79 to 1.16); the original composite in 170 against 167 (hazard ratio 1.01, 95% CI 0.82 to 1.25). Critically, methotrexate did not lower interleukin-1β, interleukin-6 or C-reactive protein at all. It did cause liver-enzyme elevations, reductions in leucocyte count and haematocrit, and more non-basal-cell skin cancers than placebo. The comparison that makes this instructive is CANTOS, published two years earlier: canakinumab, which does lower interleukin-6 and C-reactive protein, cut the same composite at 150 mg (hazard ratio 0.85, 95% CI 0.74 to 0.98, p=0.021) in 10,061 patients. The inflammatory hypothesis survived; the assumption that methotrexate is a general anti-inflammatory did not. Registered as NCT01594333.
Written into the record, not signed off as a reviewed claim
Three generic tablets matched a biologic in a blinded trial
In plain words
In the only blinded head-to-head trial of its kind, adding two cheap old tablets to methotrexate worked as well as adding an injectable biologic — on disease activity, on joint damage, on pain and on quality of life.
What was measured
Change in DAS28 at 48 weeks, with radiographic progression, pain and quality of life as secondary endpoints
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
RACAT randomised 353 patients with active rheumatoid arthritis despite methotrexate to triple therapy — methotrexate, sulfasalazine and hydroxychloroquine — or to etanercept plus methotrexate, for 48 weeks, with blinded switching at 24 weeks for those not meeting a pre-specified improvement threshold. Twenty-seven per cent of each group switched. Change in DAS28 from baseline to week 48 was -2.1 with triple therapy and -2.3 with etanercept plus methotrexate (p=0.26); triple therapy met non-inferiority, with the 95% upper confidence limit for the difference at 0.41 against a margin of 0.6 (p=0.002). There were no significant between-group differences in radiographic progression, pain, health-related quality of life, or major adverse events. The acquisition cost difference between the two regimens is roughly three orders of magnitude.
Written into the record, not signed off as a reviewed claim
The supplement that was supposed to cancel the drug does not
In plain words
Folic acid is the thing methotrexate blocks. Giving it alongside was expected to undo the treatment. Pooled trials show it removes most of the toxicity and leaves the benefit intact — which is a problem for the standard explanation of how the drug works.
What was measured
Gastrointestinal side effects, transaminase elevation, withdrawal for any reason, and disease activity, with and without folate supplementation
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
A Cochrane review of six double-blind randomised placebo-controlled trials in 624 rheumatoid arthritis patients on methotrexate at 25 mg weekly or less, restricted to low-dose supplementation of 7 mg weekly or less, found folic or folinic acid reduced gastrointestinal side effects by 26% relative and 9% absolute (RR 0.74, 95% CI 0.59 to 0.92, p=0.008), abnormal serum transaminase elevation by 76.9% relative and 16% absolute (RR 0.23, 95% CI 0.15 to 0.34, p<0.00001), and withdrawal from methotrexate for any reason by 60.8% relative and 15.2% absolute (RR 0.39, 95% CI 0.28 to 0.53, p<0.00001). Stomatitis showed a non-significant trend (RR 0.72, 95% CI 0.49 to 1.06). The review states that supplementation does not appear to have a statistically significant effect on the efficacy of methotrexate as measured by tender and swollen joint counts or physician global assessment. The label mirrors the split: section 5.10 directs supplementation for the arthritis and psoriasis indications and warns that folic acid products may decrease clinical effectiveness in neoplastic disease. The same molecule therefore has two opposite instructions about the same vitamin depending on what it is being used for, which is as clear a signal as the pharmacopoeia offers that it is doing two different things.
Written into the record, not signed off as a reviewed claim
People have died from taking it on the wrong schedule
In plain words
Each tablet is an ordinary tablet. Taken daily instead of weekly, the same tablets kill. That sentence is in the boxed warning.
What was measured
Deaths reported from once-daily administration of a once-weekly regimen
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
The boxed warning states: "Methotrexate tablets when inadvertently administered once daily have resulted in death." Section 5.9, Risk of Fatal Adverse Reactions with Medication Error, records that deaths occurred as a result of medication errors, most commonly in patients taking methotrexate daily when a weekly dosing regimen was prescribed. This is a design failure of the dosage form rather than of the molecule: almost every other oral drug a patient encounters is taken at least daily, so the default behaviour a prescription trains is precisely the one that is lethal here. The pharmacology behind it is polyglutamation — methotrexate is retained inside cells far longer than its plasma half-life suggests, so daily dosing accumulates intracellular drug in a way plasma monitoring would not reveal until mucositis and marrow failure appear.
Source
Methotrexate tablets United States prescribing information, boxed warning and section 5.9
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
Liver damage that can be invisible until it is permanent
In plain words
In psoriasis, the label states that scarring and cirrhosis of the liver can develop with no symptoms and with normal blood tests. Monitoring catches some of it, not all.
What was measured
Hepatic fibrosis and cirrhosis as a function of cumulative dose, and their detectability by liver enzyme testing
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
Section 5.5 states that methotrexate can cause severe and potentially irreversible hepatotoxicity including fibrosis, cirrhosis and fatal liver failure; that the safety of methotrexate in patients with hepatic disease is unknown; that risk increases with heavy alcohol consumption; and — the sentence that matters most — that in patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests. It attaches the risk to total cumulative dose, generally after 1.5 g or more. A monitoring strategy built on liver enzymes is therefore known by the label to have a blind spot in one of the indications, which is the historical reason serial liver biopsy was once standard in dermatological practice and the reason non-invasive fibrosis assessment replaced it rather than nothing replacing it.
Source
Methotrexate tablets United States prescribing information, section 5.5
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
A drug this old carries a modern boxed warning of four separate hazards
In plain words
Fetal death, anaphylaxis, dosing error and severe organ toxicity all sit in the boxed warning. This is not a mild anti-inflammatory that happens to be old.
What was measured
Hazards carried in the boxed warning and section 5 of the current label
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
The boxed warning covers four distinct hazards: embryo-fetal toxicity including fetal death, with the drug contraindicated in pregnancy for non-neoplastic disease; severe hypersensitivity reactions including anaphylaxis as a contraindication; death from once-daily administration of a weekly regimen; and serious adverse reactions including death affecting bone marrow, gastrointestinal tract, liver, lungs, skin and kidneys. The warnings section adds interstitial pneumonitis that can be irreversible or fatal, fatal dermatologic reactions including toxic epidermal necrolysis and Stevens-Johnson syndrome, life-threatening or fatal bacterial and fungal infection, secondary malignancies, tumour lysis syndrome, a recommendation against live vaccines, and impairment of fertility. The reason to list this in an audit rather than a safety footnote is that methotrexate is routinely described as the safe, cheap, old option relative to biologics, and the comparison that description implies is not one either label supports.
Source
Methotrexate tablets United States prescribing information, boxed warning and sections 5.1 to 5.16
Role in the trial
Not matched to a registered study
Identity check
no open identity hold
Audit mark
caution
Review state
Written into the record, not signed off as a reviewed claim
How many documents were read
45 documents were read for this substance.
RNAWiki source record
33 of them state the same bioavailability, and they agree.
RNAWiki source record
Where else this substance is registered
FDA substance identifier (UNII)
3IG1E710ZN
CAS registry number
59-05-2
PubChem compound
126941
RxNorm concept
6851
Checks this page had to pass
✓ Passed
Identity resolved
no open identity hold
✓ Passed
No unresolved merge across substance families
no quarantine open
✓ Passed
Every public sentence names a source
The opening statement carries the origin: Written into the record, not signed off.
✗ Not passed
Trial roles classified for highlighted evidence
No registered study is classified as testing this substance.
✓ Passed
No internal keys in reader text
enforced by the copy-contract test over the rendered page
✓ Passed
Safety mode resolved
Suppression classes recorded: S1, S3, S4, S6.
✓ Passed
Canonical metadata present
slug and display name present
What is missing or unclear◇Read from sources, not yet reviewed
How this medicine reached us
Kept near the foot of the page. A historical event moves up only when it changes something about this substance today.
What the approval register records
66 approved applications cover products containing this substance. The earliest was NDA008085, approved 19531207 to STRIDES PHARMA INTL.
This order is fixed in code and does not count clicks or time on the page.
What is not here
3 questions this page could not answer
These sections were prepared and left out because there was nothing to put in them. They are listed rather than hidden, so the gaps in this record are visible.
What it may clash with — found nothing in the sources checked.
Other ways to the same goal — found nothing in the sources checked.
What changed on this page — found nothing in the sources checked.
The record as stored
The full record, for auditing
Everything above is built from what is below. This layer keeps the technical vocabulary, record identifiers and every stored row, so a reader who wants to check the page can.
The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
A dihydrofolate reductase inhibitor whose own label states its mechanism in rheumatoid arthritis is unknown, which in a 353-patient double-blind trial produced a DAS28 fall of 2.1 in a three-drug combination against 2.3 with etanercept added — non-inferior at a hundredth of the price — and which, when the anti-inflammatory theory behind it was tested directly in 4,786 patients with coronary disease, reduced neither interleukin-6, nor C-reactive protein, nor cardiovascular events.
Recorded evidence blocks (13)
Q2
What did Methotrexate's largest trial (192000 people) and its longest (32 years) measure?
192000 people in Methotrexate's largest registered study, 32 years in its longest registered window, measuring Number of Participants Who Experienced Transplant Related Mortality. ClinicalTrials.gov · 2026-09-01
571 phase2, 330 phase3, 166 phase4, 165 phase1, 72 na, 43 na or unstated, 13 early phase1; NCT04725422; 2050-08. Last human test completed 2026, NCT01190930.
Interpretation These counts include studies where Methotrexate was a comparison treatment, a background treatment or an exposure in an observational study, and the longest window may be a planned end date. Trial roles have not yet been classified for this record.
Show the evidence
phase2
571
phase3
330
phase4
166
phase1
165
na
72
na or unstated
43
2 more recorded rows
early phase1
13
Last recorded human testNCT01190930
2026-03-31
recorded 2026-09-01 · last checked 2026-09-04
Q3
From yeast to human: where has Methotrexate shown lifespan?
"Study was closed early due to lack of accrual"; 129 of 1258 registered studies
Show the evidence
Trial
NCT00001880
terminated; "Study was closed early due to lack of accrual"
NCT00002961
terminated; "poor accrual"
NCT00003060
terminated; "lack of patient accrual"
NCT00003640
terminated; "low accrual"
NCT00004878
withdrawn; "study never opened"
NCT00005047
terminated; "Accrual was halted on the basis of the Data and Safety Monitoring Board review of a futility analysis."
14 further recorded trials
NCT00005641
terminated; "low study accrual"
NCT00006451
withdrawn; "Terminated (due to no accrual)"
NCT00035958
terminated; "Incorporating the recommendations of the NIH-formed DSMB in the study procedures would make the project budget over the limit for this funding mechanism."
NCT00037115
withdrawn; "Lack of funding"
NCT00041288
terminated; "Poor accrual and difficulty with multicenter logistics"
NCT00057954
terminated; "Slow accrual"
NCT00074269
terminated; "Terminated early due to poor enrollment"
NCT00121186
terminated; "poor accrual"
NCT00126191
terminated; "closed due to slow accrual"
NCT00189878
terminated; "unable to recruit"
NCT00230035
withdrawn; "Recommended by DSMB due to lack of accrual"
NCT00233558
terminated; "Study terminated due to low subject enrollment. Safety results consistent with product label."
NCT00253552
terminated; "Terminated at request of PI as study was outdated."
NCT00262925
terminated; "slow accrual"
recorded 2026-09-01 · last checked 2026-09-04
Q5
Human studies of Methotrexate used Methotrexate intravenous 25mg/ml — over how long?
8 recorded entries; human; intravenous, intravitreal; also "Methotrexate intravenous 25mg/ml", "Methotrexate 15 to 25 mg PO per week", "Arm A: methotrexate 20 to 25 mg / week for 6 months."
Show the evidence
human
NCT00779142
intravenous; Methotrexate intravenous 25mg/ml
NCT01870128
Methotrexate 15 to 25 mg PO per week
NCT02037191
Arm A: methotrexate 20 to 25 mg / week for 6 months.
Methotrexate's half-life is approximately 3 to 10 hours — which schedules were studied?
approximately 3 to 10 hours, the half-life Methotrexate's label states. openfda-label · 757d6cef-6696-7a1c-8074-01258aaa8bdd · 2026-08-27
bioavailability approximately 60% %.
Show the evidence
half life
approximately 3 to 10 hours hours; The elimination half-life of methotrexate is approximately 3 to 10 hours.
bioavailability
approximately 60% %; At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%.
metabolism
Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration.
recorded 2026-08-27 · last checked 2026-09-04
Q7
Which of adverse events, blasts and clinical response did Methotrexate's trials measure?
adverse events, blasts and clinical response lead 40 outcome terms across Methotrexate's trials. ClinicalTrials.gov · 2026-09-01
Interpretation clinical response, response, event free survival, response rate, feasibility of intensification and complete remission follow.
Show the evidence
overall response
1
complete response
1
overall survival
1
clinical response
1
response
1
event free survival
1
14 more recorded rows
response rate
1
feasibility of intensification
1
complete remission
1
disease free survival
1
dying or residual disease during induction therapy
1
time to marrow recovery
1
frequency of toxicities including infectious complications
1
marrow status
1
blasts
1
complete remission at the end of consolidation therapy
1
survival following consolidation
1
event free survival following consolidation
1
maximum tolerated dose
1
early marrow cr plus pr rate at day 21
1
recorded 2026-09-01 · last checked 2026-09-04
Q8
Which of Methotrexate's 199 ongoing trials reports first?
"Combined Chemotherapy With or Without Zoledronic Acid for Patients With Osteosarcoma"; n 318; "Event-free survival"; 2026-12
NCT00501826
"Combination Chemotherapy and Nelarabine in Treating Patients With T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma"; n 160; "Complete remission rate"; 2026-10-31
NCT00544115
"Donor Peripheral Stem Cell Transplant in Treating Patients With Advanced Hematologic Cancer or Other Disorders"; n 260; "Neutrophil Engraftment - The Days Till ANC Recovery"; 2027-03-29
NCT00683319
"Observing Young Patients With Ependymoma Undergoing Standard Combination Chemotherapy"; n 50; "Overall survival"
NCT00792948
"Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia"; n 97; "Relapse-free Survival (RFS) After Allogeneic Stem Cell Transplantation"; 2027-01-06
NCT01371630
"Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia"; n 276; "Maximum tolerated dose of inotuzumab ozogamicin based on incidence of dose limiting toxicities (Phase I)"; 2027-12-25
14 further recorded trials
NCT01424982
"Combination Chemotherapy and Ponatinib Hydrochloride in Treating Patients With Acute Lymphoblastic Leukemia"; n 88; "Event-free survival"; 2027-10-31
NCT01706692
"Swiss Dermatology Network of Targeted Therapies (SDNTT)"; n 1121; "Psoriasis Area Severity Index (PASI)"; 2032-03-15
NCT01920737
"A Novel "Pediatric-Inspired" Regimen With Reduced Myelosuppressive Drugs for Adults (Aged 18-60) With Newly Diagnosed Ph Negative Acute Lymphoblastic Leukemia"; n 39; "rate of molecular remission"; 2026-08
NCT02003222
"Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia"; n 488; "Overall Survival (OS) Among Patients Who Were MRD Negative After Induction and Intensification Chemotherapy"; 2027-02-25
NCT02101853
"Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia"; n 669; "Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients"; 2026-09-16
NCT02112916
"Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Stage II-IV T-Cell Lymphoblastic Lymphoma"; n 847; "Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients"; 2026-09-16
NCT02114229
"Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors"; n 125; "Sustained response rate of pediatric participants with recurrent or refractory AT/RT treated with alisertib (stratum A1)"; 2027-09
NCT02143414
"Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia"; n 53; "Overall Survival Rate (Cohort I)"; 2027-06-06
NCT02203526
"Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma"; n 68; "safety and feasibility in untreated PCNSL patients"; 2027-12-01
NCT02205762
"LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis"; n 1400; "Percentage of Patients with Reactivation Free Survival"; 2026-07
NCT02265770
"An International Clinical Program for the Diagnosis and Treatment of Children With Ependymoma"; n 536; "Gross Total Resection rate"; 2031-08
NCT02299999
"SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer"; n 1460; "Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm"; 2025-12
NCT02416388
"Study to Improve OS in 18 to 60 Year-old Patients, Comparing Daunorubicin Versus High Dose Idarubicin Induction Regimens, High Dose Versus Intermediate Dose Cytarabine Consolidation Regimens, and Standard Versus MMF Prophylaxis of GvHD in Allografted Patients in First CR"; n 3100; "Overall survival"; 2032-01
NCT02427620
"Ibrutinib, Rituximab, and Consolidation Chemotherapy in Treating Young Patients With Newly Diagnosed Mantle Cell Lymphoma"; n 131; "Overall response rate (complete response + partial response)"; 2027-06-30
recorded 2026-09-01 · last checked 2026-09-04
Q9
Which running trial of Methotrexate could settle lifespan?
NCT02299999 measures Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm, reading out 2025-12.
51 open trials; n 1460; "SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer"
Show the evidence
Trial
NCT02299999
"SAFIR02_Breast - Efficacy of Genome Analysis as a Therapeutic Decision Tool for Patients With Metastatic Breast Cancer"; n 1460; "Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm"; 2025-12
NCT04737889
"Rituximab, Lenalidomide Combined With Methotrexate and Temozolomide For Primary Central Nervous System Lymphoma"; n 30; "2-year progression-free survival"; 2026-01-13
NCT03121014
"Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation in High Risk AML and Myelodysplastic Syndromes"; n 38; "Relapse free survival of approximately 30% in high-risk patients conditioned with the Fludarabine/ Busulfan regimen"; 2026-04
NCT07089381
"Efficacy and Safety of Resveratrol in Patients With Rheumatoid Arthritis."; n 118; "To investigate the effects of Resveratrol on inflammation and oxidative stress by measuring: • Serum Sirtuin 1(SIRT1) • Serum Myeloperoxidase (MPO) • Serum C-reactive protein (CRP)"; 2026-06-01
NCT02205762
"LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis"; n 1400; "Percentage of Patients with Reactivation Free Survival"; 2026-07
NCT02101853
"Blinatumomab in Treating Younger Patients With Relapsed B-cell Acute Lymphoblastic Leukemia"; n 669; "Disease Free Survival (DFS) of High-risk (HR) and Intermediate-risk (IR) Relapse Patients"; 2026-09-16
14 further recorded trials
NCT02112916
"Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Stage II-IV T-Cell Lymphoblastic Lymphoma"; n 847; "Event-free Survival (EFS) for Modified Augmented Berlin-Frankfurt-Munster Backbone With or Without Bortezomib in All Randomized Patients"; 2026-09-16
NCT02877303
"Blinatumomab, Inotuzumab Ozogamicin, and Combination Chemotherapy as Frontline Therapy in Treating Patients With B Acute Lymphoblastic Leukemia"; n 80; "Relapse-free survival (RFS)"; 2026-11-01
NCT00470223
"Combined Chemotherapy With or Without Zoledronic Acid for Patients With Osteosarcoma"; n 318; "Event-free survival"; 2026-12
NCT04314219
"Comparing Post-Transplant Cyclophosphamide As GVHD Prophylaxis to Standard of Care for Acute Leukemia Patients"; n 264; "GRFS (GVHD-free/relapse-free survival)"; 2026-12
NCT04216524
"Venetoclax, SL-401, and Chemotherapy for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm"; n 40; "Progression free survival (PFS)"; 2026-12-31
NCT00792948
"Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia"; n 97; "Relapse-free Survival (RFS) After Allogeneic Stem Cell Transplantation"; 2027-01-06
NCT02003222
"Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia"; n 488; "Overall Survival (OS) Among Patients Who Were MRD Negative After Induction and Intensification Chemotherapy"; 2027-02-25
NCT03206671
"Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents"; n 650; "Event-free survival (EFS)"; 2027-06
NCT02143414
"Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia"; n 53; "Overall Survival Rate (Cohort I)"; 2027-06-06
NCT03150693
"Inotuzumab Ozogamicin and Frontline Chemotherapy in Treating Young Adults With Newly Diagnosed B Acute Lymphoblastic Leukemia"; n 303; "Event-free survival (EFS)"; 2027-08
NCT05303727
"Allogeneic Hematopoietic Stem Cell Transplantation for 4/M Neuroblastoma"; n 64; "overall survival(OS) at 3 year"; 2027-08
NCT06554626
"Blinatumomab Plus Venetoclax Sequenced With Inotuzumab Ozogamicin in Treating B-ALL"; n 20; "Event free survival(EFS)"; 2027-08-01
NCT03007147
"Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia"; n 352; "Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients)"; 2027-08-14
NCT03914625
"A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia"; n 6720; "Disease free survival (DFS) in randomization eligible patients with higher risk features (SR-High) or standard risk average (SR-Avg) B-ALL patients based on randomization with addition of blinatumomab"; 2027-09-30
Q10
Which 338 trials of Methotrexate posted no result?
Posted no result
338 of 338 completed trials
Registrations
NCT00000703, NCT00000689, NCT00000658, NCT00002755, NCT00004686 and NCT00002554, and 332 more
Completion dates
oldest 1990-03; newest 2024-06-30
Show the evidence
Trial
NCT00000703
1990-03
NCT00000689
1991-03
NCT00000658
1996-02
NCT00002755
1999-06
NCT00004686
1999-09
NCT00002554
1999-12
14 further recorded trials
NCT00003776
2000-03
NCT00001677
2000-04
NCT00002691
2000-06
NCT00309569
2000-09
NCT00005854
2000-10
NCT00074191
2000-10
NCT00001498
2000-12
NCT00004162
2001-01
NCT00199069
2001-05
NCT00002865
2001-08
NCT00002789
2001-09
NCT00003870
2001-11
NCT00005988
2002-03-08
NCT00002456
2002-04
Q11
At the median, Methotrexate's trials enrolled 76 people — anything larger?
Median enrolment
76
Largest enrolment
192000
Registered trials counted
1217
Q12
What do 78065 spontaneous reports say about Methotrexate — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Methotrexate appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 78065 reaction mentions were counted: rheumatoid arthritis 12853; drug intolerance 10270; pain 8736; arthralgia 8342. open-targets-adr · CHEMBL3244648 · 2026-06-24
Show the evidence
rheumatoid arthritis
12853
drug intolerance
10270
pain
8736
arthralgia
8342
drug hypersensitivity
7820
joint swelling
7167
4 more recorded rows
treatment failure
6943
alopecia
5711
condition aggravated
5557
abdominal discomfort
4666
recorded 2026-06-24 · last checked 2026-09-04
Q13
Was Methotrexate studied with fasting?
fasting is named in Methotrexate's label sentences: "Patients were randomized to receive methotrexate in the dose of 0.3 mg/Kg/week with or without intermittent fasting." openfda-label+europepmc · 2025-04-17
1 recorded statement; fasting
Show the evidence
fasting
Patients were randomized to receive methotrexate in the dose of 0.3 mg/Kg/week with or without intermittent fasting.
recorded 2025-04-17 · last checked 2026-09-04
Q14
What is recorded about Methotrexate and sirtuin?
"Histopathological findings further demonstrated attenuation of fibrosis-associated changes and partial improvement in hepatic architecture. <b>Conclusions:</b> Loureirin B may exert protective effects against methotrexate-associated liver injury through the modulation of oxidative stress, partial restoration of SIRT1 levels, attenuation…" — where Methotrexate and sirtuin appear together. Europe PMC · pathway abstract search · 2026-06-27
"Histopathological findings further demonstrated attenuation of fibrosis-associated changes and partial improvement in hepatic architecture. <b>Conclusions:</b> Loureirin B may exert protective effects against methotrexate-associated liver injury through the modulation of oxidative stress, partial restoration of SIRT1 levels, attenuation of profibrotic alterations associated with the TGF-β/SMAD…"
mTORPMID 40143135
"The current work aimed at an evaluation of the potential effects of perindopril in a rat model of methotrexate-induced hepatotoxicity and tried to precisely determine the molecular mechanisms that may represent the basis of these effects. <b>Methods:</b> In a model of methotrexate-elicited hepatotoxicity in male Wistar rats, the effects of different doses of perindopril were evaluated at the…"
AMPKPMID 40143135
"The current work aimed at an evaluation of the potential effects of perindopril in a rat model of methotrexate-induced hepatotoxicity and tried to precisely determine the molecular mechanisms that may represent the basis of these effects. <b>Methods:</b> In a model of methotrexate-elicited hepatotoxicity in male Wistar rats, the effects of different doses of perindopril were evaluated at the…"
autophagyPMID 40143135
"The current work aimed at an evaluation of the potential effects of perindopril in a rat model of methotrexate-induced hepatotoxicity and tried to precisely determine the molecular mechanisms that may represent the basis of these effects. <b>Methods:</b> In a model of methotrexate-elicited hepatotoxicity in male Wistar rats, the effects of different doses of perindopril were evaluated at the…"
NAD+
"IC 50 data confirm strong DHFR Nad inhibition by trimethoprim and methotrexate"
AMPK
PMID 40793247
"Methotrexate, an immunosuppressant and anticancer drug, promotes glucose uptake and lipid oxidation in skeletal muscle via activation of AMP-activated protein kinase (AMPK)."
PMID 40793247
"Methotrexate promotes AMPK activation by inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (ZMP) formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), which converts ZMP, an endogenous purine precursor and an active form of the pharmacological AMPK activator AICAR, to IMP during de novo purine synthesis."
mTOR
PMID 42364256
"Emerging therapies such as interleukin-6 receptor antagonists, Janus kinase inhibitors, and mTOR inhibitors represent promising options on top of methotrexate and TNF inhibitors for refractory sarcoid uveitis, although their use requires careful risk-benefit assessment and further validation in controlled trials."
"Finally, pancancer pharmacogenomic profiling across large cancer cell line panels suggested a broad resistance-associated pattern in CD276 high models, with reduced sensitivity (higher IC50) to PI3K/mTOR inhibitors and several cytotoxic agents used in urothelial cancer regimens (e.g., gemcitabine and methotrexate)."
recorded 2026-06-27 · last checked 2026-09-04
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