Folic acid × low-dose methotrexate: nausea in rheumatoid arthritis
research showsA direct randomized trial in adults with active rheumatoid arthritis compared oral folic acid with matched placebo on the same low-dose MTX adjustment protocol. The selected endpoint is people reporting nausea during 48 weeks: 44/133 (33.1%) with folic acid versus 55/137 (40.1%) with placebo. A descriptive recalculation gives RR 0.824 (95% CI 0.600-1.131) and a risk difference of -7.06 percentage points. The estimate points toward less nausea but does not establish a reduction under these conditions. Folinic acid, composite gastrointestinal outcomes, toxicity withdrawal and liver-enzyme outcomes are kept separate.
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Read the illustrated explanation (Korean) →
Interaction report · seven original assessment explanations
| Claim type | This is a nausea comparison for one drug pair, outside the supplied efficacy A–F scoring rules. |
|---|---|
| Endpoint | The outcome is people reporting nausea during 48 weeks, not the sum of gastrointestinal events or liver toxicity. |
| Replication | The selected trial family is separated from studies with different doses, periods or prior supplementation. A review adds no new trial participants. |
| Independence | Public support is recorded for the main trial. All sponsor roles, product supply and complete independence remain unconfirmed. |
| Effect direction and size | Nausea 44/133 versus 55/137; current descriptive RR 0.824 (95% CI 0.600-1.131), risk difference -7.06 percentage points. Direction favors folic acid but reduction is not established. |
| Risk of bias | The analysis included 411 of 434 randomized participants. Exploratory secondary symptoms, unequal realized MTX exposure and access through a copied table limit inference. |
| Precision | Original adjusted nausea effect, exact P and validated MCID are unverified. The descriptive interval includes 1 and is not equivalence evidence. |
Current common_research_prompt section 5 says not to force efficacy A-F grading onto interaction/adverse-event questions, and no dedicated numerical rule is supplied for this pair. Human RCT data exist, so this is not a no-human-study case.
Useful facts when choosing a product
- Folic acid is the sole added active substance on common MTX, distinct from folinic acid.
- Study doses are not personal dosing, prescription-change or discontinuation instructions.
- Exact salts, brands and complete excipients remain unconfirmed. Advertising was not collected.
Chamgap Semantic Classification Code
Permanent code issued
M.folic-acid-plus-low-dose-methotrexate.oral-fa1to2mgday-mtx7p5to25mgweek.mtx-naive-active-adult-ra.48weeks-nausea-people.matched-placebo-mtx-backgroundMedicine > Folic acid × low-dose methotrexate: nausea in rheumatoid arthritis > Folic acid 1→2 mg/day; MTX 7.5→maximum 25 mg/week, with adaptive escalation > MTX-naive adults aged ≥18 with active rheumatoid arthritis (1987 ACR; DAS ≥3) > People reporting nausea during 48 weeks > Matched placebo and double-dummy masking under the same MTX-adjustment protocol
Original ungraded interaction,48-week nausea,both full164-line languages,seven assessment/evidence/axis records,four nonexecution and separate numeric receipts preserved without recalculation. The code identifies the intervention and claim; it never contains the evidence grade, score, or safety result.
Exact Claim Classification
These independent facets prevent evidence from different forms, routes, populations, effects, and comparators from being mixed.
| Intervention class | M · Medicine |
|---|---|
| Canonical ingredient or intervention | Folic acid |
| Source or part used | Unverified — The manufacturing origin and process of the chemical ingredient were not verified. |
| Formulation or processing | Oral folic-acid tablets (salt and complete excipients unconfirmed); oral MTX background |
| Route | Oral, for both drugs |
| Dose | Folic acid 1→2 mg/day; MTX 7.5→maximum 25 mg/week, with adaptive escalation |
| Duration | During 48 weeks |
| Population | MTX-naive adults aged ≥18 with active rheumatoid arthritis (1987 ACR; DAS ≥3) |
| Effect or condition | Difference in nausea when folic acid is added to low-dose MTX |
| Primary endpoint | People reporting nausea during 48 weeks |
| Comparator | Matched placebo and double-dummy masking under the same MTX-adjustment protocol |
| Duplicate-detection key | folic-acid|oral-tablets|MTX-naive-active-adult-RA|MTX-adaptive-weekly|nausea-patients|48weeks|matched-placebo |
What the research actually shows
Folic acid × low-dose methotrexate: nausea in rheumatoid arthritis
3162 / TASK-1047 / R01-087 · operation=update · evidence review cutoff: 2026-09-20T22:07:03+09:00
1. Thirty-second answer
A direct randomized trial in adults with active rheumatoid arthritis compared oral folic acid with matched placebo on the same low-dose MTX adjustment protocol. The selected endpoint is people reporting nausea during 48 weeks: 44/133 (33.1%) with folic acid versus 55/137 (40.1%) with placebo. A descriptive recalculation gives RR 0.824 (95% CI 0.600-1.131) and a risk difference of -7.06 percentage points. The estimate points toward less nausea but does not establish a reduction under these conditions. Folinic acid, composite gastrointestinal outcomes, toxicity withdrawal and liver-enzyme outcomes are kept separate. [S01,S02]
The outcome is people reporting nausea at any time during the 48-week trial, not point prevalence at week 48. Nausea was not the trial's primary endpoint; the published primary endpoint was MTX withdrawal because of adverse events. [S01,S02]
Assessment: grade=null, score=null, grading_status=not_applicable_or_policy_missing. This is not because human evidence is absent. The current common rule says not to force the efficacy A-F formula onto safety or interaction questions, and no dedicated numerical scoring rule is supplied for this exact drug-pair adverse-event question. Because the existing site identity and presentation mapping already exist, this update artifact is ready_with_uncertainty. [R01,R02]
2. Fixed claim boundary
| Item | Current boundary |
|---|---|
| Population | Adults aged >=18 with active rheumatoid arthritis who were MTX-naive; this is not automatically DMARD-naive. |
| Common background | Oral MTX starting at 7.5 mg once weekly, adjusted for response/toxicity up to 25 mg/week. |
| Added intervention | Oral folic acid 1 mg daily, doubled to 2 mg/day when MTX reached >=15 mg/week. |
| Comparator | Matching placebo/double-dummy under the same MTX-adjustment protocol. |
| Period | During 48 weeks. |
| Selected outcome | People reporting nausea during 48 weeks. |
| Kept separate | Folinic acid, composite GI outcomes, MTX withdrawal due to toxicity, liver enzymes, and week-48 point prevalence. |
Daily folic acid and once-weekly MTX are not collapsed into the same dosing unit. These study regimens are not personal dosing instructions. [S01,S02]
3. Direct evidence and raw counts
The 2001 multicenter randomized double-blind placebo-controlled trial randomized 434 people. Five withdrew before taking study medication and 18 were excluded after post-randomization eligibility review, leaving 411 in the reported analysis population. The selected comparison uses 133 folic-acid and 137 placebo participants. [S01,S02]
Nausea was reported by 44/133 (33.08%) versus 55/137 (40.15%). A nausea-specific original adjusted RR, confidence interval and exact P value were not verified in the inspected material, so only a separate descriptive recalculation was performed:
- RR = 0.824
- descriptive 95% CI = 0.600–1.131
- risk difference = -7.06 percentage points
This is an unadjusted independent-binomial log-RR Wald calculation; it does not adjust for center, multiplicity, missingness, person-time or realized MTX dose. Because the interval includes 1, a reduction in nausea is not established for this exact comparison. This also does not establish equivalence or exactly zero effect. The current execution receipt is grading/numeric_execution_receipt.json.
4. Related evidence kept separate
- Griffith 2000: continuing established folic acid 5 mg/day versus switching to placebo showed a positive nausea signal at nine months (2/30 vs 9/20), but the prior-supplementation status, dose, visit denominator and time differ. It is not pooled as an identical replication. [S06,S07]
- Morgan 1990/1994: folic-acid trials with different durations, doses or toxicity endpoints; they do not directly supply the selected 48-week nausea-person count. [S04,S05]
- Cochrane review: the current bounded recheck directly verified a folic-acid-versus-placebo composite GI estimate of RR 0.76 (95% CI 0.57-1.01), 355 participants in 3 studies. It combines nausea/vomiting/abdominal pain and 24-52 week follow-up, so it is not substituted for the selected exact endpoint. [S03]
- 2018/2026 active-dose trials: both arms receive active folic acid, so they do not replicate added folic acid versus matching placebo. [S08,S11]
5. Current-rule application and why no A-F grade is assigned
rules/common_research_prompt.md section 5 states that safety, interaction and assay-interference questions should not be forced into the efficacy A-F formula. The axis-0 routing in rules/scoring.md covers physical facts, clinical efficacy and mixed claims, but supplies no dedicated numerical interaction-grade mapping for this adverse-event question. [R01,R02]
The efficacy calculator rules/calculator.py therefore received no input and its functions/CLI were not executed. No raw grade, exit code or PASS was invented. The raw-count descriptive calculation was executed separately and is not a grade calculation.
Axis traceability
| Axis | Plain meaning | Current application | Final value / limit |
|---|---|---|---|
| claim_type | Which formula applies? | This is a drug-pair adverse-event/interaction question; efficacy A/B/C routing is not forced. | null; human evidence exists. |
| endpoint | What is measured? | People reporting nausea during 48 weeks; separate from composite GI, liver enzymes and withdrawal. | null for efficacy scoring. |
| replication | Has the same question been repeated? | One exact primary trial family; Griffith differs in prior supplementation, dose and time and is not treated as R2/R0 after the comparability gate. | null. |
| independence | Who funded the evidence? | Dutch public grant 95-016 is reported; product supply and complete sponsor roles remain unverified. | null; unverified funding is not upgraded to I2. |
| effect | How large is the effect? | Descriptive RR 0.824, CI 0.600-1.131, RD -7.06 pp. | null; no E code is invented. |
| precision | How uncertain is it? | Original adjusted nausea CI and a validated clinical threshold are unverified; descriptive CI includes 1. | null; nonsignificance is not equivalence. |
| bias | How vulnerable is the design? | Randomized/double-blind report, but 434→411 analysis, secondary/exploratory symptom, variable realized MTX exposure and no new definitive Table-4 PDF visual check. | null; no B0/B1/B2 is invented. |
I1 funding rule: in an efficacy claim actually scored on the independence axis, the current score sheet says incomplete funding confirmation should not be labeled I2 and is handled as I1. Here the efficacy independence axis itself is not entered, so an I1 value is not fabricated as a final calculator input. The underlying principle is still applied: incomplete funding information is not presented as independent evidence.
? rule: no_human_study=false. A direct human RCT contains the selected nausea outcome, so the no-human-study route does not apply. Missing search-result counts are not converted to zero studies.
6. Bias, precision and independence in the actual record
Randomization, double masking and placebo control are reported, but not all 434 randomized participants entered the analysis population. Nausea is not the paper's primary endpoint. Adaptive MTX dosing means a common protocol does not guarantee identical realized exposure. These facts constrain causal precision without erasing the randomized comparison. [S01,S02]
The descriptive RR interval is wide and includes 1. No validated between-group clinically important difference for this nausea contrast was verified. We therefore do not declare either a clinically important benefit or clinically unimportant effect.
Public grant support is recorded, but complete sponsor/product-supply information was not verified. Different authors, centers, papers or review copies do not by themselves establish funding independence.
7. Evidence limits / framework limits / unfinished checks
Evidence limits: secondary/exploratory nausea outcome; no verified original adjusted nausea effect or exact P; 434 randomized versus 411 analyzed; incomplete nausea-specific follow-up/person-time; related studies differ in dose, duration, prior supplementation or outcome definition.
Framework limits: the current A-F system is an efficacy formula. No approved numerical interaction-specific grading rule is supplied for this drug-pair adverse-event question. The claim is therefore completed as a traceable ungraded interaction report rather than by inventing an efficacy letter.
Unfinished in this update: the definitive 2001 Table 4 PDF was not newly visually rechecked; no complete Embase/registry-history/manufacturer-safety-database search was performed; the narrow current web check did not capture total search-result counts. These limits do not mean zero studies.
8. Safety and action boundary
Safety label: Caution. This is not a finding that the combination is necessarily harmful and not an instruction to stop MTX or folic acid. Official MTX information separately addresses folic/folinic supplementation and blood, liver, kidney and gastrointestinal monitoring in RA. Oncology rescue therapy is a different setting. [S09,S10]
The study's daily folic acid and once-weekly MTX schedules are study conditions, not personal start/stop/day-of-week/dose instructions.
9. Current conclusion and revision triggers
In the direct 48-week trial under the same low-dose MTX adjustment protocol, nausea was reported by 44/133 folic-acid recipients and 55/137 placebo recipients. The descriptive RR was 0.824 (95% CI 0.600-1.131), pointing toward less nausea but not establishing a reduction under this exact condition. It also does not prove exactly zero effect.
The current value is grade=null, score=null because the governing rule does not force efficacy A-F scoring onto this interaction/adverse-event question.
Revise under the same ID if the definitive original table/protocol/patient data, a verified correction/retraction, a new trial with this exact boundary, or an approved interaction-specific scoring rule becomes available.
10. Current update identity
- ID/site_id: 3162
- task_id: TASK-1047
- slug:
folic-acid-low-dose-methotrexate-ra-48weeks-nausea - existing permalink and Korean/English canonical URLs preserved
- first published: 2026-09-17T16:34:16+00:00 preserved
- operation: update
- server access/deployment in this chat: not performed
Sources
[S01] van Ede et al. 2001, PMID 11465701, DOI 10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7.
[S02] Historical full-paper HTML-copy extraction from the same 2001 trial; reused, not newly accessed in this update.
[S03] Shea et al. Cochrane review, PMID 23728635; current recheck verified folic-acid-only composite GI RR 0.76 (0.57-1.01), 3 studies/355 participants.
[S04] Morgan et al. 1990, PMID 2405864.
[S05] Morgan et al. 1994, PMID 7978695.
[S06] Griffith et al. 2000, PMID 11035130.
[S07] Historical Griffith 2000 PDF-copy extraction.
[S08] Yoshida et al. 2026, DOI 10.1007/s10067-026-08195-8.
[S09] DailyMed TREXALL methotrexate prescribing information.
[S10] NIH ODS Folate Fact Sheet for Health Professionals.
[S11] 2018 high- versus low-dose weekly folic-acid pilot RCT, PMID 30001258; active folic acid in both arms.
[R01] rules/common_research_prompt.md section 5.
[R02] rules/scoring.md, axis 0 and safety/harm separation provisions.
Why the efficacy grade and score are unscored
Current common_research_prompt section 5 says not to force efficacy A-F grading onto interaction/adverse-event questions, and no dedicated numerical rule is supplied for this pair. Human RCT data exist, so this is not a no-human-study case.
Review performed and remaining limitations
Original adjusted nausea effect, exact P and validated MCID are unverified. The descriptive interval includes 1 and is not equivalence evidence.
Original evidence table
| Study identifier | Role | Endpoint | Result | Limitations | Sources |
|---|---|---|---|---|---|
| VAN_EDE_2001 | Direct primary comparison | Nausea during 48 weeks | Folic acid: 44/133; placebo: 55/137. Descriptive RR 0.824, 95% CI 0.600–1.131. | The 411 analyzed participants differ from the 434 randomized. Table 4 was inspected in an HTML copy, not visually in the definitive PDF. | S01 · S02 |
| MORGAN_1990 | Different duration and toxicity scope | Overall toxicity over 24 weeks | Folic acid 1 mg/day; 32 completers. The selected nausea effect is null. | Overall toxicity scores are not converted to nausea patient counts. | S04 |
| MORGAN_1994 | Different doses and composite outcome | Overall toxicity score | 79 participants; folic acid 5 or 27.5 mg/week. The selected nausea effect is null. | Abstract access only; exact co-interventions and nausea denominators/time remain unconfirmed. | S05 |
| GRIFFITH_2000 | Separate positive comparison | Nausea at 9 months | Continued folic acid: 2/30; switched to placebo: 9/20. | Established 5 mg/day users; continuation versus withdrawal. Visit denominators, attrition and multiplicity differ. Not pooled with the 48-week comparison. | S06 · S07 |
| SHEA_REVIEW_2013 | Review map; mixed molecules excluded from attribution | Composite gastrointestinal outcome | Combined folic/folinic acid: RR 0.74, 95% CI 0.59–0.92. The adopted folic-acid-only value is null. | Original trials are not counted again. The 2014 republication is not a new trial. | S03 |
| YOSHIDA_2026 | Active-dose comparison excluded from the primary contrast | Toxicity over 12 weeks | 44 participants; folic acid 10 versus 5 mg/week. The no-added-folate effect is null. | Both arms received active folic acid; diagnoses included different rheumatic diseases. Liver enzymes are not a GI effect. | S08 |
| OFFICIAL_SAFETY | Regulatory and safety information | Co-treatment cautions | No trial effect estimate or efficacy grade is assigned. | Context for RA supplementation, MTX monitoring, vitamin B12 and oncology boundaries; not the primary GI effect. | S09 · S10 |
Receipt — 10 References
Evidence access cutoff: 2026-09-20. Each citation states its actual access level (full-text transcription, abstract, index, or other) and remaining limitations. Bibliographic checking does not certify the study results or treatment efficacy.
Technical integration by: Codex · Evidence date: 2026-09-20 · Corrections: none
Revision history
2026-09-20: Integrated the current submitted manuscript and paired explanation. The verdict ID, URLs and first publication date are preserved. The current conclusion and limitations are presented in the report above.
Cite this interaction report
Current common_research_prompt section 5 says not to force efficacy A-F grading onto interaction/adverse-event questions, and no dedicated numerical rule is supplied for this pair. Human RCT data exist, so this is not a no-human-study case.
[Chamgap] Folic acid × low-dose methotrexate: nausea in rheumatoid arthritis — Efficacy grade and score unscored · Safety caution. https://chamgap.com/en/verdicts/general/folic-acid-low-dose-methotrexate-ra-48weeks-nausea/ · CC BY 4.0What this document does and does not do
Chamgap is an information source. It reports what research has and has not confirmed; it does not tell readers what to take or buy. That decision belongs to readers and, when needed, medical or legal professionals. This verdict reflects literature available up to the search date and may change as new research appears. Nothing here is medical advice.