Folic acid × low-dose methotrexate: nausea in rheumatoid arthritis
research showsDirect human trials of folic acid added to low-dose oral methotrexate (MTX) in adults with active rheumatoid arthritis exist. This report selects **people reporting nausea during a 48-week trial**. The folinic-acid arm is not pooled with folic acid. [S01, S02] Nausea was reported in **44/133 (33.08%)** folic-acid recipients and **55/137 (40.15%)** placebo recipients. A descriptive recalculation gives a risk ratio of **0.824**, a **95% confidence interval of 0.600–1.131**, and a risk difference of **−7.06 percentage points**. This is not the original adjusted effect. A nausea reduction is not established under these conditions. That does not establish equivalence, exactly zero effect, or the absence of every benefit of folate co-treatment. [S02; numeric_evidence.json] A positive trial of continuing versus stopping established folic acid, and a review combining folic with folinic acid, are presented separately. They are not treated as identical replications of the selected comparison. [S03, S06, S07]
ads claimAdvertising or promotional product claims were not collected in this task.
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 occurred in 44/133 versus 55/137 participants. The descriptive risk ratio is 0.824 (95% CI 0.600–1.131), with a difference of −7.06 percentage points; uncertainty remains. |
| 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 | The original adjusted effect, exact P value and MCID are null. The descriptive interval does not adjust for multiplicity, center, missingness or exposure time. |
The efficacy calculator exists, but no approved scoring rule maps this interaction question, so it was not executed. The separate numeric check is descriptive statistics, not grade calculation.
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
TASK-1047 / R01-087 · New independent interaction report
Input snapshot: 2026-09-18T00:37:26+09:00 · Content verification: 2026-09-18T01:06:19+09:00
## Thirty-second answer
Direct human trials of folic acid added to low-dose oral methotrexate (MTX) in adults with active rheumatoid arthritis exist. This report selects **people reporting nausea during a 48-week trial**. The folinic-acid arm is not pooled with folic acid. [S01, S02]
Nausea was reported in **44/133 (33.08%)** folic-acid recipients and **55/137 (40.15%)** placebo recipients. A descriptive recalculation gives a risk ratio of **0.824**, a **95% confidence interval of 0.600–1.131**, and a risk difference of **−7.06 percentage points**. This is not the original adjusted effect. A nausea reduction is not established under these conditions. That does not establish equivalence, exactly zero effect, or the absence of every benefit of folate co-treatment. [S02; numeric_evidence.json]
A positive trial of continuing versus stopping established folic acid, and a review combining folic with folinic acid, are presented separately. They are not treated as identical replications of the selected comparison. [S03, S06, S07]
## Question and prior-material boundary
The original request proposed an interaction question without assuming a verified drug pair, formulation or comparator. Research fixed one pair (folic acid–MTX), one outcome (nausea), and one period (48 weeks). “Folic acid alone” here means **the sole additional randomized active substance on common MTX**, not treatment without MTX.
Existing record 1043 concerns MTX disease control and joint damage in rheumatoid arthritis. Its general folate safety statement is not a completed assessment of this sole-added-folic-acid, nausea and time-specific comparison. The complete Korean and English bodies, evidence and citations of all 13 supplied candidates were compared. Searching the 3,161-record index does not mean that 3,161 complete original reports were available or read. [reuse_audit.json]
## Actual primary comparison
| Item | Verified boundary | |---|---| | Population | Adults aged at least 18; 1987 ACR rheumatoid arthritis; active disease with DAS ≥3; MTX-naive, not necessarily naive to every disease-modifying drug. | | Added substance | Oral folic-acid tablets, 1 mg every morning; doubled to 2 mg/day when MTX reached at least 15 mg/week. | | Background | Oral MTX starting at 7.5 mg **once weekly**, adapted for response and toxicity up to 25 mg/week. | | Comparator | Matched placebo and double-dummy masking under the same MTX-adjustment protocol. The active folinic-acid arm is excluded. | | Common therapy | Stable nonsteroidal anti-inflammatory drugs and steroids were allowed; other disease-modifying drugs were prohibited. | | Time | Nausea reported during 48 weeks, not point prevalence on the final day or an analysis limited to completers. | | Unit | People reporting nausea, not repeated episodes or a union of all gastrointestinal events. |
Source: primary methods and Table 4. [S01, S02]
The nominal folic-acid totals of 7 or 14 mg/week are arithmetic conversions of daily dosing, not weekly-bolus prescriptions. No recommendation to skip the MTX day is inferred. Salts, complete excipients, brands and batches remain null. Equal final MTX doses and equal realized exposure are not assumed.
## Denominators, analysis and statistics
Of 434 randomized participants, five withdrew before taking treatment and 18 were excluded after eligibility review. The 411-person population called “intention to treat” by the authors is not the complete randomized population. The primary denominators of 133 and 137 refer to that analyzed population. [S02]
Nausea was an exploratory secondary toxicity outcome. The published primary outcome was MTX withdrawal for toxicity. Liver-enzyme-driven reductions in total withdrawal cannot substitute for a nausea effect. Symptoms were collected every three weeks, but nausea-specific missingness, complete follow-up after withdrawal and person-level exposure times were unavailable. [S01, S02]
Table 4 states P >0.08 for all listed symptoms; it does not provide an exact nausea P value. The original nausea-specific adjusted risk ratio, confidence interval and exact P value are null. The descriptive independent-binomial log-Wald interval does not adjust for center, multiplicity, individual exposure or the 23 exclusions.
The calculation is RR = (44/133)/(55/137), with SE(log RR) = sqrt(1/44 − 1/133 + 1/55 − 1/137). The risk difference is 100 × (44/133 − 55/137). The actual Python input, output, standard error stream and exit code are in numeric_execution_receipt.json. This statistical check is not execution of the efficacy-grade calculator.
## Original-language evidence table: seven entries
| Study or information | Role and outcome | Verified result | Limits | |---|---|---|---| | 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] |
## Counterevidence and results not pooled
Griffith 2000 found a protective signal at nine months: 2/30 participants continuing folic acid versus 9/20 switched to placebo reported nausea. It studied established 5 mg/day users, unlike the new MTX users receiving 1–2 mg/day in the selected 48-week trial. At 12 months, the counts were 7/27 versus 7/17. Different visit denominators, attrition and multiple comparisons preclude treating the most favorable nine-month result as the present primary effect. The abstract's P =.001 and the table's P <.001 display difference is retained. [S06, S07]
Cochrane 2013 combined folic and folinic acid for a gastrointestinal risk ratio of 0.74 (95% CI 0.59–0.92), mixing molecules and composite symptom definitions. Its original folic-acid-only subgroup table could not be sufficiently reverified, so the adopted folic-acid-only value is null. This access limit does not mean that no subgroup analysis or no human research exists. The 2014 republication is not another independent trial. [S03]
The 2026 trial of 10 versus 5 mg/week gave active folic acid to both groups for 12 weeks. It does not estimate supplementation versus no added folate. Liver enzymes, fatigue and MTX polyglutamates are not substituted for between-group nausea. [S08]
## Design, exposure and independence
The primary trial describes randomization, centrally held codes and double masking. Reported procedures do not prove the absence of all bias. MTX doses changed with response and toxicity; a common background protocol is different from identical realized exposure. The comparison addresses assigned co-treatment strategies, not a pure pharmacokinetic experiment at a fixed MTX exposure. [S02]
Dutch public grant 95-016 is recorded, but product supply, sponsor roles and all conflicts remain null. Multiple centers, different authors and different copies do not automatically establish independence. An estimated creatinine clearance below 50 mL/min was an exclusion criterion. The results are not generalized to every renal, vitamin B12 or nutritional subgroup. [S02]
## Efficacy scoring versus interaction format
**The efficacy grade, numeric score and all seven axis codes are explicitly uncalculated (null).** The supplied rules prohibit forcing efficacy A–F scores onto interaction questions. NUT/R01 guidance and an efficacy calculator are present, but an approved scoring and publication mapping for this interaction was not supplied. [policy_applicability.json]
The original calculator source was read and its hash checked before and after the task. Its functions, check_verdict and command-line interface were not executed. The four grading receipts record the reason, the actual final report's SHA-256, and null calls, returns, exceptions, error counts, exit code, raw grade and numeric anchor. Descriptive statistics are not presented as grade calculation.
| Assessment field | Applicable scope | |---|---| | 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 | Nausea occurred in 44/133 versus 55/137 participants. The descriptive risk ratio is 0.824 (95% CI 0.600–1.131), with a difference of −7.06 percentage points; uncertainty remains. | | 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 | The original adjusted effect, exact P value and MCID are null. The descriptive interval does not adjust for multiplicity, center, missingness or exposure time. |
## Seven null-axis explanations
### claim_type
Not calculated (null). This is an adverse-event interaction report for a specific pair. The physical/efficacy/mixed A/B/C taxonomy is not imposed.
### endpoint
Not calculated (null). The actual outcome is people reporting nausea during 48 weeks. Liver enzymes, total withdrawal, RA response, pharmacokinetics and efficacy endpoint codes are not substitutes.
### replication
Not calculated (null). Related human trials exist, but doses, prior supplementation and periods differ. Reviews, originals and copies are not independent replications.
### independence
Not calculated (null). Multiple centers or different authors do not establish complete funding and product independence. Public funding and unverified sponsor roles are reported together.
### effect
Not calculated (null). A descriptive risk ratio of 0.824 points toward benefit with uncertainty. Non-significance is not an E0 code, exactly zero effect or proof of a harmful interaction.
### bias
Not calculated (null). Randomization and masking are reported, but 23 exclusions, exploratory symptom comparisons, unequal realized MTX exposure and copied-table access limit inference. No artificial bias code is assigned.
### precision
Not calculated (null). The original nausea confidence interval and MCID are null. The separate descriptive log-Wald interval is not the original adjusted analysis, established clinical importance or an efficacy precision code.
## Safety
Safety label: **Caution**. This is neither a finding that the combination is necessarily harmful nor an instruction to stop treatment.
Official MTX labeling separately addresses folic or folinic supplementation in rheumatoid arthritis and monitoring of blood, liver, kidney and gastrointestinal toxicity. Supplementation does not prevent all serious MTX adverse reactions. High-dose oncology rescue is a different setting. Study schedules for daily folic acid and weekly MTX are not personal dosing instructions. [S09, S10]
Correction of vitamin B12-deficiency anemia with folate does not treat its neurological injury. Unverified B12 status and total intake are not replaced by assumptions of adequacy, deficiency correction or proven safety. Pregnancy, lactation, liver or kidney disease, and co-medications require individual clinical judgment. This report recommends no prescription change, discontinuation or dosing calendar. [S10]
## Unknowns and revision conditions
Definitive primary-PDF visual verification, the original adjusted nausea effect, baseline nutrition and B12 status, total intake, actual adherence or crossover, registered protocol, complete funding independence and every correction or retraction lie beyond the verified scope. Each null has a complete Korean and English reason in unresolved.json.
Revise within the same boundary when definitive original tables, protocols, patient data, verified corrections or new direct trials change the assessment. An approved interaction-specific scoring policy would require a policy revision. These limitations do not place the completed current report on clinical hold.
## Classification, editing and handoff
Kind M describes a medically managed drug co-treatment strategy involving folic-acid tablets. It does not claim that the precise trial product's regulatory status was established. Provisional kind S was not automatically imposed on every oral vitamin use. The representative list tag is Folic acid; INTERACT is an internal workflow abbreviation, not an official medical code. The ID, slug, URL, semantic code and first-publication date are null.
Document quality A is the same model's assessment of source traceability, boundaries, bilingual content, uncertainty and format. It is not an efficacy grade, independent external review, journal certification or an error-free guarantee. Initial corrections=[]; pre-submission edits are recorded in a separate audit.
Result: completed_with_uncertainty. Grading status: not_applicable_or_policy_missing. Publication status: needs_format_mapping. Clinical tasks: clinical_todo=[]. The technical recipient maps the original bilingual body, tables and null reasons from reports/TASK-1047.json. No clinical re-research, regrading or calculator execution is requested.
The recipient-confirmed FULL3/5 status for the new publications of tasks 84 and 85 and duplicate linking of task 86 is preserved. This attachment does not itself claim FULL4/5. No server access, deployment or next task 88 was performed.
## Sources
[S01] van Ede et al. 2001: 48-week randomized folic/folinic acid MTX trial. https://onlinelibrary.wiley.com/doi/10.1002/1529-0131(200107)44:7%3C1515::AID-ART273%3E3.0.CO;2-7 · Abstract: methods/results/conclusion
[S02] van Ede 2001 primary-paper full text, third-party HTML transcription. https://www.academia.edu/27952481/Effect_of_folic_or_folinic_acid_supplementation_on_the_toxicity_and_efficacy_of_methotrexate_in_rheumatoid_arthritis_A_forty_eight_week_multicenter_randomized_double_blind_placebo_controlled_study · pp1516–1521; Patients and methods; Tables1,2,4,6; Table4 nausea row
[S03] Shea et al. Cochrane 2013 systematic review. https://pubmed.ncbi.nlm.nih.gov/23728635/ · Abstract main results; review family; search cutoff2March2012
[S04] Morgan et al. 1990 folic acid supplementation trial. https://pubmed.ncbi.nlm.nih.gov/2405864/ · Abstract
[S05] Morgan et al. 1994 supplementation with folic acid during MTX therapy. https://pubmed.ncbi.nlm.nih.gov/7978695/ · Abstract
[S06] Griffith et al. 2000 continuation versus stopping folic acid. https://pubmed.ncbi.nlm.nih.gov/11035130/ · Abstract: methods/results
[S07] Griffith2000 primary PDF copy. https://scispace.com/pdf/do-patients-with-rheumatoid-arthritis-established-on-1f9jqak04o.pdf · pp1102,1106–1107; Table4; screenshots pages0,4,5
[S08] Yoshida et al. 2026 folic acid dose-comparison RCT. https://link.springer.com/article/10.1007/s10067-026-08195-8 · Abstract; Methods/interventions/outcomes
[S09] DailyMed TREXALL methotrexate prescribing information. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e942f8db-510f-44d6-acb5-b822196f5e8c · Sections2.3,5.3–5.10,7
[S10] NIH ODS Folate professional fact sheet. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/ · Health risks/excessivefolate; Interactions/Methotrexate
Why the efficacy grade and score are unscored
The efficacy calculator exists, but no approved scoring rule maps this interaction question, so it was not executed. The separate numeric check is descriptive statistics, not grade calculation.
| Claim type | null | Not calculated (null). This is an adverse-event interaction report for a specific pair. The physical/efficacy/mixed A/B/C taxonomy is not imposed. |
| Endpoint | null | Not calculated (null). The actual outcome is people reporting nausea during 48 weeks. Liver enzymes, total withdrawal, RA response, pharmacokinetics and efficacy endpoint codes are not substitutes. |
| Replication | null | Not calculated (null). Related human trials exist, but doses, prior supplementation and periods differ. Reviews, originals and copies are not independent replications. |
| Independence | null | Not calculated (null). Multiple centers or different authors do not establish complete funding and product independence. Public funding and unverified sponsor roles are reported together. |
| Effect size | null | Not calculated (null). A descriptive risk ratio of 0.824 points toward benefit with uncertainty. Non-significance is not an E0 code, exactly zero effect or proof of a harmful interaction. |
| Risk of bias | null | Not calculated (null). Randomization and masking are reported, but 23 exclusions, exploratory symptom comparisons, unequal realized MTX exposure and copied-table access limit inference. No artificial bias code is assigned. |
| Precision | null | Not calculated (null). The original nausea confidence interval and MCID are null. The separate descriptive log-Wald interval is not the original adjusted analysis, established clinical importance or an efficacy precision code. |
Review performed and remaining limitations
Original-table visual verification, effect and MCID, nutrition and realized exposure, registration, independence and correction status have declared limits in the body and unresolved.json.
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: 2026-09-18. 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: 2026-09-18 · Corrections: none
Cite this interaction report
The efficacy calculator exists, but no approved scoring rule maps this interaction question, so it was not executed. The separate numeric check is descriptive statistics, not grade calculation.
[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.