Dantrolene and Methotrexate: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Dantrolene
Methotrexate
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy
Interaction Deep Dive
Use caution when methotrexate is coadministered with hepatotoxic agents like dantrolene as it may increase methotrexate exposure, which may increase the risk of methotrexate severe adverse reactions2. In some cases, the coadministration of methotrexate with dantrolene may also subsequently reduce active metabolite formation, which may reduce the clinical effectiveness of methotrexate. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic products 1. One case report described methotrexate toxicity in a 16-year-old girl who had received both medications 2.
Why it happens (mechanism)
Impaired renal clearance of methotrexate; altered protein binding; additive hepatotoxicity
Literature reports
1 report — tap to read
a) In a case report, coadministration of dantrolene and methotrexate appeared to significantly increase methotrexate concentrations, resulting in methotrexate intoxication. A 16-year-old girl with non-metastatic femoral osteosarcoma was treated with high-dose methotrexate (12 g/m(2)), along with ondansetron and methylPREDNISolone, both of which were started concomitantly. She had also received intravenous nalbuphine and oral dantrolene for 4 days and 1 day, respectively. At 24 hours post initial methotrexate dose, methotrexate serum concentrations were significantly elevated (418 micromoles/liter), with evidence of methotrexate toxicity (cytolytic hepatitis, renal failure, grade I thrombopenia, and grade IV mucositis). The patient also experienced a seizure on day 9 due to elevated blood pressure. The patient received intense urine alkalinization, leucovorin rescue, carboxypeptidase-G2, and the dantrolene was stopped. The threshold value of 0.2 micromoles/liter was reached at 324 hours after the initial methotrexate dose was given. Methotrexate was resumed at a lower dose (total 10 g) 3 weeks later with good tolerance and standard decreases in plasma concentrations. Use of the Naranjo probability scale indicated a probable association between the methotrexate toxicity and dantrolene therapy in this patient. The mechanism of action was postulated to be altered renal excretion of methotrexate by dantrolene or its metabolite, 5-hydroxydantrolene, and altered protein binding of methotrexate to serum proteins 2.
Common questions
Can I take Dantrolene and Methotrexate together?
Increased methotrexate exposure, an increased risk of methotrexate toxicity or methotrexate-related severe adverse reactions, reduced active metabolite formation and possibly reduced methotrexate efficacy Always confirm with your pharmacist or prescriber before making any change.
How serious is the Dantrolene and Methotrexate interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Dantrolene or Methotrexate need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (2)
Keep reading about Dantrolene
Keep reading about Methotrexate
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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