What question did this study set out to answer?

The central aim is to assess methotrexate's effectiveness in spinal cord injury through both preclinical and clinical studies.

February 22, 2026

Neuroprotection or Neurotoxicity? Insights from preclinical and clinical studies of methotrexate in spinal cord injury

Key Points

The central aim is to assess methotrexate's effectiveness in spinal cord injury through both preclinical and clinical studies.
Literature search conducted in PubMed, Scopus, and Web of Science until 2024.
Inclusion of animal studies focused on methotrexate in spinal cord injury.
Independent data extraction and quality assessment by two reviewers.
Random-effects meta-analysis performed where suitable.
Human evidence analyzed, particularly large-scale retrospective data.
Six animal studies identified, showing improved functional recovery with methotrexate.
Administration reduced apoptosis and oxidative stress, preserving myelinated axons.
Meta-analysis indicated a significant reduction in myeloperoxidase activity (–3.40 standardized mean difference).
Clinical evidence revealed neurotoxicity in oncology patients, with a 5.2% incidence of symptoms like encephalopathy.
Increased neurotoxicity risk noted in children and with intrathecal administration.

Abstract

Background: Spinal cord injury (SCI) remains a serious condition with limited treatment options. Methotrexate (MTX), an immunosuppressant with anti-inflammatory and neuroprotective properties, has shown promising effects in experimental SCI, but clinical observations in oncology patients raise concerns regarding neurotoxicity. The aim of this study was to systematically evaluate the effect of MTX on SCI in preclinical models and to compare these findings with available human evidence. Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science up to the end of 2024. Animal studies investigating MTX in SCI were included. Data extraction and quality assessment were performed independently by two reviewers. A random-effects meta-analysis was conducted where appropriate. Human evidence, including large-scale retrospective data, was synthesized for interpretation. Results: Six animal studies (five rats, one rabbit) met the inclusion criteria. MTX administration consistently improved functional recovery, reduced apoptosis, decreased oxidative stress, and improved preservation of myelinated axons. Meta-analysis demonstrated a significant reduction in myeloperoxidase activity (standardized mean differences = –3.40, 95% confidence interval CI –5.73 to –1.08, I 2 = 91.18%). In contrast, clinical evidence, mostly from oncology patients with intact spinal cords, consistently reported MTX-associated neurotoxicity, including encephalopathy, dorsal column myelopathy, and polyradiculopathy. The largest cohort identified a 5.2% incidence of neurotoxicity, with a higher risk in children and intrathecal (IT) administration. Conclusion: Preclinical evidence supports MTX as a potential neuroprotective agent in SCI, but human data demonstrate neurotoxicity in noninjured spinal cords, especially with IT use. Differences in route of administration, dosing, host condition, and injury context likely explain this contrast. IT MTX should not be considered in traumatic SCI. Future studies should define safe systemic dosing windows in injured spinal cord models and evaluate cautious early-phase clinical trials under strict monitoring.

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