Can Methotrexate Toxicity Cause Neurological Symptoms?

Call 911 or your local emergency number immediately. Do not drive yourself to the hospital. Sudden trouble speaking, confusion, or weakness on one side of your body are warning signs of a stroke. Even if the symptoms go away quickly, it is a medical emergency.

• Note the exact time the symptoms started (or the “last known well” time).
• Bring your complete medication list, including your specific methotrexate dose and how you take it (oral, injection, IV, or spinal).
• Do not take your next dose of methotrexate until an emergency doctor or your specialist explicitly tells you it is safe to do so.

Yes, methotrexate toxicity can cause severe neurological symptoms, including stroke-like episodes. While rare overall, methotrexate-induced neurotoxicity can cause sudden transient aphasia (trouble speaking or understanding speech), hemiparesis (weakness on one side of the body), confusion, and seizures ^[1][2][3]. Because these symptoms are identical to an acute ischemic stroke (a blocked blood vessel in the brain), anyone experiencing them must seek immediate emergency medical evaluation ^[4][5].

What Does Methotrexate Neurotoxicity Look Like?

When methotrexate causes sudden brain dysfunction, doctors may refer to it as acute methotrexate encephalopathy (a broad term for brain dysfunction) or toxic leukoencephalopathy (specifically meaning injury to the brain’s white matter) ^[1].

A patient experiencing this type of toxicity may suddenly develop:

• Difficulty finding words, understanding others, or slurred speech (dysarthria) ^[1][6]
• Weakness or paralysis on one side of the body ^[1][3]
• Confusion, altered mental status, or extreme lethargy ^[1]
• Seizures or involuntary muscle movements ^[1][3]

In the acute form, these symptoms typically appear between 2 and 14 days after receiving a dose, but this timeline applies primarily to patients receiving high-dose or spinal fluid treatments ^[1][3]. Delayed neurological symptoms can occur outside of this window.

While symptoms can sometimes be transient (fluctuating and improving over several days), waiting at home is never safe ^[1][6]. The recovery process is unpredictable. Some patients can develop persistent neurological deficits, severe seizures, or long-term complications ^[7].

Who is Most at Risk?

Neurological toxicity is not a common risk for everyone taking methotrexate. The likelihood depends heavily on how the drug is administered:

• High-Dose and Oncology Patients: Neurotoxicity is predominantly seen in patients receiving high-dose intravenous (IV) methotrexate or intrathecal methotrexate (injected directly into the spinal fluid) for cancer treatments, such as acute lymphoblastic leukemia or osteosarcoma ^[1][8]. In certain specific pediatric oncology groups receiving intensive regimens, up to 10% to 14% of patients have experienced these events, though rates vary widely by treatment protocol ^[9][10].
• Low-Dose Rheumatology Patients: For patients taking low weekly doses of oral or injected methotrexate for inflammatory conditions (like rheumatoid arthritis or psoriasis), acute neurotoxicity is extremely rare ^[1][8].

Other potential contributors to toxicity include decreased kidney function, which slows the body’s ability to clear the drug. Factors like vitamin B12 deficiency or the use of interacting medications are also being studied as possible, though less certain, risks ^[9][11].

Why It Is a Medical Emergency

If you develop sudden weakness, speech difficulties, or confusion, do not assume it is just a side effect of methotrexate. These symptoms are indistinguishable from an acute stroke or a TIA (transient ischemic attack, or “mini-stroke”) ^[12][13]. Sudden neurological symptoms can also have other causes, including infections, bleeding, or metabolic problems, all of which require immediate medical attention.

Emergency evaluation will typically include:

• Brain Imaging: Doctors will often start with a CT scan and may use an MRI. While imaging is crucial to rule out a brain hemorrhage or a large blood clot, it cannot perfectly distinguish between a stroke and methotrexate toxicity right away, as both can look similar on a scan ^[12][13]. The diagnosis relies on the full clinical picture.
• Additional Tests: The emergency team will likely check your blood sugar, conduct a thorough neurological exam, check kidney and liver function, blood cell counts, and—if you are on high-dose regimens—your blood methotrexate levels.
• Stopping the Medication: If methotrexate neurotoxicity is suspected, the immediate step is for doctors to withhold further doses until a specialist has thoroughly evaluated you ^[12][14]. Do not resume your medication without an explicit medical plan from your oncology or rheumatology team.
• Specialist Treatment: There is no universal “antidote” for methotrexate neurotoxicity. Treatment is directed by specialists (neurologists, oncologists, or toxicologists) and involves supportive care, seizure management, and airway protection if needed. In some specific cases, doctors might try medications like leucovorin or aminophylline (aminophylline is an asthma medication that has shown some potential in small studies to reverse neurotoxicity symptoms). However, evidence for these treatments is limited to small reports or specific protocols, and they must be closely managed by your medical team ^[12][15].

Even if your symptoms completely resolve before you reach the hospital, you still require urgent assessment to confirm the cause and determine if and how you can safely continue your treatments ^[4][5].