Does Methotrexate Change Your Mood? Understanding a Rare Side Effect

October 10, 2025 •

4 min read

While methotrexate is a cornerstone for treating conditions like rheumatoid arthritis and psoriasis, mood and behavioral changes are documented, albeit rare, side effects. Some patients, including children, have experienced symptoms like irritability and depressed mood that resolve upon stopping the medication.

Quick Summary

Methotrexate can cause mood changes, a rare but documented neurological side effect that includes irritability, anxiety, and depression. Understanding the potential mechanisms and who is at higher risk can help patients and doctors manage these symptoms.

Key Points

Mood Changes Are a Rare Side Effect: Although methotrexate is an important medication, mood and behavioral changes such as irritability, anxiety, and depression have been reported, primarily as part of broader neurological side effects.
Stopping the Medication Can Reverse Symptoms: In some documented cases, patients experienced a full reversal of mood changes and neurological symptoms within weeks of discontinuing methotrexate.
Neurochemical Pathways Are Involved: The drug may affect brain function by altering extracellular adenosine levels, interfering with folate metabolism required for neurotransmitter synthesis, and potentially causing neuroinflammation.
Risk Factors Include Age and Dosage: Older patients and those receiving high-dose MTX (often for cancer) are at higher risk for CNS toxicity and mood alterations. High doses are more strongly linked to significant neurotoxic effects.
Folic Acid and Dose Adjustment May Help: Folic acid supplementation is standard practice and helps mitigate common side effects, but its direct effect on mood changes is not as clear. Dose adjustments or switching to an injectable form may be necessary to manage these symptoms.
Open Communication with Your Doctor is Essential: Patients should report any mood changes to their healthcare provider for proper evaluation and management, rather than attempting to self-treat or stop the medication.

The Link Between Methotrexate and Mood

Methotrexate (MTX) is a powerful medication used to treat a variety of inflammatory and autoimmune conditions, as well as certain types of cancer. While its efficacy is well-established, it is also known to cause a range of side effects, including gastrointestinal issues like nausea, fatigue, and mouth ulcers. Less commonly, MTX can affect the central nervous system (CNS), leading to neurological and psychiatric symptoms, including mood changes.

Clinical observations and case reports have documented instances where patients on low-dose MTX experienced mood alterations such as irritability, anxiety, and depression. In some cases, these symptoms were severe enough to warrant stopping the medication, after which the patient's mood returned to normal. The exact mechanism for this is not fully understood, but several neurobiological pathways are believed to be involved, indicating that MTX can affect brain function in susceptible individuals.

Potential Neurochemical Mechanisms

The complex pharmacology of methotrexate means it can interfere with several biological processes that are essential for regulating mood and cognitive function. Several hypotheses have been proposed to explain how this medication might influence mood:

Impact on Adenosine: MTX increases extracellular adenosine levels in inflamed areas, which is believed to be the primary anti-inflammatory mechanism of low-dose MTX. However, in the brain, increased adenosine can affect synaptic plasticity and neuronal excitability, which are implicated in mood changes.
Folate Metabolism Disruption: While MTX is a folate antagonist, the low doses used for rheumatologic diseases are usually offset by folic acid supplementation. However, some pathways might still be affected. Disruption of folate metabolism can interfere with the synthesis of neurotransmitters like serotonin and dopamine, both of which are crucial for mood regulation.
Neurotransmitter Interference: Some studies suggest that MTX may directly interfere with key neurotransmitters. Animal studies have shown that high-dose MTX can decrease levels of serotonin, dopamine, and norepinephrine in the brain, though the effect of lower doses is less clear.
Neuroinflammation: Inflammation is increasingly linked to mood disorders. By affecting cytokines and other inflammatory mediators, MTX could potentially influence the inflammatory status of the brain.

Documented Mood and Neurological Side Effects

Patients taking methotrexate have reported a variety of CNS-related side effects, from subtle moodiness to more severe psychiatric symptoms. Some of these documented issues include:

Irritability and moodiness
Depressed mood
Anxiety and restlessness
Difficulty concentrating or cognitive fog
Headaches and dizziness
Rarely, more severe conditions like seizures or encephalopathy, particularly with high doses

Risk Factors and Patient Sensitivity

Not everyone who takes methotrexate will experience mood changes. Several factors can influence an individual's susceptibility to this side effect:

Age: Older patients, especially those with mild renal impairment, may be at higher risk for CNS toxicity, including mood alterations.
Dosage: While low-dose MTX is generally well-tolerated, some patients report dose-related neuropsychological symptoms.
High-Dose or Intrathecal Administration: The risk of severe neurotoxicity, including mood and cognitive changes, is significantly higher with high-dose intravenous or intrathecal MTX, which is often used in cancer treatment.
Individual Metabolism: Genetic and metabolic factors can affect how a person processes MTX, potentially leading to higher concentrations in the CNS and an increased risk of side effects.

Managing Mood Changes on Methotrexate

If you believe methotrexate is affecting your mood, it's crucial to discuss your symptoms with your healthcare provider. Do not stop taking the medication on your own. Your doctor may suggest a few strategies to help manage the side effects, including:

Folic Acid Supplementation: Folic acid is routinely prescribed alongside MTX to minimize common side effects like nausea and mouth sores. While its effect on mood changes is less certain, ensuring adequate folate levels is an important part of managing therapy.
Splitting the Dose: For some patients, splitting the weekly oral dose of MTX into two smaller doses taken 12 hours apart can help reduce gastrointestinal side effects and might help with other issues as well.
Switching to Injections: If mood changes are particularly linked to oral administration, switching to injectable MTX can sometimes alleviate symptoms.
Discussing Other Medications: Your doctor may review your other medications, as some can interact with MTX and potentially exacerbate side effects. In some cases, a different treatment might be considered.

Methotrexate Side Effects: Mood vs. Physical


Feature	Mood/Neurological Side Effects	Physical Side Effects
Prevalence	Uncommon to rare	Common
Common Examples	Irritability, depression, anxiety, fatigue, cognitive issues	Nausea, fatigue, mouth sores, hair loss, upset stomach
Time of Onset	Can be immediate or gradual, sometimes over weeks or months	Often starts shortly after taking the weekly dose
Association with Folic Acid	Less clear if supplementation helps	Supplementation with folic acid is very effective at reducing these side effects
Resolution	Often resolve within weeks of stopping medication	Typically improves with dose adjustments or supplementary folic acid

Conclusion

While methotrexate is an effective treatment for many chronic inflammatory diseases, its potential to affect mood and cause neurological symptoms should not be overlooked. Although these are rare side effects, they are real and can significantly impact a patient's quality of life. The connection appears to involve MTX's effects on brain neurochemistry, particularly pathways related to adenosine and folate metabolism. Patients with pre-existing mental health conditions or certain risk factors, such as advanced age, may be more susceptible. It is essential for patients to openly discuss any mood or behavioral changes with their healthcare provider, as symptoms may be managed through dose adjustments, supplementary folic acid, or a change in treatment strategy. Prompt and honest communication is key to ensuring the best possible outcome while managing a chronic condition. For further information, consider consulting resources from organizations like the Arthritis Foundation, which provides comprehensive information on methotrexate management.

Frequently Asked Questions

No, mood changes are considered a rare side effect of methotrexate, especially at the low doses typically used for rheumatologic and dermatologic conditions. However, they are a documented adverse event that should be discussed with a doctor if they occur.

Reported mood changes include irritability, anxiety, and depressed mood. In addition to these emotional symptoms, some patients also report fatigue and cognitive issues such as trouble concentrating.

The onset can vary. Some case reports describe mood changes appearing relatively quickly, within days or a few weeks of starting the medication. In other instances, psychiatric symptoms can develop subtly and gradually over a longer period.

The mechanism is not fully understood, but it is thought to be related to methotrexate's impact on brain neurochemistry. One hypothesis is that it alters the levels of adenosine, which influences neuronal function and synaptic plasticity. Another is that interference with folate metabolism could affect neurotransmitter levels.

Folic acid is routinely prescribed to counteract many common methotrexate side effects, particularly those affecting the gut and mouth. While it is less certain if it prevents mood changes, ensuring adequate folate levels is important for overall management and might help reduce the risk of neurochemical disruptions.

You should contact your healthcare provider immediately to report the symptoms. Your doctor will evaluate the situation and may consider adjusting your dose, switching to an injectable form, or exploring alternative medications.

Yes, older patients, especially those with mild renal insufficiency, may be more susceptible to central nervous system toxicity from low-dose methotrexate, which can include mood alterations and cognitive impairment.

In many reported cases, patients who stopped taking methotrexate experienced a resolution of their mood and neurological symptoms within weeks. However, this is not a guarantee for all individuals.