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Leucovorin side effects and how to avoid them

Leucovorin is generally safe but sometimes causes mild side effects
Sarah Bradley writer headshot
By | Dec. 16, 2025 Medically reviewed by Leslie Greenberg, MD
A prescription bottle with an exclamation mark on it: Leucovorin side effects and how to avoid them

Key takeaways

  • Leucovorin is a prescription form of folate (vitamin B9) that’s easy for the body to metabolize and can counteract the effects of folate deficiency. 

  • It’s usually given to people taking methotrexate and other cancer medications that reduce folic acid levels, but emerging research is causing a new interest in leucovorin as a potential autism treatment.

  • Leucovorin is considered generally safe for most people to take and doesn’t cause many side effects. Kids taking leucovorin for autism symptoms may experience a temporary worsening of behavioral symptoms that usually resolve within a few weeks.

In this article:

Leucovorin, or folinic acid, is a prescription form of folate (vitamin B9). Unlike other forms of folate that need to be metabolized, leucovorin can quickly replenish your folic acid levels, relieving the side effects of folate deficiency. The Food & Drug Administration (FDA) has approved leucovorin to treat the harmful effects of methotrexate, a drug often used in chemotherapy, and to treat accidental overdoses of methotrexate and other medications that lower folic acid levels. In September 2025, the FDA announced plans to also approve leucovorin for the treatment of cerebral folate deficiency (CFD), a neurological condition that has been linked to autism symptoms, seizures, and developmental delays. Leucovorin has several off-label uses (not approved by the FDA) as well. Here’s what to know about leucovorin’s side effects.

Common side effects of leucovorin

According to Suzanne Goh, MD, pediatric behavioral neurologist and founder of autism therapy provider Cortica, leucovorin is a water-soluble vitamin that can usually be used safely in most people. However, some people do have mild side effects. 

Per Cherian Verghese, MD, hematology and oncology specialist at MU Health Care, common side effects of leucovorin may include:

  • Nausea
  • Diarrhea
  • Fatigue
  • Mouth pain or sores (mucositis)

Dr. Verghese notes, though, that it can be hard to tell if these side effects are caused directly by leucovorin or by its combined use with other cancer-treating drugs like methotrexate and 5-fluorouracil. 

Serious side effects of leucovorin

Serious side effects when taking leucovorin are rare but can happen. Usually, serious side effects are related to an allergic reaction and include:

  • Rash
  • Hives
  • Itching 
  • Wheezing
  • Trouble swallowing or breathing

In rare cases, leucovorin can cause seizures.

Side effects of leucovorin in children

The side effects of leucovorin in children are not that different from side effects in adults, especially when it comes to mild gastrointestinal upset like nausea and diarrhea. But per Dr. Goh, research about leucovorin’s effects on autism spectrum disorder (ASD) symptoms shows that kids may also experience some additional side effects, including:

  • Headache
  • Hyperactivity
  • Irritability
  • Trouble sleeping 
  • Agitation

According to Dr. Goh, these symptoms are more likely to occur when a child is first starting to take leucovorin or when the dose is being increased. She also notes that, in studies about leucovorin’s use in treating ASD, these side effects are typically not more common with leucovorin than with the placebo.

It’s also worth noting that leucovorin can have positive side effects, especially relating to behaviors, when used to treat ASD in children. 

“Depending on the child’s age, we’ve seen increases in vocabulary and length of utterance, going from words to phrases to sentences, and improvements to the back-and-forth nature of language (reciprocity) and the time it takes to respond to someone,” Dr. Goh says.

How soon do leucovorin side effects start?

Because leucovorin can be used by the body right away, side effects usually occur fairly quickly. According to Amir Miodovnik, MD, MPH, a developmental-behavioral pediatrician practicing in the Washington Metropolitan Area, studies of children with autism and cerebral folate deficiency (CFD) have found that leucovorin side effects start within the first few days to one week after dosing. 

For people taking leucovorin for other purposes, it’s difficult to determine when side effects start since many side effects are caused by medication combinations, like leucovorin plus 5-fluorouracil. However, the timeline is likely the same as it is for treating autism symptoms: because leucovorin works quickly in the body, side effects are likely to occur soon after starting the medication.  

How long do leucovorin side effects last?

Most side effects of leucovorin go away on their own within the first few weeks of starting the medication, per Dr. Miodovnik. Reducing the dose can also help relieve side effects, he adds. If side effects are more severe or are interfering with daily life, Dr. Verghese says they will generally go away soon after stopping the medication.

What are the long-term side effects of leucovorin?

We don’t know much about the long-term side effects of leucovorin because it’s usually not used this way: “Leucovorin is not a medicine that’s usually taken long-term unless there is a folate deficiency that is not responding to folic acid replacement,” Dr. Verghese says.  

For most people, leucovorin is a temporary medication taken to offset the effects of methotrexate toxicity or to supplement another type of cancer medication or treatment. However, with the growing interest in leucovorin as a potential autism treatment, that may be changing. 

The research and clinical experience we do have so far, notes Dr. Goh, shows that long-term use of leucovorin is extremely safe—especially when a person is under medical supervision. 

Leucovorin interactions

Leucovorin may interact with certain drugs or substances. You should always talk to your healthcare provider about any other medications or supplements you’re taking so they can check for potential interactions.  

The most important interaction to be aware of is the chance of leucovorin making certain seizure medications less effective, including:

  • Phenobarbital
  • Phenytoin
  • Primidone

Leucovorin can also increase the toxicity of cancer medications like 5-fluorouracil and capecitabine, so you should only combine these medications under the supervision of your healthcare provider.

Safety measures while using leucovorin

Leucovorin is a relatively safe medication. It’s not habit-forming, and the FDA hasn’t issued any black box warnings for its use. However, some people will need to use it with extra caution:

  • Pregnant or breastfeeding women: According to Dr. Verghese, we don’t have any evidence of leucovorin causing harm to pregnant women or their babies, but we also don’t have any evidence that the medication is safe because it’s untested in this group. We also don’t know how much, if any, of the drug passes through breastmilk. But in general, “the benefits outweigh the risks” in these situations, Dr. Verghese says.
  • Some children with behavior issues: Some children with preexisting hyperactivity, sensory hypersensitivity, or anxiety may initially experience a worsening of these behaviors, per Dr. Mio. As we noted, this could be a sign that the dose needs to be reduced, or these behaviors may go away on their own after a few weeks.  
  • People with some underlying health conditions: According to Dr. Goh, people with liver or kidney disease or a history of seizures should discuss the benefits of taking leucovorin with their healthcare provider. These people can still use leucovorin in most cases, but more intervention may be needed to make sure it doesn’t exacerbate their existing medical conditions. It should also not be given to treat people with anemia caused by a vitamin B12 deficiency, since this can make B12 deficiency side effects worse.

It’s also important to follow the dosing instructions for leucovorin given to you by your provider. There’s no single amount that’s considered “too much.” Doses vary by age, formulation (like injection versus oral tablet), and by treatment (for ASD versus cancer, for example). Taking too much leucovorin usually won’t cause life-threatening side effects, but if you are using it with cancer medications, taking too much leucovorin can interfere with how well those medications work for you. 

How to avoid leucovorin side effects

Leucovorin is a relatively easy drug to take, but there are a few things you can do to make dosing even easier:

  • Per Dr. Verghese, you can take leucovorin with or without food (though taking it with food is a good idea if it causes nausea), and there are no foods you should avoid while taking it.
  • Make sure you tell your healthcare provider if you are pregnant or breastfeeding, or if you have a history of liver or kidney disease or seizures, as you may need to be monitored more closely while using this medication.
  • There’s no evidence that leucovorin causes drowsiness or insomnia, according to Dr. Mio, so you can usually take it at any time of day.

If you are taking leucovorin to offset the effects of methotrexate, your provider will determine how many doses you need. Most people using leucovorin for this reason are given one or more doses each day for several days.

If you are taking leucovorin to improve autism-associated behaviors, there’s no established timeline for its use. Per Dr. Mio, it’s been used safely for six months to two years in clinical trials and open-label follow-up studies without any serious adverse effects. In her clinical practice, Dr. Goh typically recommends that a child benefiting from leucovorin take it for about one year, and then decides, along with the child’s family, whether to continue beyond that.  

How to treat the side effects of leucovorin

Most of the side effects of leucovorin aren’t serious or life-threatening and can be treated at home with OTC remedies or prescription medications. In general, you can follow guidelines for treating common chemotherapy side effects when trying to treat leucovorin side effects.

For example, if you have an upset stomach, you can try eating small, bland meals, staying hydrated, and taking prescription antiemetics like ondansetron or Reglan (for nausea or vomiting) or OTC Imodium (for diarrhea). Bland meals, extra hydration, and using a gentle, non-alcohol mouthwash can help with mouth sores. If your child has a headache while taking leucovorin, talk to your healthcare provider; they may recommend that you use an OTC pain reliever like Tylenol (children’s or regular-strength, depending on your child’s age) to relieve headache symptoms. 

Kids taking leucovorin for autism symptoms are usually monitored closely for side effects, but make sure you tell your child’s provider if you notice a worsening of behaviors that doesn’t improve after a few weeks.

If you or your child is having an allergic reaction to leucovorin, that is a medical emergency. Get immediate care if you notice symptoms like rash, hives, or difficulty breathing, per Dr. Mio.

Bottom line: Is leucovorin safe?

In general, leucovorin is a safe drug that helps many people counteract the side effects of methotrexate and other cancer medications. Even when used in children to treat symptoms of cerebral folate deficiency, including autism-like symptoms, leucovorin appears to be safe and doesn’t usually cause serious side effects. That said, side effects are always a possibility with any medication, so let your provider know if you or your child has symptoms of allergic reaction when taking leucovorin, or if you have persistent side effects like nausea or vomiting, diarrhea, headache, or significant behavior changes.

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