{"id":634688,"date":"2025-12-16T13:24:04","date_gmt":"2025-12-16T18:24:04","guid":{"rendered":"https:\/\/www.singlecare.com\/blog\/?p=634688"},"modified":"2025-12-16T13:28:14","modified_gmt":"2025-12-16T18:28:14","slug":"leucovorin-side-effects","status":"publish","type":"post","link":"https:\/\/www.singlecare.com\/blog\/leucovorin-side-effects\/","title":{"rendered":"Leucovorin side effects and how to avoid them"},"content":{"rendered":"<p><a href=\"https:\/\/www.singlecare.com\/prescription\/leucovorin-calcium\"><span style=\"font-weight: 400;\">Leucovorin<\/span><\/a><span style=\"font-weight: 400;\">, 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 &amp; Drug Administration (FDA) has approved leucovorin to treat the harmful effects of <\/span><a href=\"https:\/\/www.singlecare.com\/prescription\/methotrexate-sodium\"><span style=\"font-weight: 400;\">methotrexate<\/span><\/a><span style=\"font-weight: 400;\">, 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\u2019s what to know about leucovorin\u2019s side effects.<\/span><\/p>\n<h2 id=\"common-side-effects-of-leucovorin\"><span style=\"font-weight: 400;\">Common side effects of leucovorin<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">According to <\/span><a href=\"https:\/\/www.corticacare.com\/bios\/suzanne-goh\"><span style=\"font-weight: 400;\">Suzanne Goh<\/span><\/a><span style=\"font-weight: 400;\">, 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.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Per <\/span><a href=\"https:\/\/www.muhealth.org\/doctors\/cherian-verghese-md\"><span style=\"font-weight: 400;\">Cherian Verghese<\/span><\/a><span style=\"font-weight: 400;\">, MD, hematology and oncology specialist at MU Health Care, common side effects of leucovorin may include:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Nausea<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Diarrhea<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Fatigue<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Mouth pain or sores (mucositis)<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400;\">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 <\/span><a href=\"https:\/\/www.singlecare.com\/blog\/methotrexate-side-effects\/\"><span style=\"font-weight: 400;\">methotrexate<\/span><\/a><span style=\"font-weight: 400;\"> and 5-fluorouracil.\u00a0<\/span><\/p>\n<h2 id=\"serious-side-effects-of-leucovorin\"><span style=\"font-weight: 400;\">Serious side effects of leucovorin<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">Serious side effects when taking leucovorin are rare but can happen. Usually, <\/span><a href=\"https:\/\/medlineplus.gov\/druginfo\/meds\/a682336.html\"><span style=\"font-weight: 400;\">serious side effects<\/span><\/a><span style=\"font-weight: 400;\"> are related to an allergic reaction and include:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Rash<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Hives<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Itching\u00a0<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Wheezing<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Trouble swallowing or breathing<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400;\">In rare cases, <\/span><a href=\"https:\/\/www.mayoclinic.org\/drugs-supplements\/leucovorin-oral-route-intravenous-route-injection-route\/description\/drg-20064503\"><span style=\"font-weight: 400;\">leucovorin can cause seizures<\/span><\/a><span style=\"font-weight: 400;\">.<\/span><\/p>\n<h2 id=\"side-effects-of-leucovorin-in-children\"><span style=\"font-weight: 400;\">Side effects of leucovorin in children<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">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\u2019s effects on autism spectrum disorder (ASD) symptoms shows that kids may also experience some <\/span><a href=\"https:\/\/www.childrensmercy.org\/health-care-providers\/refer-or-manage-a-patient\/connect-with-childrens-mercy\/newsletter-the-link\/the-link-2025\/the-link---october-2025\/mental-health-leucovorin-and-autism-what-pediatricians-should-know\/\"><span style=\"font-weight: 400;\">additional side effects<\/span><\/a><span style=\"font-weight: 400;\">, including:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Headache<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Hyperactivity<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Irritability<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Trouble sleeping\u00a0<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Agitation<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400;\">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\u2019s use in treating ASD, these side effects are typically not more common with leucovorin than with the placebo.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">It\u2019s also worth noting that leucovorin can have positive side effects, especially relating to behaviors, when used to treat ASD in children.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">\u201cDepending on the child\u2019s age, we\u2019ve 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,\u201d Dr. Goh says.<\/span><\/p>\n<h2 id=\"how-soon-do-leucovorin-side-effects-start\"><span style=\"font-weight: 400;\">How soon do leucovorin side effects start?<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">Because leucovorin can be used by the body right away, side effects usually occur fairly quickly. According to <\/span><a href=\"https:\/\/www.drmio.com\/about\"><span style=\"font-weight: 400;\">Amir Miodovnik<\/span><\/a><span style=\"font-weight: 400;\">, 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.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">For people taking leucovorin <\/span><a href=\"https:\/\/www.mskcc.org\/cancer-care\/patient-education\/medications\/adult\/leucovorin-calcium\"><span style=\"font-weight: 400;\">for other purposes<\/span><\/a><span style=\"font-weight: 400;\">, it\u2019s 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.\u00a0\u00a0<\/span><\/p>\n<h2 id=\"how-long-do-leucovorin-side-effects-last\"><span style=\"font-weight: 400;\">How long do leucovorin side effects last?<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">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.<\/span><\/p>\n<h2 id=\"what-are-the-long-term-side-effects-of-leucovorin\"><span style=\"font-weight: 400;\">What are the long-term side effects of leucovorin?<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">We don\u2019t know much about the long-term side effects of leucovorin because it\u2019s usually not used this way: \u201cLeucovorin is not a medicine that\u2019s usually taken long-term unless there is a folate deficiency that is not responding to folic acid replacement,\u201d Dr. Verghese says.\u00a0\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">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.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">The research and clinical experience we do have so far, notes Dr. Goh, shows that <\/span><a href=\"https:\/\/everycure.org\/cfd\/\"><span style=\"font-weight: 400;\">long-term use of leucovorin<\/span><\/a><span style=\"font-weight: 400;\"> is extremely safe\u2014especially when a person is under medical supervision.\u00a0<\/span><\/p>\n<h2 id=\"leucovorin-interactions\"><span style=\"font-weight: 400;\">Leucovorin interactions<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">Leucovorin may interact with certain drugs or substances. You should always talk to your healthcare provider about any other medications or supplements you\u2019re taking so they can check for potential interactions.\u00a0\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">The most important interaction to be aware of is the chance of leucovorin making certain seizure medications less effective, including:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Phenobarbital<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Phenytoin<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">Primidone<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400;\">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.<\/span><\/p>\n<h2 id=\"safety-measures-while-using-leucovorin\"><span style=\"font-weight: 400;\">Safety measures while using leucovorin<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">Leucovorin is a relatively safe medication. It\u2019s not habit-forming, and the FDA hasn\u2019t issued any black box warnings for its use. However, some people will need to use it with extra caution:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><b>Pregnant or breastfeeding women: <\/b><span style=\"font-weight: 400;\">According to Dr. Verghese, we don\u2019t have any evidence of leucovorin causing harm to pregnant women or their babies, but we also don\u2019t have any evidence that the medication is safe because it\u2019s untested in this group. We also don\u2019t know how much, if any, of the drug passes through breastmilk. But in general, \u201cthe benefits outweigh the risks\u201d in these situations, Dr. Verghese says.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><b>Some children with behavior issues: <\/b><span style=\"font-weight: 400;\">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.\u00a0\u00a0<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><b>People with some underlying health conditions:<\/b><span style=\"font-weight: 400;\"> 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\u2019t 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.<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400;\">It\u2019s also important to follow the dosing instructions for leucovorin given to you by your provider. There\u2019s no single amount that\u2019s considered \u201ctoo much.\u201d 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\u2019t 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.\u00a0<\/span><\/p>\n<h2 id=\"how-to-avoid-leucovorin-side-effects\"><span style=\"font-weight: 400;\">How to avoid leucovorin side effects<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">Leucovorin is a relatively easy drug to take, but there are a few things you can do to make dosing even easier:<\/span><\/p>\n<ul>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">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.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">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.<\/span><\/li>\n<li style=\"font-weight: 400;\" aria-level=\"1\"><span style=\"font-weight: 400;\">There\u2019s no evidence that leucovorin causes drowsiness or insomnia, according to Dr. Mio, so you can usually take it at any time of day.<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400;\">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 <\/span><a href=\"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-023-03054-2\"><span style=\"font-weight: 400;\">one or more doses each day<\/span><\/a><span style=\"font-weight: 400;\"> for several days.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">If you are taking leucovorin to improve autism-associated behaviors, there\u2019s no established timeline for its use. Per Dr. Mio, it\u2019s been used safely for six months to two years <\/span><a href=\"https:\/\/www.mdpi.com\/2075-4426\/11\/11\/1141\"><span style=\"font-weight: 400;\">in clinical trials<\/span><\/a><span style=\"font-weight: 400;\"> and <\/span><a href=\"https:\/\/link.springer.com\/article\/10.1007\/s00431-024-05762-6\"><span style=\"font-weight: 400;\">open-label follow-up studies<\/span><\/a><span style=\"font-weight: 400;\"> 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\u2019s family, whether to continue beyond that.\u00a0\u00a0<\/span><\/p>\n<h2 id=\"how-to-treat-the-side-effects-of-leucovorin\"><span style=\"font-weight: 400;\">How to treat the side effects of leucovorin<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">Most of the side effects of leucovorin aren\u2019t serious or life-threatening and can be treated at home with OTC remedies or prescription medications. In general, you can follow guidelines for <\/span><a href=\"https:\/\/www.mskcc.org\/cancer-care\/patient-education\/managing-your-chemotherapy-side-effects\"><span style=\"font-weight: 400;\">treating common chemotherapy side effects<\/span><\/a><span style=\"font-weight: 400;\"> when trying to treat leucovorin side effects.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">For example, if you have an upset stomach, you can try eating small, bland meals, staying hydrated, and taking prescription antiemetics like <\/span><a href=\"https:\/\/www.singlecare.com\/prescription\/ondansetron-hcl\"><span style=\"font-weight: 400;\">ondansetron<\/span><\/a><span style=\"font-weight: 400;\"> or <\/span><a href=\"https:\/\/www.singlecare.com\/prescription\/reglan\"><span style=\"font-weight: 400;\">Reglan<\/span><\/a><span style=\"font-weight: 400;\"> (for nausea or vomiting) or OTC <\/span><a href=\"https:\/\/www.singlecare.com\/prescription\/imodium-a-d\"><span style=\"font-weight: 400;\">Imodium<\/span><\/a><span style=\"font-weight: 400;\"> (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 (<\/span><a href=\"https:\/\/www.singlecare.com\/prescription\/tylenol-childrens-chewables\"><span style=\"font-weight: 400;\">children\u2019s<\/span><\/a><span style=\"font-weight: 400;\"> or <\/span><a href=\"https:\/\/www.singlecare.com\/prescription\/tylenol\"><span style=\"font-weight: 400;\">regular-strength<\/span><\/a><span style=\"font-weight: 400;\">, depending on your child\u2019s age) to relieve headache symptoms.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400;\">Kids taking <a href=\"https:\/\/www.singlecare.com\/blog\/leucovorin-for-kids-with-autism\/\">leucovorin for autism<\/a> symptoms are usually monitored closely for side effects, but make sure you tell your child\u2019s provider if you notice a worsening of behaviors that doesn\u2019t improve after a few weeks.<\/span><\/p>\n<p><span style=\"font-weight: 400;\">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.<\/span><\/p>\n<h2 id=\"bottom-line-is-leucovorin-safe\"><span style=\"font-weight: 400;\">Bottom line: Is leucovorin safe?<\/span><\/h2>\n<p><span style=\"font-weight: 400;\">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\u2019t 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.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"<p>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 &amp; Drug Administration (FDA) has approved leucovorin to treat the harmful effects of methotrexate, a drug [&hellip;]<\/p>\n","protected":false},"author":149,"featured_media":634690,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[4589],"tags":[794,12752],"coauthors":[8860],"class_list":["post-634688","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-drug-info","tag-cancer","tag-medication-side-effects","wpautop"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v27.4 (Yoast SEO v27.4) - https:\/\/yoast.com\/product\/yoast-seo-premium-wordpress\/ -->\n<title>Leucovorin side effects and how to avoid them<\/title>\n<meta name=\"description\" content=\"Nausea, diarrhea, and headache are common Leucovorin side effects. 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