Leucovorin vs. folic acid: Differences and similarities explained

In this article:

• Key differences
• Conditions treated
• Is leucovorin better than folic acid for autism?
• Insurance coverage and cost
• Side effects
• Interactions and warnings

In this article

• Key differences
• Conditions treated
• Is leucovorin better than folic acid for autism?
• Insurance coverage and cost
• Side effects
• Interactions and warnings

Leucovorin is a prescription medication that’s approved by the Food and Drug Administration (FDA) to counteract the side effects of other medications that block folic acid activity in the body. It can be helpful in people going through certain types of chemotherapy, managing megaloblastic anemia, a specific type of anemia, and it has many off-label uses. Leucovorin, also known as folinic acid or 5-formyl tetrahydrofolic acid, is similar to folic acid, an essential vitamin also known as vitamin B9. Folic acid and folate require processing in the body before they’re used, while folinic acid is an active form of the vitamin ready to use. This article compares leucovorin and folic acid, including what they’re used for, cost differences, and side effects you should know. 

Leucovorin vs. folic acid: Key differences

Leucovorin and folic acid are similar, but there are key differences when it comes to how they’re classified or used. Leucovorin is a generic prescription medication used for specific indications approved by the FDA. It may also be prescribed for off-label uses. Leucovorin is taken orally as a tablet or injected intravenously (IV). 

Folic acid or folate is a B vitamin that doesn’t need a prescription. It can be found over the counter in supplements or even added to foods like cereals and breads. 

Suzanne Goh, MD, pediatric behavioral neurologist and founder of Cortica, shares, “I often will explain to the families that I work with that you can think of folinic acid (leucovorin) as a form of folate that’s already turned on… Folic acid, on the other hand, is a synthetic version of folate, and you can think of it as the version of folate that’s turned off.” 

In 2025, drug manufacturer GlaxoSmithKline (GSK) announced its submission for Wellcovorin, its brand-name version of leucovorin, for the treatment of a rare disorder called cerebral folate deficiency (CFD). Wellcovorin is the brand-name leucovorin that was marketed from 1983 to 1997. 

Both leucovorin and folic acid are taken as needed. There’s no standard dosage for leucovorin, but it’s not recommended to take more than 25 mg orally. There’s also no standard dosage for folic acid or folate supplements, but the recommended daily allowance (RDA) is 400 mcg for adults over 19 years old. The Centers for Disease Control and Prevention (CDC) recommends 400 mcg daily for people who are capable of getting pregnant to prevent neural tube defects. Up to 15 mg of oral folate can be recommended per day in patients with anemia. 

Compare leucovorin vs. folic acid key differences
Difference	Leucovorin	Folic acid
Drug class	Folic acid analog	B vitamin
Brand/generic status	Generic	Over the counter
What is the generic name? Or What is the brand name?	Generic leucovorin calcium; brand name Wellcovorin	N/A
What form(s) does the drug come in?	Tablet, injectable solution	Tablet, capsule
What is the standard dosage?	Varies by indication; less than 25 mg daily when taken orally	Recommended daily allowance (RDA): 400 mcg for adults over 19 years old
How long is the typical treatment?	As needed	As needed
Who typically uses the medication?	People undergoing treatments (e.g., certain cancer treatments) that block folic acid in the body,	People at risk or with folate deficiency, pregnant people, and people trying to conceive

Leucovorin vs. folic acid: Conditions treated

Leucovorin and folic acid are recommended for different reasons. Leucovorin is approved by the FDA to prevent side effects of treatments that block folic acid (folic acid antagonists) and improve elimination or metabolism of methotrexate, a drug used to treat certain types of cancer and rheumatoid diseases. There are no FDA-approved indications for folic acid because it’s considered a dietary supplement. 

Off-label uses for leucovorin include:

• Treating megaloblastic anemia
• Added to treatment for colorectal and bladder cancers
• Added to treatment for advanced esophageal, stomach, and pancreatic cancers
• Preventing side effects of pyrimethamine treatment in people with acquired immunodeficiency syndrome (AIDS)
• Treating ectopic pregnancy

Folic acid supplements are recommended for people who have a folate deficiency and who are able to get pregnant. They may also be recommended for people with megaloblastic anemia, along with vitamin B12. 

Zishan Khan, MD, a board-certified child, adolescent, and adult psychiatrist (CAP) with Mindpath Health, explains that doctors sometimes use leucovorin instead of regular folic acid when a person’s body doesn’t properly use folate. Some people, like those with cerebral folate deficiency or certain genetic differences, have trouble turning folic acid into a form the brain can use. In those cases, leucovorin can help get around the problem and support normal brain function. This may even help improve certain symptoms of autism for some patients.

In September 2025, the FDA stated that its review of research found support for leucovorin in people with cerebral folate deficiency, a neurological condition that prevents enough folate from getting into the brain. CFD has been associated with autism-like symptoms, and leucovorin may be recommended by some healthcare providers for this reason. “[Leucovorin] can have a lot of benefits for development in language and communication, but this can also extend to socialization and even cognitive skills,” Dr. Goh explains. However, the American Academy of Pediatrics warns that the use of leucovorin in children with autism is still experimental, and there are no large published studies showing its safety and effectiveness. 

Medical experts we interviewed stress the importance of working with qualified healthcare providers for the best outcomes. “It’s important for families to understand that leucovorin is not a general treatment for autism, but it may be helpful for a subset of children who have abnormalities in folate metabolism or transport, such as the presence of folate receptor alpha autoantibodies (FRAA),” Dr. Khan says. 

It’s also important to get a full workup of the patient’s case before using leucovorin, Dr. Goh says. “Leucovorin could potentially mask other nutritional deficiencies or make it harder to diagnose and then harder to treat them. The main example of that is vitamin B12 deficiency,” she explains. 

Compare leucovorin vs. folic acid conditions treated
Condition	Leucovorin	Folic acid*
Prevent side effects of certain chemotherapy treatments	Yes	No
Preventing side effects of certain medications that block folic acid	Yes	No
Megaloblastic anemia	Off-label	Yes
Ectopic pregnancy	Off-label	No
Preventing neural tube defects in people who can get pregnant	No	Yes
Cerebral folate deficiency	Off-label**	No

* Folic acid has no FDA-approved indications as a dietary supplement

** Label update announced September 2025

Is leucovorin better than folic acid for autism?

Based on current research, there’s no definite answer for whether folic acid or leucovorin is better for supporting people with autism. Reviews of studies found associations between children with autism and certain genetic markers that affect how folate is processed. Studies also found associations between the presence of antibodies against folate receptors and autism. 

There are studies suggesting that supplementing either folic acid or folinic acid (leucovorin) in children with autism may improve symptoms, but more clinical trials with strong study design and larger sample sizes are needed to be sure. 

Medical experts we interviewed encourage a multi-disciplinary approach to managing autism spectrum disorder. “Leucovorin is only one of a number of different medical therapies that can be really life-changing in a positive way for children. And the standard of care right now for autism, unfortunately, is one where most children don’t get appropriate medical care for autism. A lot of children are provided with applied behavior analysis (ABA) therapy, which is a behavior-only service,” she says. She explains that there are opportunities for some children to address the underlying biological causes of autism with therapies like leucovorin. “So, I think for parents out there, it’s just so important for them to know it really is this combined medical and behavioral approach that will lead to the best progress and the best outcomes, especially for young children,” she states.

Leucovorin vs. folic acid: Insurance coverage and cost comparison

Leucovorin is a prescription medication that may be covered by certain insurance plans, but the same coverage may not extend to folic acid, which is a dietary supplement. Typically, prescription medications are covered by health insurance plans when prescribed for an FDA-approved indication, which means off-label uses of leucovorin may not result in coverage. But, because of the FDA’s label update to include CFD as an approved indication for leucovorin, it may be covered for more people prescribed the drug for CFD, including Medicare or Medicaid beneficiaries. 

If you don’t have insurance coverage for leucovorin or are using it off-label, you can still save. On average, leucovorin costs $36 for 12, 5 mg tablets without insurance. You can use a SingleCare coupon to get the drug for as low as $9 for 12, 5 mg tablets. SingleCare coupons are free to use and are accepted in many retail pharmacies.

In comparison, folic acid may not be covered by most insurance plans unless it’s medically necessary or prescribed for a specific condition. Without insurance, folic acid costs $29 for 90, 1 mg tablets. With a SingleCare coupon, folic acid can cost $8 for 90, 1 mg tablets. 

Compare leucovorin vs. folic acid cost and coverage
Coverage details	Leucovorin	Folic acid
Typically covered by insurance?	Yes	No
Typically covered by Medicare Part D?	Yes	No
Quantity	12, 5 mg tablets	90, 1 mg tablets
SingleCare cost	$9 for 12, 5 mg tablets with a SingleCare coupon at Kroger Pharmacy	$8 for 90, 1 mg tablets with a SingleCare coupon at Kroger Pharmacy

Prescription drug prices often change. These are the most accurate medication prices at the time of publishing in ZIP code 23666 as of Dec. 9, 2025. The listed SingleCare price references the price of generic drugs if available.

Leucovorin vs. folic acid: Side effects

Leucovorin and folic acid have different side effect profiles to consider. Leucovorin can cause allergic reactions such as anaphylaxis or skin itching. Other side effects of leucovorin include:

• Diarrhea
• Rash
• Hives
• Itching
• Difficulty breathing or swallowing

Dr. Khan shares, “Leucovorin is generally well tolerated, but some children may experience mild side effects such as irritability, hyperactivity, sleep disturbance, gastrointestinal upset, or increased agitation. These usually present when treatment is first started, and these effects are typically transient and can usually be easily managed by simply adjusting the dosage.”

In comparison, side effects of folic acid are rare as long as patients follow dosing instructions recommended by a healthcare provider. Sometimes, megaloblastic anemia can appear to be pernicious anemia, which is due to a vitamin B12 deficiency rather than a B12 and B9 (folate) deficiency. When people with pernicious anemia take folic acid, they might experience some neurological side effects, such as altered cognition.

Interestingly, high doses of folate in children and expectant people have been associated with increased risk of autism and epilepsy, so it’s important to work with your healthcare provider to make sure your dosage isn’t putting you or your child at risk for other neurological issues. 

Leucovorin vs. folic acid: Drug interactions

Leucovorin and folic acid may interact with other drugs that affect folate in the body. Leucovorin may increase the risk of side effects due to other drugs. For example, when leucovorin is administered with fluorouracil or 5-fluorouracil, drugs used in certain cancers, it can cause:

• Skin-related side effects such as hair loss (alopecia) and skin irritation (dermatitis)
• Digestive-related side effects such as nausea, diarrhea, vomiting, loss of appetite, and mouth inflammation (stomatitis)
• Nervous system-related side effects, such as fatigue and malaise

Leucovorin can affect how trimethoprim-sulfamethoxazole (TMP-SMX), a commonly prescribed antibiotic, works. It may decrease its effectiveness and increase the chances of complications, especially in people with human immunodeficiency virus (HIV) managing pneumonia caused by Pneumocystis carinii.

Taking folic acid along with antiepileptic medications such as primidone, phenobarbital, and phenytoin can decrease their effectiveness, making seizures more common. Yet, some antiepileptic medications can also cause folate deficiencies. These medications include gabapentin, phenytoin, carbamazepine, valproate, and primidone. “This interaction is likely more important to keep in mind, and therefore I encourage parents to ensure their children’s providers are well aware of each medication and supplement being taken,” Dr. Khan says.

Compare leucovorin vs. folic acid drug interactions
Drug	Drug class	Leucovorin	Folic acid
5-fluorouracil	Chemotherapy drug	Yes	No
Trimethoprim-sulfamethoxazole (TMP-SMX)	Sulfonamide antibiotics	Yes	No
Primidone	Antiepileptic	No	Yes
Phenobarbital	Antiepileptic	No	Yes
Phenytoin	Antiepileptic	No	Yes

Leucovorin vs. folic acid: drug warnings

Leucovorin has more drug warnings than folic acid. Most drug warnings about leucovorin have to do with its use in people undergoing chemotherapy. Methotrexate can cause low white cells, red cells, and platelets. Leucovorin is routinely given to counteract the effects of chemotherapy drugs on blood cells. 

As mentioned before, leucovorin can increase the side effects of fluorouracil. Older adults taking leucovorin and fluorouracil are especially at risk of enterocolitis, diarrhea, and dehydration due to the drug interaction. 

Finally, as mentioned before, certain people treated with TMP-SMX antibiotics may be at risk of treatment failure and side effects when taking leucovorin. 

In contrast, the only warning for folic acid is around its use in pernicious anemia and other types of anemia. In these cases, folic acid is recommended along with vitamin B12 to address anemia.

Bottom line 

Folic acid is an essential B vitamin with many functions in the body. It can prevent and treat certain neurological concerns when taken under medical guidance. Leucovorin is a prescription medication similar to folic acid and is the biologically active form of folic acid. Leucovorin is used in certain people undergoing chemotherapy, and more recently, those with CFD. It has many off-label uses in people with autism, but more research is needed to understand its safety and effectiveness on a large scale. Medical experts stress that leucovorin is just one of the many therapies available for autism, and a comprehensive assessment and treatment plan is needed for the best results.

Since leucovorin is a prescription medication with approved indications, it’s more likely to be covered under health plans compared to folic acid, a dietary supplement. People can use SingleCare coupons to save up to 75% on leucovorin or folic acid.