Folic Acid and Folinic Acid For Reducing the Side Effects of Methotrexate

People who take methotrexate often suffer from side effects of this medication. Learn how folic and folinic acid alleviate the adverse effects of methotrexate and how to take them alongside methotrexate therapy.

Folic and Folinic Acid – What’s the Difference

Folic acid and folinic acid are two different forms of vitamin B9 (folate). Both are commonly taken for reducing the side effects of the medication methotrexate.

Even though folic and folinic acid work in a similar way, there is a slight difference between them.

While folinic acid is a form of folate that can be found in nature, folic acid is a wholly synthetic substance. Once ingested, both forms convert into the form of folate that is used by the body – tetrahydrofolate.

This requires a multi-step conversion process. The process is more complicated in the case of folic acid and necessitates the use of the enzyme Methylenetetrahydrofolate reductase (MTHFR). It is estimated that between 40-60% of people have impaired activity of this enzyme, which means that they have problems converting folic acid into the form of folate circulating in the body.

Unlike folic acid, the conversion of folinic acid into bioactive folate doesn’t involve the use of the enzyme MTHF. For that reason, folinic acid is often considered a better option than folic acid. However, in many cases folic acid is still prescribed as first line treatment as it is a cheaper alternative.

Methotrexate Toxicity

Methotrexate is a medication that is used for treating severe rheumatoid arthritis and psoriasis. It is also sometimes used in the treatment of other inflammatory diseases, such as Crohn’s disease, asthma, lupus, and vasculitis.

Methotrexate is also taken as an anti-cancer drug (chemotherapy agent). It is used for treating acute lymphocytic anemia (ALL), cancers of the skin, head, neck, breast and lung.

The doses of methotrexate used for treating cancer are much higher than taken used by people with arthritis or psoriasis.  Severe side effects typically happen with high doses. Still, even with low dose methotrexate you can experience a range of health issues.

Many people who take methotrexate report feeling unwell and complain of tiredness, problems with concentration and loss of appetite.

Methotrexate also causes more specific problems. These include:

  • Blood and bone marrow problems

Methotrexate lowers blood cells that help you fight infection and enable your blood to clot. If you are taking methotrexate you are more likely to have frequent infections, bleeding problems, anemia, fever and chills.

  • Kidney damage

Majority of the methotrexate is excreted through the kidneys. Signs of kidney problems are change in the amount of urine, painful urination and blood in urine.

  • Toxic effects on the liver

Methotrexate may also damage the liver and cause liver fibrosis, necrosis, cirrhosis and other liver conditions. Signs to watch for are dark urine, frequent nausea, abdominal pain, and yellowing of the skin and eyes. 

  • Lung abnormalities

Lung problems can come up after a single dose of methotrexate. Symptoms include dry cough and difficulty breathing; sometimes also fever.

  • Skin and mucosal reactions

Methotrexate may cause stomatitis (inflammation of the lips and lining of the mouth), skin discoloration, canker sores and hair loss (hair generally grows back after you stop taking methotrexate).

  • Gastrointestinal problems

These include inflammation of the lining of the stomach and intestines, stomach ulcers, nausea, abdominal pain, vomiting and diarrhea.

  • Neurological issues

You may suffer from burning and tingling sensations, headaches, muscle weakness, seizures and mood changes; in rare cases even brain damage.

How Do Folinic Acid and Folic Acid Reduce the Toxic Effects of Methotrexate

Methotrexate is a folate antagonist, which means that it blocks the action of folate in the body and depletes your blood folate levels.  This affects all the cells in your body, but is especially detrimental to those in the gastrointestinal tract, bone marrow, skin, liver, mouth, and hair follicles.

Folic acid and folinic acid are both a form of folate. By taking them, you prevent some of the side effects of methotrexate that arise from folate deficiency.  

Summing Up: Benefits of Taking a Folate Supplement Alongside Methotrexate

Folic and folinic acid supplements have been shown to:

  • Alleviate gastrointestinal problems caused by methotrexate
  • Reduce the risk of developing mouth sores
  • Support normal liver function
  • Prolong the time people stick with methotrexate therapy (due to having fewer side effects)
  • Maintain the effectiveness of methotrexate (when folate is taken in the usual doses)
  • Help lower the risk of cardiovascular disease (since they offset raised homocysteine levels)

Cochrane review from 2013 (1) examined the effect of folic and folinic acid supplements in people taking methotrexate for rheumatoid arthritis. The researchers found out that both folic as well as folinic acid supplements lead to significant decrease in nausea and abdominal pain. 

Taking either form of supplement also seem to reduce the risk of having abnormal liver test. People on folic or folinic acid supplement also had less mouth sores than people who took only placebo; however, there were too few patients in the reviewed studies for the difference to be statistically significant

The review has also shown that people who took folic or folinic supplement alongside methotrexate stayed with their therapy for a longer time. The dropout rate is probably lower due to experiencing fewer side effects.

The review included 6 different studies in which the dose of supplemental folic and folinic acid didn’t exceed 7 grams per weeks. It has been shown that at this dose folate supplementation doesn’t decrease the effectiveness of methotrexate on the symptoms of the rheumatoid arthritis.

It is a well known fact that methotrexate alongside other adverse effects also causes an increase in homocysteine levels. Homocysteine is an amino acid that is associated with higher risk of cardiovascular disease. Several studies in people with psoriatic and rheumatoid arthritis (23)  have shown that taking folate supplement decreases high homocysteine levels – any may thus lower the risk of developing cardiovascular disease in people taking methotrexate.

Recommended Folic and Folinic Acid Supplements

Below we’ve included 2 popular folinic and folic acid supplements. They provide 800 and 1.000 mcg of folate respectively. These are fairly high doses as the usual dose of folate in OTC supplements is 400 mcg.

Nature's Blend Folic Acid

Nature’s Blend Folic Acid tablets contain 1.000 mcg of folic acid each. There are 1.000 tablets in the bottle, which means that it will last you for quite a while. The supplement is a bargain since you typically pay around the same amount or slightly less for much fewer tablets.

Nature’s Blend Folic Acid tablets are surprisingly small for this large dose. They are also scored, so you can easily break them in half if you have troubles swallowing pills.

Get more info and read customer reviews on Amazon: Nature's Blend Folic Acid

Source Naturals MegaFolinic

MegaFolinic by Source Naturals contains folinic acid in the form of calcium folinate (most common type of folinic acid in supplements).  Each tablet provides 800 mcg of folinic acid.

This type of folate is more easily absorbed than folic acid because it doesn’t require the same enzymatic conversion. For that reason, many people do better on folinic acid than they do when taking folic acid per pill.  

Get more info and read customer reviews on Amazon: Source Naturals MegaFolinic

How to Take Folic Acid and Folinic Acid Supplements

Methotrexate is generally taken for 2 different reasons: for controlling the symptoms of inflammatory conditions and as an anti-cancer therapy.

How to take your folate supplement mainly depends on your reason for being on methotrexate therapy.

Folate and Methotrexate for Inflammatory Conditions (Rheumatoid Arthritis and Psoriasis)

Methotrexate seems to relieve pain and other symptoms of inflammatory diseases through mechanisms that are not related to folate. Namely, it triggers the release of the substance adenosine, which then blocks other chemicals that promote inflammation.

Some doctors prescribe folic or folinic acid to all patients on methotrexate therapy. Others give these supplements only to those who are suffering from side effects of methotrexate.

However, since methotrexate decreases your blood folate levels, it is probably better if you start taking a folate supplement before you begin to show the signs of folate depletion.

Dosage and Timing

Typical dosage of folate taken by people with psoriasis or rheumatoid arthritis is between 5 and 10mgs per week.

Some people take their supplement in 1 weekly dose. They start with 5 mgs and increase the dose up to 10 mgs if they still experience side effects from methotrexate. This is a popular way of taking folate since it is more convenient than taking it daily.

Others choose to take a daily supplement as it provides a more even supply of folate. Daily dose is 1 mg of folic or folinic acid.

Folate supplementation is most often started on the day of taking methotrexate. In the past, many people waited at least a day between methotrexate and folate as they feared that it would reduce the effectiveness of medication.

Newer studies have shown that folate in the usual doses (up to 10 mgs) weekly doesn't affect the way methotrexate works for inflammatory diseases (4). However, there was one study that examined the effect of 45 mgs of folinic acid per week. This study has shown that at high doses folinic acid (brand name Leucovorin) significantly decreases the effects of methotrexate in rheumatoid patients (5).

Folinic Acid as a Rescue Drug in Cancer Patients (Methotrexate Chemotherapy)

Originally methotrexate was developed as an anti cancer drug. Methotrexate works by preventing cancer cells from getting folate, which is needed for cell division. This way it stops cancer cells from multiplying.

People taking methotrexate for chemotherapy receive very high doses of this medication. Folinic acid is given to them as a sort of rescue therapy – to alleviate the toxic effects of methotrexate on the body.

It is important that there is at least a 24 hour delay between methotrexate and folinic acid, so that folinic acid doesn't counteract the anti-cancer effects of methotrexate.

One study in patients with acute lymphocytic leukemia (ALL) has shown that the optimal time for giving folinic acid rescue may be 36 hours after methotrexate therapy. This time delay enables methotrexate to work on cancer cells, while at the same time folinic acid is still given early enough to stop many of the toxic effects that methotrexate has on healthy cells (6).

Supplements commonly used for Methotrexate Toxicity:

Folate and Folic Acid

Folic and Folinic Acid – What’s the Difference

Folic acid and folinic acid are two different forms of vitamin B9 (folate). Both are commonly taken for reducing the side effects of the medication... read more…

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