What are the benefits and uses of methylfolate (Methylated Folate) supplementation in humans?

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Last updated: June 15, 2025View editorial policy

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From the FDA Drug Label

L-METHYLFOLATE CALCIUM Tablets is a medical food for use under medical supervision and direction L-METHYLFOLATE CALCIUM Tablets is a medical food dispensed by prescription. 5-MTHF has been shown to enhance antidepressant effects of known antidepressants.

The benefits of methylfolate supplementation in humans include:

  • Enhancing antidepressant effects: Methylfolate has been shown to enhance the effects of known antidepressants 1.
  • Medical food for certain conditions: Methylfolate is used as a medical food under medical supervision and direction, and is dispensed by prescription 1. It is essential to note that methylfolate should be used with caution, particularly in patients with a history of bipolar illness or those at risk for bipolar disorder, as it may precipitate a mixed/manic episode 1.

From the Research

Methylfolate supplementation is highly recommended for individuals with MTHFR gene mutations, certain health conditions, and those who cannot properly metabolize regular folic acid, as it offers significant benefits in improving mood disorders, reducing homocysteine levels, and supporting pregnancy outcomes. The benefits of methylfolate supplementation are well-documented in recent studies, including a 2022 study published in Alternative Therapies in Health and Medicine 2, which highlights the advantages of (6S)5-Methyltetrahydrofolate supplementation in fertility and pregnancy.

Key Benefits of Methylfolate Supplementation

  • Improves mood disorders like depression
  • Reduces homocysteine levels, lowering cardiovascular risk
  • Supports pregnancy outcomes by preventing neural tube defects
  • Enhances cognitive function
  • Complements treatment for conditions like PCOS and autoimmune disorders

Recommended Dosage

The typical recommended dosage of methylfolate ranges from 400-1000 mcg daily, though individuals with specific conditions may require higher doses under medical supervision, as noted in a 2013 study published in the Journal of Perinatal Medicine 3.

Importance of Methylfolate Over Folic Acid

Methylfolate (L-methylfolate or 5-MTHF) is the active form of folate that bypasses conversion steps in the body, making it immediately bioavailable. Unlike regular folic acid, methylfolate doesn't require enzymatic conversion, making it particularly valuable for those with genetic variations affecting folate metabolism, as discussed in a 1994 study published in Biochemical Medicine and Metabolic Biology 4.

Side Effects and Precautions

Side effects of methylfolate supplementation are generally mild but can include sleep disturbances, irritability, and headaches. It's essential to start with lower doses and increase gradually, especially for those sensitive to supplements. While methylfolate is generally safe, consulting with a healthcare provider before starting supplementation is recommended, particularly for pregnant women or those with existing health conditions, as emphasized in a 1994 study published in Ciba Foundation Symposium 5.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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