Mechanism of Action
Active vitamin B9 (5-MTHF) feeds into the folate cycle, a metabolic crossroads where DNA synthesis and remethylation converge. 5-MTHF donates its methyl group to homocysteine, converting it into methionine, an amino acid that subsequently generates S-adenosylmethionine (SAMe). SAMe is the body's primary methyl donor: it participates in the methylation of DNA, proteins and neurotransmitters. In parallel, folates supply the one-carbon units required for the synthesis of purine and pyrimidine bases, the building blocks of DNA. This dual role explains why rapidly renewing tissues (blood cells, digestive mucosa) are the first affected when folate status declines.
Key Benefits
- Strong
Folate contributes to normal blood formation. A meta-analysis of 25 controlled trials confirms that folate supplementation significantly improves erythrocyte markers in adults with suboptimal status.
- Strong
Folate contributes to normal homocysteine metabolism. A 25% reduction in plasma homocysteine is documented from 200 µg per day of folate in a meta-analysis of 12 randomised trials.
- Strong
Folate contributes to normal psychological functions. Several controlled trials show that adequate folate status is associated with better maintenance of cognitive function and mood in adults.
- Strong
Folate plays a role in the process of cell division. It provides the one-carbon units essential for faithful DNA replication in all body tissues.
- Strong
A large-scale randomised trial (20,702 participants) demonstrated a significant reduction in first stroke risk among hypertensive adults supplemented with folic acid over 4.5 years.
- Moderate
Folate contributes to normal immune system function. Lymphocyte proliferation depends directly on folate availability for DNA synthesis.
- Moderate
A controlled trial in older adults with mild cognitive impairment showed that B-vitamin supplementation (including folate) slows the rate of brain atrophy measured by MRI.
Dosage & Forms
Three forms of vitamin B9 coexist on the market. Folic acid, the most common synthetic form, requires four enzymatic reduction steps before reaching the active form. Folinic acid (5-formylTHF) partially bypasses this cascade but remains an intermediate form. Calcium L-5-methyltetrahydrofolate is the directly bioactive form, identical to that circulating in human plasma. European dietary reference values are set at 200 µg per day. The Singular formula offers three calibration levels: 250, 350 or 500 µg of 5-MTHF, adjusted according to individual biological profile. This choice of form ensures immediate utilisation by the body, regardless of each person's genetic profile.
In the Singular Formula
Inclusion rationale
Folates contribute to normal blood formation, to normal homocysteine metabolism, to normal psychological functions, to the normal functioning of the immune system and play a role in the process of cell division. Essential for DNA synthesis and methylation, folates are particularly active in rapidly renewing tissues: bone marrow, intestinal mucosa, and during embryonic development. Synthetic folic acid must be converted to 5-MTHF by the enzyme MTHFR before it can perform its biological functions. However, approximately 10% of the European population carries the MTHFR C677T polymorphism in homozygous state, reducing the activity of this enzyme by 70%. This genetic limitation can compromise the effectiveness of conventional folic acid. The 5-MTHF (active folate) form selected in the formula completely bypasses this issue: it is the predominant circulating form in human plasma, directly usable without depending on individual conversion capacity. In the methylation cycle, B9 works in synergy with vitamin B12 (methylcobalamin), TMG and vitamin B6 (P-5-P), also present in the formula, to ensure optimal remethylation of homocysteine.
Selected form
Vitamin B9 as calcium L-5-methyltetrahydrofolate (5-MTHF), stabilised crystalline form. 5-MTHF is the biologically active form of folate, directly usable by the body. Unlike synthetic folic acid, it requires no enzymatic reduction by MTHFR (methylenetetrahydrofolate reductase), an enzyme whose activity is reduced in a significant portion of the population due to common genetic polymorphisms. Folate contributes to maternal tissue growth during pregnancy and to normal immune system function. Quality: non-GMO.
Formula dosage
0 to 500 µg.
Synergies in the formula
Safety & Precautions
Vitamin B9 in 5-MTHF form has a favourable tolerability profile at nutritional doses. The European Food Safety Authority has set the upper safety limit at 1,000 µg per day for folic acid in adults. 5-MTHF is not associated with the risk of masking increased vitamin B12 needs (an effect described with high-dose folic acid), but maintaining adequate B12 status during folate supplementation remains advisable. Individuals taking methotrexate or antiepileptic medications should consult a healthcare professional before supplementing, as folates may interfere with the mechanism of action of these molecules. Supplementation is not recommended for children under 3 years without medical advice. No toxicity has been reported at standard nutritional doses.
Scientific Studies
| Authors | Year | Type | Journal | |
|---|---|---|---|---|
| Homocysteine Lowering Trialists' Collaboration | 2005 | Meta-analysis | American Journal of Clinical Nutrition | View on PubMed |
Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials Meta-analysis of 25 randomised trials showing that daily folic acid supplementation reduces plasma homocysteine by 25% on average, with a dose-dependent effect. | ||||
| Huo Y et al. | 2015 | Randomised Controlled Trial | JAMA | View on PubMed |
Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial Randomised trial in 20,702 hypertensive adults: folic acid supplementation (0.8 mg/d) combined with enalapril reduced first stroke risk by 21% over 4.5 years. | ||||
| Prinz-Langenohl R et al. | 2009 | Randomised Controlled Trial | British Journal of Pharmacology | View on PubMed |
[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase Crossover trial in 144 women: 5-MTHF increases plasma folate more effectively than folic acid, regardless of MTHFR genotype. | ||||
| Scaglione F, Panzavolta G | 2014 | Systematic Review | Xenobiotica | View on PubMed |
Folate, folic acid and 5-methyltetrahydrofolate are not the same thing Review detailing the pharmacokinetic and metabolic differences between folic acid, dietary folates and 5-MTHF. Concludes in favour of 5-MTHF for supplementation. | ||||
| Smith AD et al. | 2010 | Randomised Controlled Trial | PLoS ONE | View on PubMed |
Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial Controlled trial (VITACOG) in 168 older adults with mild cognitive impairment: B-vitamin supplementation (including folate) slowed brain atrophy by 30% over 2 years. | ||||