Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia

Nutr Res. 2015 Jun;35(6):489-95. doi: 10.1016/j.nutres.2015.02.006. Epub 2015 Feb 26.


Folic acid supplementation is the mainstay treatment of hyperhomocysteinemia (HHcy). However, no recommendations are currently available in regard to the optimal replacement therapy. Therefore, this prospective study hypothesized that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-methyltetrahydrofolate (5-MTHF) would reduce plasma levels of fasting total homocysteine (tHcy) in patients with mild/moderate HHcy. Patients with a new diagnosis of mild/moderate HHcy were evaluated for the methylenetetrahydrofolate reductase genotype and the presence of major features of metabolic syndrome. All enrolled subjects received a cyclic 5-MTHF oral supplementation and were reevaluated after each treatment cycle for a total of 2 years. In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 ± 13.6 to 14.4 ± 5.77 μmol/L, P < .001) and during the whole 2-year follow-up (from 31.6 ± 13.6 to 12.18 ± 3.03 μmol/L, P < .001). The values of tHcy returned to reference range in 117 subjects (51.3%) after the first cycle and in 198 (86.8%) during the follow-up. The risk of failure in tHcy level normalization was increased in patients with metabolic syndrome (hazard ratio [HR], 3.49; 95% confidence interval [CI], 1.46-8.36), higher baseline tHcy levels (HR, 1.045; 95% CI, 1.018-1.073), or methylenetetrahydrofolate reductase homozygous mutation (HR, 6.59; 95% CI, 2.64-16.4). This study clearly shows that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-MTHF supplementation is able to significantly reduce tHcy levels in patients with mild/moderate HHcy.

Keywords: 5-Methyl-tetra-hydro-folate; Cyclic folate supplementation; Folate; Homocysteine; Hyperhomocysteinemia; Patient.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Dietary Supplements*
  • Female
  • Genotype
  • Homocysteine / blood*
  • Homocysteine / genetics
  • Humans
  • Hyperhomocysteinemia / blood
  • Hyperhomocysteinemia / drug therapy*
  • Hyperhomocysteinemia / genetics
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Middle Aged
  • Prospective Studies
  • Tetrahydrofolates / administration & dosage*
  • Tetrahydrofolates / therapeutic use
  • Treatment Outcome


  • Tetrahydrofolates
  • Homocysteine
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-methyltetrahydrofolate