Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)

Xiao Huang, Huihui Bao, Congcong Ding, Junpei Li, Tianyu Cao, Lishun Liu, Yaping Wei, Ziyi Zhou, Nan Zhang, Yun Song, Ping Chen, Chongfei Jiang, Liling Xie, Xianhui Qin, Yan Zhang, Jianping Li, Ningling Sun, Genfu Tang, Xiaobin Wang, Hong WangYong Huo, Xiaoshu Cheng

Research output: Contribution to journalArticlepeer-review


Background: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. Methods: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. Results: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0–1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2–1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. Conclusions: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. ClinicalTrials.gov Identifier: NCT03472508 (Registration Date: March 21, 2018).

Original languageEnglish
JournalEuropean Journal of Nutrition
Early online dateFeb 13 2024
StateE-pub ahead of print - Feb 13 2024


  • Folic acid
  • Homocysteine
  • MTHFR C677T genotypes
  • Optimal dosage


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