Scientific opinion on the tolerable upper intake level for folate

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. 2023 Nov 13;21(11):e08353. doi: 10.2903/j.efsa.2023.8353

Reference Study Country Duration Funding	Design	Subject characteristics at baseline	Intervention	Endpoint assessed	Results
Durga et al. (2007) FACIT trial The Netherlands 3 years Mixed	RCT (parallel), double blind Inclusion/exclusion criteria : age 50–70 yrs, men and post‐menopausal women Exclusion: Hcy <13 or >26 μmol/L, cobalamin <200 pmol/L, renal or thyroid disease, medications that influence folate metabolism or atherosclerotic progression, intestinal disease, B‐vitamin users, <80% compliance during first 6 weeks N participants randomised/completed/analysed G1: 406/389/405 G2: 413/405/413	Sex (% women) G1: 28% G2: 30% Age (mean ± SD) G1: 60 ± 5 G2: 60 ± 6 Nutrient status marker, cobalamin (pmol/L), median (IQR): G1: 290 (239–366) G2: 286 (247–363) BMI (kg/m²): G1: 26.6 (3.6) G2: 26.5 (3.6) Current smokers: G1: 21% G2: 20% Dyslipidemia: G1: 39% G2: 33%	Folic acid Doses: G1: 800 μg/day G2: placebo Background nutrient intake, baseline, median (IQR): G1: 192 (159–238) G2: 195 (158–242) Compliance: 99% of capsules consumed	Cognition: Global cognitive function, Memory, Sensorimotor speed, Comple × speed, Information processing speed, Word fluency Word learning test, Concept shifting test, Stroop colour‐word test, Verbal fluency test, Letter digit substitution test	Effects among those with baseline cobalamin <250 pmol/L (n = 230), all as change versus placebo: Sensorimotor speed, mean (95% CI) Z‐score: 0.112 (0.001–0.223) Information processing speed, mean (95% CI) Z‐score: 0.190 (0.055–0.325) Effects among those with baseline cobalamin ≥250 pmol/L (n = 588), all as change versus placebo: Sensorimotor speed, mean (95% CI) Z‐score: 0.046 (−0.033–0.126) Information processing speed, mean (95% CI) Z‐score: 0.048 (−0.036–0.131) Overall effects (all participants), all as change versus placebo: Global cognitive function, mean (95% CI) Z‐score: 0.050 (0.004–0.096), p = 0.033 Memory, mean (95% CI) Z‐score: 0.132 (0.032–0.233), p = 0.010 Sensorimotor speed, mean (95% CI) Z‐score: 0.064 (−0.001–0.129), p = 0.055 Complex speed, mean (95% CI) Z‐score: 0.037 (−0.049–0.122), p = 0.40 Information processing speed, mean (95% CI) Z‐score: 0.087 (0.016–0.158), p = 0.016 Word fluency, mean (95% CI) Z‐score: −0.07 (−0.188–0.048), p = 0.245

Reference Study Country Duration Funding

Design

Subject characteristics at baseline

Intervention

Endpoint assessed

Results

Durga et al. (2007)

FACIT trial

The Netherlands

3 years

Mixed

RCT (parallel), double blind

Inclusion/exclusion criteria : age 50–70 yrs, men and post‐menopausal women Exclusion: Hcy <13 or >26 μmol/L, cobalamin <200 pmol/L, renal or thyroid disease, medications that influence folate metabolism or atherosclerotic progression, intestinal disease, B‐vitamin users, <80% compliance during first 6 weeks N participants randomised/completed/analysed G1: 406/389/405 G2: 413/405/413

Sex (% women)

G1: 28%

G2: 30%

Age (mean ± SD)

G1: 60 ± 5

G2: 60 ± 6

Nutrient status marker, cobalamin (pmol/L), median (IQR):

G1: 290 (239–366)

G2: 286 (247–363)

BMI (kg/m²):

G1: 26.6 (3.6)

G2: 26.5 (3.6)

Current smokers:

G1: 21%

G2: 20%

Dyslipidemia:

G1: 39%

G2: 33%

Folic acid

Doses:

G1: 800 μg/day

G2: placebo

Background nutrient intake, baseline, median (IQR):

G1: 192 (159–238)

G2: 195 (158–242)

Compliance: 99% of capsules consumed

Cognition: Global cognitive function, Memory, Sensorimotor speed, Comple × speed, Information processing speed, Word fluency Word learning test, Concept shifting test, Stroop colour‐word test, Verbal fluency test, Letter digit substitution test

Effects among those with baseline cobalamin <250 pmol/L (n = 230), all as change versus placebo:

Sensorimotor speed, mean (95% CI) Z‐score: 0.112 (0.001–0.223) Information processing speed, mean (95% CI) Z‐score: 0.190 (0.055–0.325) Effects among those with baseline cobalamin ≥250 pmol/L (n = 588), all as change versus placebo:

Sensorimotor speed, mean (95% CI) Z‐score: 0.046 (−0.033–0.126)

Information processing speed, mean (95% CI) Z‐score: 0.048 (−0.036–0.131)

Overall effects (all participants), all as change versus placebo:

Global cognitive function, mean (95% CI) Z‐score: 0.050 (0.004–0.096), p = 0.033

Memory, mean (95% CI) Z‐score: 0.132 (0.032–0.233), p = 0.010

Sensorimotor speed, mean (95% CI) Z‐score: 0.064 (−0.001–0.129), p = 0.055

Complex speed, mean (95% CI) Z‐score: 0.037 (−0.049–0.122), p = 0.40 Information processing speed, mean (95% CI) Z‐score: 0.087 (0.016–0.158), p = 0.016 Word fluency, mean (95% CI) Z‐score: −0.07 (−0.188–0.048), p = 0.245

Abbreviations: BMI, body mass index; CI, confidence interval; CT, controlled trial; FACIT, Folic Acid and Carotid Intimamedia Thickness; G, group; Hcy, homocysteine; IQR, Interquartile range; RoB, risk of bias; RCT, randomised controlled trial; yrs, years.