Table 2 Findings from key studies reporting the effects of dietary nitrate on brain health in humans

Aamand et al. 2013 [89]

Healthy young men.

n = 18.

Age = 25 ± 0.9 SD.

Weight = 77 kg ± 1.5 SD.

Double-blind, crossover, placebo-controlled RCT.

fMRI (BOLD; oxygenation metabolism and ASL; CBF), nitrate, nitrite, BP, pulse oximetry, expired CO_2,

Duration: three days for each intervention with a washout period of 9–11 days.

Two groups:

1. Start with dietary nitrate (NaNO₃⁻; saline solution), n = 9, followed by Placebo (NaCl; saline solution).

2. The opposite of the first group, n = 9.

Dietary nitrate decrease haemodynamic lag significantly (p < 0.005), which associate significantly with NO₃⁻ concentration (p < 0.05). In addition, it improves the BOLD amplitude significantly (3-way ANOVA; p < 0.05), without significant association with NO₃⁻ concentration. Moreover, a significant correlation between the lag and amplitude (p < 0.005). Furthermore, dietary nitrate increases the NO₃⁻ concentration significantly (p < 0.001) despite the intervention order, but it were not significant for the NO₂⁻ in both intervention. However, there was no significant difference in the other measurement.

Kelly et al. 2013 [119]

Healthy old adults.

n = 12 (M/F = 6/6), two were excluded.

Age (M/F) = 64 ± 4 SD / 63 ± 2 SD.

BMI (M/F) = 23.1/25.1.

Double-blind, crossover, placebo-controlled RCT.

Nitrite, BP, physiological and cognitive examinations.

Duration: two and half days for each intervention with a washout period of three days.

Two groups:

1. Start with dietary nitrate (high-nitrate beetroot juice; 2 × 70 ml/d), n = 6, followed by placebo (depleted-nitrate beetroot juice; 2 × 70 ml/d).

2. The opposite of the first group, n = 6.

Dietary nitrate enhanced NO₂⁻ concentration significantly (p < 0.01) when compared to placebo and baseline. In addition, it significantly reduced systolic and diastolic BP when compared to baseline (p < 0.01) and placebo (p < 0.05). However, there was no significant difference in the cognitive function between nitrate intake and placebo or baseline.

Wightman et al. 2015

[45]

Healthy adults.

n = 40 (M/F = 12/28).

Age = 21.

BMI = 24.36

Double-blind, parallel, placebo-control RCT.

Cognitive function (COMPASS), CBF (oxyhaemoglobin and deoxyhaemoglobin by NIRS), BP, nitrite.

Duration: single high dose, over three portions, separated by 10 min, measurements performed after one and half hours from the first portion for one hour approximately during cognitive tasks.

Two groups:

1. Beetroot Juice 450 ml (nitrate-rich), n = 20.

2. Placebo (nitrate-depleted), n = 20.

Inorganic nitrate increase nitrite significantly (p < 0.01).

In addition, it significantly increases CBF at the beginning of the tasks (total Hb; P < 0.05) and decreases it significantly afterwards (p < 0.01) compared to placebo. However, there was no significant difference between the groups regarding the deoxy Hb. Moreover, it improves cognitive function (p < 0.01). However, there was no significant difference on BP.

Fan et al. 2019 [90]

Healthy young adults.

n = 17 (M/F = 10/7).

Age = 24.4 ± 5.7 SD.

BMI = 23.2 ± 2.1 SD.

Single-blind, crossover, placebo-controlled RCT.

CBF, cerebrovascular CO₂ activity, cerebral autoregulation (BP and MCAv), nitrate and nitrite.

Duration: one week for the baseline assessment plus one week for each intervention with a washout period of one week.

Two groups:

1. Start with dietary nitrate (NaNO₃⁻; 3 capsules/d), followed by placebo (microcrystalline cellulose; 3 capsules/d)

2. The opposite of the first group

Dietary nitrate enhanced NO₃⁻and NO₂⁻concentrations significantly compared to baseline and placebo (p < 0.002), without a significant difference between males and females. In addition, it improved the arterial stiffness significantly compared to baseline and placebo (p < 0.008). Moreover, it improved significantly cerebral autoregulation compared to placebo but not to baseline in males but not females (p < 0.025). Furthermore, it improved MCAv-CO₂ only in males compared to placebo (p < 0.014). However, there was no significant difference in BP or cerebrovascular haemodynamic

Fan et al. 2020 [91]

Transient ischemic attack overweight patients (TIA).

n = 26.

Age = 67.4 ± 10.2 SD.

BMI = 27.9 ± 6.4 SD.

Single-blind, parallel, placebo-controlled RCT.

Cerebrovascular function (BP and CBF), cerebrovascular CO₂ activity, cerebral autoregulation, nitrate and nitrite.

Duration: one week.

Two groups:

1. Dietary nitrate (NaNO₃⁻; 3 capsules/d), n = 13.

2. Placebo (microcrystalline cellulose; 3 capsules/d), n = 13.

Dietary nitrate significantly increased concentrations of NO₃⁻ (p < 0.001) and NO₂⁻ (p < 0.004) compared to placebo and baseline (p < 0.001). Additionally, placebo was not significant for both NO₃⁻and NO₂⁻ compared to baseline. In addition, it decreased the BP significantly compared to placebo and baseline (p < 0.05). Moreover, it improves MCAv variability (p < 0.018) and cerebral autoregulation (p < 0.045) compared to placebo. However, there was no significant difference in cerebral haemodynamics compared to placebo.

Babateen et al. 2022 [92]

Healthy overweight and obese adult.

n = 62 (M/F = 24/38).

Age = 66.3 ± 3.7 SD.

BMI = 30.3 ± 3.7 SD.

Single-blind, parallel, placebo-controlled pilot RCT.

CBF (oxyhaemoglobin and deoxyhaemoglobin by NIRS) and cognitive function (COMPASS).

Duration: 13 weeks.

Four groups:

1. High dietary nitrate (high-nitrate beetroot juice; 2 × 70 ml/d) n = 16.

2. Moderate dietary nitrate (high-nitrate beetroot juice; 70 ml/d) n = 17.

3. Low dietary nitrate (high-nitrate beetroot juice; 70 ml/alternate days) n = 14.

4. Placebo (depleted-nitrate beetroot juice; 70 ml/ alternate days) n = 15.

There was no significant difference between the groups and baseline in terms of CBF and cognitive function.

Alharbi et al. 2023 [13]

Healthy overweight and obese adult.

n = 29 (M/F = 7/22).

Age = 61.3 ± 5.9. SD.

BMI = 34.5 ± 5.8 SD.

Open-label, parallel, pilot RCT.

Body composition, REE,

resting BP, endothelial activity, microvascular perfusion (Laser Doppler), cognitive function, hand-grip strength, physical activity, and oxidative stress biomarker.

Duration: 2 weeks.

Two groups:

1. CR (40% reduction in EI) plus dietary nitrate (high-nitrate beetroot juice; 70 ml/d) n = 15.

2. CR alone (40% reduction in EI) n = 14.

There was significant improvement of systolic BP (p = 0.06), microvascular perfusion (p = 0.03), endothelial activity (p = 0.02), cognitive function (p = 0.01), and oxidative stress biomarker (p = 0.02) among CR + dietary nitrate group compared to CR alone. In addition, there was significant inversed correlation between oxidative stress biomarker and microvascular perfusion (r=-0.53, p = 0.003).