Emma L. Wightman

Background: Resveratrol appears to offer greater cognitive benefit to compromised models, such as in type II diabetes mellitus, menopause, and high body mass index (BMI), relative to healthy cohorts. With regards high BMI, hypertension, insulin resistance, oxidative stress, and inflammation have been posited as mechanisms underpinning cognitive decrements, and recent advancements in gut-brain-axis research have linked high BMI with inflammation via gut dysbiosis. Polyphenols have been evidenced to act prebiotically in the gut, to mediate anti-inflammatory effects in animal models, and this presents a mechanism by which resveratrol could bolster cognition in high BMI individuals. Aims: The current study investigates whether resveratrol can confer cognitive benefit to individuals with a high BMI, and whether these effects coincide with changes in the gut microbiome, urinary metabolome and biological markers of adiposity (anthropomorphic and blood biomarkers) and inflammation/oxidation. Methods: N = 99 male and females (35–60 years, mean age 47.51 years), with a BMI between 25 and 42 kg/m ² , received either 500 mg Veri-te™ resveratrol, or placebo, daily for 12 weeks. This supplementation period was bookended by visits to the laboratory for urine, blood, and stool sampling, and cognitive testing, which was assessed pre-and post-dose during both the acute and chronic testing visit. Results: Participants in the placebo control group presented with existing differences on cognitive outcomes at baseline, which makes interpretation of apparent improvements in this group relative to resveratrol, problematic. No significant differences were observed within or between groups on any microbiome, urinary metabolome, biological markers of adiposity or inflammation/oxidation markers. Conclusion: The absence of effects on the underlying biological mechanisms rationalized to underpin cognitive improvements in high BMI individuals likely explains the null results in the resveratrol intervention group. Effects attributed to the placebo control condition are explained as the persistence of pre-existing effects in this group of participants, and this may underlie the need to factor pre-enrolment aptitude into randomization in nutritional intervention trials. The lack of change in the gut microbiome of a healthy human cohort, following 12 weeks of resveratrol supplementation, is a positive indication, showing no deleterious disruption within this environment. Future studies may wish to investigate these effects in those with a disrupted gut microbiome. Clinical trial registration: The study was pre-registered on clinicaltrials.gov (identifier: NCT03448094).

Background: The effects of herbs on brain function are often investigated in isolation, yet herbal preparations are often complex combinations of phytochemicals, designed to target widespread mechanisms.Objective: To assess the effects of chronic, 12 weeks, supplementation of a multi-ingredient herbal supplement (containing Bacopa monnieri, Gotu kola leaf, Turmeric whole powder, Reishi full spectrum, Rosemary, Cardamom, Holy Basil, Turmeric Wholistic^™ extract, Green Tea & Seagreens) on cognitive function in older adults with subjective memory decline. Secondly, to investigate whether effects are underpinned by shifts in microbial composition and/or metabolism of the herbs.Methods: Male and female participants (N = 128) aged between 55–75 years completed lab-based cognitive assessments, and provided stool and urine samples, at baseline and then following 90 days of multi-ingredient herb, or placebo, supplementation.Results: Deficits in memory were observed in response to 90 days of multi-ingredient herbal supplement supplementation but the positive effects were all focused on speed of cognitive task performance, with an additional improvement in the false alarm rate on the rapid visual information processing task. These improvements coincided with an increased presence of tyrosine in the urinary metabolome and this may implicate the role of dopamine in these processing and/or motor speed increases. Finally, multi-ingredient herbal supplementation significantly reduced levels of 3 bacterial species in the gut microbiome and one of these, Sutterella, coincides with lower levels of constipation reported in the multi-ingredient herbal supplement condition.Conclusion: A multi-ingredient herbal supplement increases speed of cognitive task performance and increased metabolism of tyrosine suggests that this is modulated by increased dopaminergic activity. Reduced levels of Sutterella in the gut is associated with improved bowel movements of participants. Interpretation of the negative effects on memory are, however, stymied by an unequal randomization of participants into treatment groups pre- and post-COVID 19.Clinical trial registration: identifier NCT05504668.

The plant defence compound caffeine is widely consumed as a performance enhancer in a sporting context, with potential benefits expected in both physiological and psychological terms. However, although caffeine modestly but consistently improves alertness and fatigue, its effects on mental performance are largely restricted to improved attention or concentration. It has no consistent effect within other cognitive domains that are important to sporting performance, including working memory, executive function and long-term memory. Although caffeine’s central nervous system effects are often attributed to blockade of the receptors for the inhibitory neuromodulator adenosine, it also inhibits a number of enzymes involved both in neurotransmission and in cellular homeostasis and signal propagation. Furthermore, it modulates the pharmacokinetics of other endogenous and exogenous bioactive molecules, in part via interactions with shared cytochrome P450 enzymes. Caffeine therefore enjoys interactive relationships with a wide range of bioactive medicinal and dietary compounds, potentially broadening, increasing, decreasing, or modulating the time course of their functional effects, or vice versa. This narrative review explores the mechanisms of action and efficacy of caffeine and the potential for combinations of caffeine and other dietary compounds to exert psychological effects in excess of those expected following caffeine alone. The review focusses on, and indeed restricted its untargeted search to, the most commonly consumed sources of caffeine: products derived from caffeine-synthesising plants that give us tea (Camellia sinensis), coffee (Coffeagenus), cocoa (Theabroma cacao) and guaraná (Paullinia cupana), plus multi-component energy drinks and shots. This literature suggests relevant benefits to mental performance that exceed those associated with caffeine for multi-ingredient energy drinks/shots and several low-caffeine extracts, including high-flavanol cocoa and guarana. However, there is a general lack of research conducted in such a way as to disentangle the relative contributions of the component parts of these products.

Nitrate-rich food increases nitric oxide (NO) production and may have beneficial effects on vascular, metabolic, and brain function. This pilot study tested the effects of prolonged consumption of a range of doses of dietary nitrate (NO₃⁻), provided as beetroot juice, on cognitive function and cerebral blood flow (CBF) in overweight and obese older participants. The study had a 13-week single-blind, randomised, parallel design, and 62 overweight and obese older participants (aged 60 to 75 years) received the following interventions: (1) high NO₃⁻ (2 × 70 mL beetroot juice/day) (2) medium NO₃⁻ (70 mL beetroot juice/day), (3) low NO₃⁻ (70 mL beetroot juice on alternate days), or (4) placebo (70 mL of NO₃⁻-depleted beetroot juice on alternate days). Cognitive functions were assessed using the Computerised Mental Performance Assessment System (COMPASS) assessment battery. CBF, monitored by concentration changes in oxygenated and deoxygenated haemoglobin, was assessed in the frontal cortex using near-infrared spectroscopy. The findings of this pilot study showed that cognitive function and CBF were not affected by supplementation with NO₃⁻-rich beetroot juice for 13 weeks, irrespective of the NO₃⁻ dose administered. These findings require confirmation in larger studies using more sophisticated imaging methods (i.e., MRI) to determine whether prolonged dietary NO₃⁻ supplementation influences brain function in older overweight people.

Background: Polyphenols from coffee berry (chlorogenic acid) and apple (flavanol) have been shown to improve mood and increase cerebral blood flow in healthy humans. These effects may underpin the cognitive effects of polyphenols seen previously. Objective: The aim of the present paper was to extend previous research by investigating the effects of coffee berry at high and low doses when combined with apple extract on cognitive performance and mood. Design: This randomised, double-blind, placebo controlled, crossover trial included 46 healthy males and females,18–49 years of age (mean age 23 years),consuming: 1100 mg coffee berry extract, 1100 mg coffee berry extract plus 275 mg apple extract, 100 mg coffee berry extract plus 275 mg apple extract or placebo on 4 separate occasions, completing cognitive and mood assessments pre-dose and then again at 1-, 3- and 6 hrs post-dose. Results: Analysis revealed a consistent pattern of alerting effects following 1100 mg coffee berry extract. Limited effects on cognitive function were observed. Specifically, faster peg and ball performance (executive function) was observed following 1100 mg coffee berry plus apple extract and accuracy on the Rapid Visual Information Processing (RVIP) task increased on the third of four repetitions following 1100 mg coffee berry alone. Interestingly, more false alarms on RVIP were observed following the same intervention. Conclusions: In line with previous findings, 1100 mg coffee berry engendered increased arousal. The absence of effects on mood when an apple extract was added, and the potential for the low dose of caffeine within the coffee berry to act synergistically with polyphenols, raise interesting future avenues of research. Abbreviations: Cognitive demand battery (CDB), Profile Of Mood States (POMS), Visual Analogue Scale (VAS), Rapid Visual Information Processing (RVIP)

Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO₃⁻) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m²) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO₃⁻ (HN: 2 × 70 mL BJ/day) (2) medium-NO₃⁻ (MN: 70 mL BJ/day), (3) low-NO₃⁻ (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO₃⁻-depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO₃⁻ intake, and by measuring NO₃⁻ and NO₂⁻ concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO₃⁻ dose and the increase in plasma and urinary NO₃⁻ concentration (R² = 0.71, p < 0.001 and R² = 0.46 p < 0.001, respectively), but relationships between NO₃⁻ dose and changes in salivary NO₃⁻ and NO₂⁻ were non-linear (R² = 0.35, p = 0.002 and R² = 0.23, p = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults.

The sage (Salvia) plant contains a host of terpenes and phenolics which interact with mechanisms pertinent to brain function and improve aspects of cognitive performance. However, previous studies in humans have looked at these phytochemicals in isolation and following acute consumption only. A preclinical in vivo study in rodents, however, has demonstrated improved cognitive outcomes following 2-week consumption of Cognivia^TM, a proprietary extract of both Salvia officinalis polyphenols and Salvia lavandulaefolia terpenoids, suggesting that a combination of phytochemicals from sage might be more efficacious over a longer period of time. The current study investigated the impact of this sage combination on cognitive functions in humans with acute and chronic outcomes. Participants (n = 94, 25 M, 69 F, 30–60 years old) took part in this randomised, double-blind, placebo-controlled, parallel groups design where a comprehensive array of cognitions were assessed 120- and 240-min post-dose acutely and following 29-day supplementation with either 600 mg of the sage combination or placebo. A consistent, significant benefit of the sage combination was observed throughout working memory and accuracy task outcome measures (specifically on the Corsi Blocks, Numeric Working Memory, and Name to Face Recall tasks) both acutely (i.e., changes within day 1 and day 29) and chronically (i.e., changes between day 1 to day 29). These results fall slightly outside of those reported previously with single Salvia administration, and therefore, a follow-up study with the single and combined extracts is required to confirm how these effects differ within the same cohort.

Background: In whole foods, polyphenols exist alongside a wide array of other potentially bioactive phytochemicals. Yet, investigations of the effects of combinations of polyphenols with other phytochemicals are limited. Objective: The current study investigated the effects of combining extracts of beetroot, ginseng and sage with phenolic-rich apple, blueberry and coffee berry extracts. Design: This randomized, double-blind, placebo-controlled crossover design investigated three active beverages in 32 healthy adults aged 18–49 years. Each investigational beverage comprised extracts of beetroot, ginseng and sage. Each also contained a phenolic-rich extract derived from apple (containing 234 mg flavanols), blueberry (300 mg anthocyanins) or coffee berry (440 mg chlorogenic acid). Cognition, mood and CBF parameters were assessed at baseline and then again at 60, 180 and 360 min post-drink. Results: Robust effects on mood and CBF were seen for the apple and coffee berry beverages, with increased subjective energetic arousal and hemodynamic responses being observed. Fewer effects were seen with the blueberry extract beverage. Conclusions: Either the combination of beetroot, ginseng and sage was enhanced by the synergistic addition of the apple and coffee berry extract (and to a lesser extent the blueberry extract) or the former two phenolic-rich extracts were capable of evincing the robust mood and CBF effects alone.

Extracts made from the leaves of the mango food plant (Mangifera indica L., Anacardiaceae) have a long history of medicinal usage, most likely due to particularly high levels of the polyphenol mangiferin. In rodent models, oral mangiferin protects cognitive function and brain tissue from a number of challenges and modulates cerebro-electrical activity. Recent evidence has confirmed the latter effect in healthy humans following a mangiferin-rich mango leaf extract using quantitative electroencephalography (EEG). The current study therefore investigated the effects of a single dose of mango leaf extract, standardised to contain >60% mangiferin (Zynamite^®), on cognitive function and mood. This study adopted a double-blind, placebo-controlled cross-over design in which 70 healthy young adults (18 to 45 years) received 300 mg mango leaf extract and a matched placebo, on separate occasions, separated by at least 7 days. On each occasion, cognitive/mood assessments were undertaken pre-dose and at 30 min, 3 h and 5 h post-dose using the Computerised Mental Performance Assessment System (COMPASS) assessment battery and the Profile of Mood States (POMS). The results showed that a single dose of 300 mg mango leaf extract significantly improved performance accuracy across the tasks in the battery, with domain-specific effects seen in terms of enhanced performance on an ‘Accuracy of Attention’ factor and an ‘Episodic Memory’ factor. Performance was also improved across all three tasks (Rapid Visual Information Processing, Serial 3s and Serial 7s subtraction tasks) that make up the Cognitive Demand Battery sub-section of the assessment. All of these cognitive benefits were seen across the post-dose assessments (30 min, 3 h, 5 h). There were no interpretable treatment related effects on mood. These results provide the first demonstration of cognition enhancement following consumption of mango leaf extract and add to previous research showing that polyphenols and polyphenol rich extracts can improve brain function.

Green oat (Avena sativa) extracts contain several groups of potentially psychoactive phytochemicals. Previous research has demonstrated improvements in cognitive function following a single dose of these extracts, but not following chronic supplementation. Additionally, whilst green oat extracts contain phytochemicals that may improve mood or protect against stress, for instance species-specific triterpene saponins, to date this possibility has not been examined. The current study investigated the effects of a single dose and four weeks of administration of a novel, Avena sativa herbal extract (cognitaven^®) on cognitive function and mood, and changes in psychological state during a laboratory stressor. The study adopted a dose-ranging, double-blind, randomised, parallel groups design in which 132 healthy males and females (35 to 65 years) received either 430 mg, 860 mg, 1290 mg green oat extract or placebo for 29 days. Assessments of cognitive function, mood and changes in psychological state during a laboratory stressor (Observed Multitasking Stressor) were undertaken pre-dose and at 2 h and 4 h post-dose on the first (Day 1) and last days (Day 29) of supplementation. The results showed that both a single dose of 1290 mg and, to a greater extent, supplementation for four weeks with both 430 mg and 1290 mg green oat extract resulted in significantly improved performance on a computerised version of the Corsi Blocks working memory task and a multitasking task (verbal serial subtractions and computerised tracking) in comparison to placebo. After four weeks, the highest dose also decreased the physiological response to the stressor in terms of electrodermal activity. There were no treatment-related effects on mood. These results confirm the acute cognitive effects of Avena sativa extracts and are the first to demonstrate that chronic supplementation can benefit cognitive function and modulate the physiological response to a stressor.