Supplementation of the diet with phosphatidylserine (PS) is associated with cognitive and neuropsychological benefits in healthy and neuro-compromised adults. It has also been shown to mitigate symptoms of inattention in children with attention-deficit hyperactivity disorder. However, there is little data on the effects of PS in healthy children. The aim of this randomized, placebo-controlled clinical trial was to examine the effects of sunflower-derived PS on cognitive performance in healthy, neurotypical children aged 8–12 years. Participants received 100 mg of sunflower-derived PS daily in gummy form or a matching placebo for 12 weeks and completed an assessment battery at baseline and after 6 and 12 weeks to monitor changes in cognitive performance, mood, and sleep. Retrospectively registered at Clinicaltrials.gov; NCT05177978 There were no differences in the primary or secondary outcomes in the total cohort. However, in a pre-defined subgroup analysis of children who were selected based on their constant below median performance across the cognitive tasks at baseline, PS-supplementation showed benefit on a visuospatial memory task. The supplementation with 100 mg of Sharp PS green was shown to be safe and well tolerated. Although there were no differences in the primary and secondary outcomes, the findings suggest that future research should focus on children with below median performance, who are more prone to benefit from PS supplementation.

BACKGROUND:Current treatment options for attention deficit hyperactivity disorder (ADHD) are limited by factors such as adherence and cost, whilst no treatment options are available for sub-clinical or undiagnosed ADHD. Herbal preparations may therefore offer an alternative approach to the management of symptoms; Aloysia citriodora Paláu (lemon verbena) is a promising candidate. AIM:To assess the behavioural, cognitive, psychological and physiological effects of 56 days of supplementation with lemon verbena extract (LVE) in children exhibiting symptoms of ADHD at the sub-clinical level. METHODS:This exploratory study followed a randomised, double-blind parallel groups design wherein 120 healthy participants aged 8-17 years received 15 mg/kg bw/d LVE or matched placebo for 56 days. Behavioural, cognitive, mood and physiological measures were collected in the lab at baseline and 28 and 56 days post-dose. Parents also evaluated the child's behaviour throughout the study. RESULTS:Participants who received LVE reported greater subjective fatigue, defined as reduced energy levels according to the Profile of Mood States subscale, without impairments in cognitive performance across the 56-day intervention and lower depression symptoms on day 56, compared to placebo. The effect of LVE on parent ratings of hyperactive/impulsive behaviour also approached significance with fewer concerns being reported following the active treatment. Exploratory analyses showed further benefits to cognition and mood. CONCLUSIONS:This study revealed novel, beneficial effects of LVE supplementation in children exhibiting a high frequency of behaviours characteristic of ADHD. Overall, LVE was safe and well-tolerated by participants, with no unexpected safety events.

IntroductionExtracts made from the leaves of the edible mango plant (Mangifera indica L., Anacardiaceae) have a long history of medicinal usage, most likely due to the presence of high levels of mangiferin, a polyphenol compound. Previous research has demonstrated that mango leaf extract (MLE) can beneficially modulate cognitive function in both animals and humans. This study aimed to assess the effects of an acute dose of 300 mg MLE (standardised to contain ≥60% mangiferin) on cognitive performance and mood in healthy adults.MethodsIn this double-blind, placebo-controlled, crossover study, 114 healthy men and women (18–43 years) received either MLE or a matched placebo at each testing visit (separated by at least 7 days). Cognitive performance (including the cognitive demand battery) and mood were measured at 30, 180, and 300 min post-dose.ResultsThe results showed that, compared to placebo, the group taking MLE displayed a significant increase in serial 3 s and serial 7 s subtraction errors overall. There were no other significant effects on cognitive performance.DiscussionThe results of the current study suggest that the consumption of 300 mg MLE in the absence of an observed multitasking psychological stressor does not improve cognitive performance or mood at up to 300 min post-dose. Due to the very limited nature of the effects and since they were observed among many analyses, these findings should be treated with caution.Clinical trial registration: http://ClinicalTrials.gov, identifier [NCT05182450].

Background: Coffeeberry extract, rich in chlorogenic acids, shows promise in improving mood and cognition, particularly when co-supplemented with phenolic compounds. However, limited work has considered the effects of coffeeberry in isolation, especially at low doses. Objective: The current study investigated the effect of low and moderate doses of coffeeberry extract on cognition and mood. Design: This randomized, double-blind, placebo-controlled crossover design investigated three active beverages on a sample of 72 healthy adults aged 18–49 years. The investigational beverages contained 100 mg or 300 mg coffeeberry extract (standardized to 40% chlorogenic acid), or 75 mg caffeine (positive control). Cognition, mood, and subjective energy were measured at baseline and then again at 60 and 120 min post-treatment. Results: Analysis revealed no effect of 300 mg coffeeberry extract, while 100 mg resulted in increased mental fatigue during the performance of cognitively demanding tasks (p = 0.025) and decreased accuracy on a task of sustained attention (p = 0.003), compared to placebo, at 60 min post dose. Conclusions: Administration of 100 mg and 300 mg coffeeberry extracts revealed limited, transient negative effects following 100 mg coffeeberry. Given the large number of outcome measures analysed and the absence of findings following the 300 mg dose, these negative findings should be interpreted with caution. Overall, the findings of the current study suggest that coffeeberry extract at a low or moderate dose does not have a beneficial effect on mood, mental and physical energy levels, or cognition; higher doses, as have been administered previously, may be more effective.

Background Beneficial effects of nut supplementation on cognitive function have previously been demonstrated in young and older adults. Alterations to gut microbiota have also been shown following tree nut consumption. However, no data exists on the effects of nuts on cognition and intestinal microbial communities assessed within the same study. Objectives The study aimed to examine the effects of daily consumption of tree nuts for 4 wk on cognitive function (primary outcome), mood, metabolomics, and gut microbial species (secondary outcomes) in healthy, nonelderly adults. Methods This randomized, placebo-controlled, double-blind, counterbalanced crossover study assessed the effects of 4 wk of supplementation with 30 g/d mixed tree nuts versus placebo on cognition and mood in 79 healthy adults aged 18-49 y. Metabolic responses, gut bacterial community structure, and the potential for these to impact cognition were explored using a multi-omic approach. Bacterial community analysis was conducted in Quantitative Insights Into Microbial Ecology 2 (QIIME2). Results Mixed model analysis indicated that nut consumption led to significant improvements to accuracy (placebo M = 92.2% compared with NUTS M = 94.5%; P = 0.019) and speed of response (placebo M = 788 ms compared with NUTS M = 757 ms; P = 0.004) on a picture recognition task. No significant changes to bacterial community alpha or beta diversity were observed when comparing nut consumption to the placebo arm. However, an unclassified Lachnospiraceae amplicon sequence variant (ASV) was significantly enriched in participants when supplemented with nuts (P = 0.015). No correlations were observed between the changes to picture recognition and the changes to the unclassified Lachnospiraceae ASV. There were no significant changes to the urinary metabolome. Conclusions These findings indicate a positive effect of nut on cognition following only 4 wk of consumption in a healthy nonelderly sample, as well as upregulation of a microbial taxa associated with gut health. The effects appear to be independent of one another, but further exploration is required in those experiencing cognitive decline and/or gut dysbiosis.

Background: Global lifetime prevalence of anxiety disorders has been estimated at approximately 16.6%, with subclinical prevalence likely much higher. Herbal approaches to reduce anxiety may be as effective as pharmacological treatments and are less likely to be associated with adverse side effects. The herbal species, namely, valerian, passionflower, hawthorn and ballota, have a long history of use as anxiolytics in traditional medicine, further supported by recent pre-clinical and clinical trials. Aims: To assess the effects of chronic (14 days) supplementation with a multi-herb extract preparation (MHEP, Euphytose®) on psychological state and psychological and physiological stress responses during a laboratory stressor. Methods: In this crossover study, 31 healthy participants (aged 19–58 years) received a MHEP and placebo for 14 days with a 28-day washout. Anxiety (State-Trait Anxiety Inventory), mood and physiological measures of stress (heart rate, galvanic skin response, salivary α-amylase and cortisol levels) were measured before and after an Observed Multitasking Stressor. Cognitive performance was also assessed. Results: MHEP was associated with reduced tension-anxiety ( p = 0.038), with participants showing an attenuated response to the observed multitasking psychosocial stressor following MHEP, evidenced by lower salivary α-amylase ( p = 0.041) and galvanic skin response ( p = 0.004). Conclusions: The combination of herbal extracts contained within the MHEP reduced subjective anxiety in a healthy population and lowered electrodermal skin conductance and concentration of salivary α-amylase in response to a psychosocial stressor, compared to placebo. The study was registered on clinicaltrials.gov (identifier: NCT03909906).

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 CogniviaTM, 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:Evidence regarding the effects of the omega-3 (ɷ-3) PUFAs (n-3 PUFAs) DHA and EPA on cognition is lacking. OBJECTIVES:We investigated whether supplementation with oils rich in EPA or DHA improves cognition, prefrontal cortex (PFC) hemoglobin (Hb) oxygenation, and memory consolidation. METHODS:Healthy adults (n = 310; age range: 25-49 y) completed a 26-wk randomized controlled trial in which they consumed either 900 mg DHA/d and 270 mg EPA/d (DHA-rich oil), 360 mg DHA/d and 900 mg EPA/d (EPA-rich oil), or 3000 mg/d refined olive oil (placebo). Cognitive performance and memory consolidation were assessed via computerized cognitive test battery. PFC Hb oxygenation was measured using near infrared spectroscopy (NIRS). RESULTS:Both global accuracy and speed improved with EPA-rich oil compared with placebo and DHA-rich oil [EPA vs. placebo accuracy: estimated marginal mean (EMM) = 0.17 (95% CI: 0.09, 0.24) vs. EMM = 0.03 (95% CI = -0.04, 0.11); P = 0.044; EPA vs. placebo speed: EMM = -0.15 (95% CI: -0.22, -0.07) vs. EMM = 0.03 (95% CI: -0.05, 0.10); P = 0.003]. Accuracy of memory was improved with EPA compared with DHA [EMM = 0.66 (95% CI: 0.26, 1.06) vs. EMM = -0.08 (95% CI: -0.49, 0.33); P = 0.034]. Both EPA- and DHA-rich oils showed trends towards reduced PFC oxygenated Hb (oxy-Hb) compared with placebo [placebo: EMM = 27.36 µM (95% CI: 25.73, 28.98); DHA: EMM = 24.62 µM (95% CI: 22.75, 26.48); P = 0.060; EPA: EMM = 24.97 µM (95% CI: 23.35, 26.59); P = 0.082]. CONCLUSIONS:EPA supplementation improved global cognitive function and was superior to the oil enriched with DHA. Interpreted within a neural efficiency framework, reduced PFC oxygenated Hb suggests that n-3 PUFAs may be associated with increased efficiency.These trials were registered in the clinical trials registry (https://clinicaltrials.gov/) as NCT03158545, NCT03592251, NCT02763514.

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.

Emerging evidence suggests that adequate intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs), which include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), might be associated with better sleep quality. N-3 PUFAs, which must be acquired from dietary sources, are typically consumed at suboptimal levels in Western diets. Therefore, the current placebo-controlled, double-blind, randomized trial, investigated the effects of an oil rich in either DHA or EPA on sleep quality in healthy adults who habitually consumed low amounts of oily fish. Eighty-four participants aged 25–49 years completed the 26-week intervention trial. Compared to placebo, improvements in actigraphy sleep efficiency (p = 0.030) and latency (p = 0.026) were observed following the DHA-rich oil. However, these participants also reported feeling less energetic compared to the placebo (p = 0.041), and less rested (p = 0.017), and there was a trend towards feeling less ready to perform (p = 0.075) than those given EPA-rich oil. A trend towards improved sleep efficiency was identified in the EPA-rich group compared to placebo (p = 0.087), along with a significant decrease in both total time in bed (p = 0.032) and total sleep time (p = 0.019) compared to the DHA-rich oil. No significant effects of either treatment were identified for urinary excretion of the major melatonin metabolite 6-sulfatoxymelatonin. This study was the first to demonstrate some positive effects of dietary supplementation with n-3 PUFAs in healthy adult normal sleepers, and provides novel evidence showing the differential effects of n-3 PUFA supplements rich in either DHA or EPA. Further investigation into the mechanisms underpinning these observations including the effects of n-3 PUFAs on sleep architecture are required.

Anxiety, stress, and low mood are closely related and may contribute to depressive symptoms. Among non-pharmacological solutions to improve subclinical mood symptoms and resilience to stress, natural products such as saffron—identified as promising following preliminary beneficial effects in major depressive disorder—represent a relevant strategy. This study aimed to assess the efficacy of 8 weeks' supplementation with 30 mg standardized saffron extract on emotional well-being in healthy adults with subclinical feelings of low mood and anxiety and/or stress and evaluate the acute effect of saffron in response to a lab-based psychosocial stressor. The study adopted a double-blind, randomized, parallel groups design in which 56 healthy male and female individuals (18–54 years) received either a saffron extract or a placebo for 8 weeks. Chronic effects of saffron on subjective anxiety, stress, and depressive feelings were assessed using a questionnaire battery [including Profile of Mood State-2, (POMS)] and acute effects in response to a lab-based psychosocial stressor were measured through psychological and physiological parameters. Urinary crocetin levels were quantified. Participants who received the saffron extract reported reduced depression scores and improved social relationships at the end of the study. Urinary crocetin levels increased significantly with saffron supplementation and were correlated with change in depression scores. The typical stress-induced decrease in heart rate variability (HRV) during exposure to the stressor was attenuated following acute saffron intake. Saffron extract appears to improve subclinical depressive symptoms in healthy individuals and may contribute to increased resilience against the development of stress-related psychiatric disorders. Clinical trials number: NCT03639831.

Knowledge of the diurnal variation in circulating omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be an important consideration for the development of dosing protocols designed to optimise tissue delivery of these fatty acids. The objective of the current study was to examine the variation in plasma concentrations of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) over a 24-h period in healthy adults under eating and sleeping conditions generally approximate to a free-living environment. Twenty-one healthy participants aged 25-44 years took part in a single laboratory visit encompassing an overnight stay. EPA and DHA were measured in plasma samples collected every two hours from 22:00 until 22:00 the following day, with all meals being provided at conventional times. Cosinor analysis was used to estimate the diurnal variation in each fatty acid from pooled data across all participants. A significant diurnal variation in the pooled plasma concentrations of both fatty acids was detected. However, evidence of distinct rhythmicity was strongest for DHA. The timing of the peak concentration of DHA was 17:43 with a corresponding nadir at 05:43. In comparison, the observed acrophase for EPA was delayed by three hours, occurring at 20:41, with a nadir at 08:41. This is the first time that the diurnal variation in these important bioactive fatty acids has been described in a sample of healthy adults following a normal pattern of eating and sleeping. In the absence of any dietary intake of EPA and DHA, circulating levels of these fatty acids fall during the overnight period and reach their lowest point in the morning. Consumption of n-3 PUFAs at night time, which counteracts this pattern, may have functional significance.

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.

AbstractIntroductionVitamins and minerals play an essential role within many cellular processes including energy production and metabolism. Biochemical changes and heightened metabolic demands lead to increases in the requirement for certain micronutrients alongside higher excretion of micronutrients through waste products, such as sweat and urine. Previously, supplementation with a multivitamin/mineral (MVM) for ≥ 28 days resulted in improvements to cognition and subjective state. Shifts in metabolism have also been demonstrated during cognitively demanding tasks following MVM in females, both acutely and following 8-week supplementation, suggesting that enhanced recovery is possible following MVM supplementation. The current study aimed to assess these effects further in males and females using metabolically challenging exercise and cognitive tasks.Materials and MethodsThis randomised, placebo-controlled, parallel groups study investigated the effects of a MVM complex in 82 healthy young (18–35y) exercisers. Subjective ratings and substrate metabolism were assessed during 30 minutes each of increasingly effortful incremental exercise and demanding cognitive tasks. Assessments took place on acute study days following a single dose (Day 1) of MVM, containing 3 times recommended daily allowance of water-soluble vitamins plus CoQ10, and following 4-week supplementation (Day 28).ResultsEnergy expenditure (EE) was increased during cognitive tasks following MVM across Day 1 and Day 28, with greater effects in males. In males, MVM also increased carbohydrate oxidation and EE during exercise across Day 1 and Day 28. In females, mental tiredness was lower during exercise; increases in physical tiredness following 30 minutes of exercise were attenuated; and stress ratings following cognitive tasks were reduced following MVM. In males, MVM only lowered mental tiredness following 10 minutes of exercise. Those receiving MVM also reported lower ratings of perceived exertion following 10 minutes of exercise. These effects were apparent irrespective of day, but effects on mental tiredness were greater on Day 28. Ferritin levels were also higher on Day 28 in those receiving MVM.DiscussionThese findings extend on existing knowledge, demonstrating increased carbohydrate oxidation and EE in males following MVM supplementation for the first time. Importantly, they show modulation of EE and subjective tiredness following a single dose, providing further evidence for acute effects of MVM. Differential effects in men and women suggest that whilst males expend more energy, females may conserve their energy but report lower tiredness instead, demonstrating that sex may play an important role in the effects of MVM on energy metabolism and should be considered in future research.

AbstractIron deficiency remains the most prevalent nutritional deficiency worldwide and is considered the most significant contributor to anaemia onset in children and women of reproductive age in both developing and developed countries. Iron plays a role in neurodevelopment and early deficits in iron have been found to impact hippocampal function affecting cognition and subjective mood. However, it is now recognised that neural structures can adapt throughout the lifespan and it is possible that changes in iron levels beyond infancy could stimulate neural changes and subsequent cognitive deficits at any time of life. Evidence for a causal link through the conduct of intervention studies is still sparse and varied in regards to the impact of iron deficiency in women of reproductive age. Our aim was to systematically review current evidence from intervention studies to determine the impact of iron supplementation upon cognition, subjective mood, well-being and fatigue in women of reproductive age. Searches included PubMed, Web of Science, Cochrane and bibliographies. Study selection and risk of bias assessment were duplicated and all intervention studies assessing cognition, subjective fatigue, mood and/or well-being that met the inclusion criteria were included in the review. Fifteen RCTs of women aged 12–49 were included. Nine studies investigated cognitive function following iron supplementation; eight found significant beneficial effects. All studies suggested that a reduced iron status at baseline was detrimental to one or more cognitive parameters, including attention and memory domains. Seven studies investigated subjective fatigue following iron supplementation; five found significant beneficial effects from baseline. Nine studies investigated mood and well-being; seven found significant effects, however they were somewhat conflicting. There is evidence to suggest that iron supplementation can improve attention, memory, subjective fatigue, mood and well-being, but additional studies using consistent measures, intervention methods and definitions of iron deficiency are warranted. Further studies should consider controlling for extraneous variables of diet, lifestyle choices and menstrual cycle to ensure an accurate measure of iron status.

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.