Inulin and Freeze-Dried Blueberry Intervention Lead to Changes in the Microbiota and Metabolites within In Vitro Studies and in Cognitive Function within a Small Pilot Trial on Healthy Children.

The relationship between the gut microbiota and cognitive health is complex and bidirectional, being significantly impacted by our diet. Evidence indicates that polyphenols and inulin can impact cognitive function via various mechanisms, one of which is the gut microbiota. In this study, effects of a wild blueberry treatment (WBB) and enriched chicory inulin powder were investigated both in vitro and in vivo. Gut microbiota composition and metabolites, including neurotransmitters, were assessed upon faecal microbial fermentation of WBB and inulin in a gut model system. Secondly, microbiota changes and cognitive function were assessed in children within a small pilot (n = 13) trial comparing WBB, inulin, and a maltodextrin placebo, via a series of tests measuring executive function and memory function, with faecal sampling at baseline, 4 weeks post-intervention and after a 4 week washout period. Both WBB and inulin led to microbial changes and increases in levels of short chain fatty acids in vitro. In vivo significant improvements in executive function and memory were observed following inulin and WBB consumption as compared to placebo. Cognitive benefits were accompanied by significant increases in Faecalibacterium prausnitzii in the inulin group, while in the WBB group, Bacteroidetes significantly increased and Firmicutes significantly decreased (p < 0.05). As such, WBB and inulin both impact the microbiota and may impact cognitive function via different gut-related or other mechanisms. This study highlights the important influence of diet on cognitive function that could, in part, be mediated by the gut microbiota.

Wild Blueberry Extract Intervention in Healthy Older Adults: A Multi-Study, Randomised, Controlled Investigation of Acute Cognitive and Cardiovascular Effects.

BACKGROUND: Circadian and homeostatic declines in cognitive performance are observed during the day, most commonly at 14:00. Additionally, postprandial reductions in cognitive ability have been widely demonstrated 1 h after lunch consumption, affecting domains of executive functioning (EF), episodic memory (EM), and attention. Existing evidence shows that anthocyanin-rich foods such as berries may improve or attenuate the decline in EF and EM in ageing adults. Further research is required to assess whether extracts such as wild blueberry extract (WBE) may be beneficial for cognitive function across an acute timeframe, including known periods of reduced functioning. OBJECTIVES: (1) Study 1: ROAB: To investigate the efficacy of WBE in maintaining EF and EM throughout the day alongside measures of cardiovascular outcomes in healthy older adults. A range of WBE doses were utilised to identify the optimal dose at which cognitive and cardiovascular effects occur. (2) Study 2: BEAT: To replicate alleviation of cognitive decline during a predicted post-lunch dip whilst also improving cardiovascular outcomes following acute WBE 222 mg supplementation. METHODS: Both studies employed a randomised, double-blind, cross-over, placebo-controlled design to explore the effects of WBE intervention versus placebo on several outcomes, including EM, EF, blood pressure, and heart rate in a healthy older adult population (aged 68-75). In ROAB, 28 participants received a single dose of WBE 111 mg, 222 mg, 444 mg, or 888 mg or placebo over a 5-week period, each separated by a 1-week washout. Outcomes were measured at 0 h, 2 h, 4 h, and 6 h post intervention, with intervention occurring immediately after baseline (0 h). In BEAT, 45 participants received WBE 222 mg and placebo (1-week washout). Outcomes were measured at 0 h and 6 h (14:00) when a post-lunch dip was anticipated. This was further enhanced by consumption of lunch 1 h prior to cognitive testing. The WBE 222 mg intervention aligned with known peaks in plasma blueberry polyphenol metabolites at 2 h post dosing, which would coincide with a predicted drop in post-lunch performance. RESULTS: ROAB: A significant dip in executive function was apparent at the 4 h timepoint for placebo only, indicating attenuation for WBE doses. Strikingly, WBE 222 mg produced acute reductions in both systolic and diastolic blood pressure compared with placebo. BEAT: EF reaction time was found to be significantly faster for WBE 222 compared to placebo at the predicted post-lunch dip (14:00), with no other notable benefits on a range of cognitive and cardiovascular outcomes. CONCLUSION: These two studies indicate that WBE may have cardiovascular benefits and attenuate the natural cognitive decline observed over the course of the day, particularly when a decline is associated with a circadian rhythm-driven postprandial dip. However, it is important to acknowledge that effects were subtle, and benefits were only observed on a small number of outcomes. Further research is required to explore the utility of WBE in populations already experiencing mild cognitive impairments.

The Relationship between Mushroom Intake and Cognitive Performance: An Epidemiological Study in the European Investigation of Cancer-Norfolk Cohort (EPIC-Norfolk).

The previous literature suggests that regular consumption of edible mushrooms may confer neuroprotective cognitive health benefits. To further investigate the possible association between mushrooms and brain function during ageing, data from a population-based study of diet and chronic disease (EPIC-Norfolk cohort) were analysed. Changes in mushroom intake were measured using a food frequency questionnaire at three health check (HC) points over an 18-year period, with participants categorised based on their consumption frequency. Cognitive performance was assessed at the final health check (3HC) via a battery of validated tests assessing a range of different cognitive domains. The findings revealed a significant reduction in mushroom intake over time, with 4.12% of the cohort giving up mushrooms after previously consuming them. At 3HC, mushroom consumers displayed better cognitive performance than non-consumers across multiple cognitive domains. This relationship was observed to be dose-dependent, with those consuming 1 or more portions per week showing the highest cognitive scores. These findings suggest that regular mushroom consumption may be beneficial for cognitive function during aging. Further randomised controlled trials will be needed to confirm any potential benefits of mushrooms on long-term cognitive health, alongside public health initiatives to promote mushroom consumption in this older-adult demographic.

Dietary Flavonoids and Human Cognition: A Meta-Analysis.

Improving cognition is important in all age groups, from performance in school examinations to prevention of cognitive decline in later life. Dietary polyphenols, in particular flavonoids, have been examined for their benefits to cognitive outcomes. This meta-analysis evaluates the effects of dietary flavonoids on cognition across the lifespan. In January 2020 databases were searched for randomized controlled trials investigating flavonoid effects on human cognition. Eighty studies, comprising 5519 participants, were included in the final meta-analysis. The global analysis indicates dietary flavonoids induced significant benefit to cognitive performance (g = 0.148, p < 0.001), with subgroup analyses revealing that cocoa (g = 0.224, p = 0.036), ginkgo (g = 0.187, p ≤ 0.001), and berries (g = 0.149, p = 0.009) yielded the most notable improvements. Significant benefits were observed from chronic studies, in middle-aged and older adults, and with low and medium doses. The domains of long-term memory, processing speed, and mood showed sensitivity to flavonoid intervention. This meta-analysis provides evidence for the positive effects of flavonoids on cognition and highlights several moderating factors. Flavonoid-based dietary interventions therefore potentially offer a highly accessible, safe, and cost-effective treatment to help tackle the burden of cognitive decline.

Grape seed polyphenol extract and cognitive function in healthy young adults: a randomised, placebo-controlled, parallel-groups acute-on-chronic trial.

Grapes are polyphenol-rich, and grape juice intake has shown cognitive benefits in middle-aged females and older adults with mild cognitive impairment. Extracts obtained from grape seeds have similarly been associated with cognitive benefits in older adults. The aim of this research was to investigate whether a highly purified grape seed-derived polyphenol extract was associated with cognitive benefits in healthy young adults following a single acute dose, and chronically following repeated daily dosage over 12 weeks. Following an acute-on-chronic, parallel groups, randomised, double-blind, placebo-controlled design, sixty adults aged 18-30 consumed either a 400 mg grape seed polyphenol extract (GSPE, n = 30) or a placebo (n = 30). Cognitive function was assessed acutely at baseline and 2, 4 and 6 h post consumption, and chronically at 6 and 12 twelve weeks with a computerised battery of multiple cognitive tests. Mood was assessed with the Positive and Negative Affect Schedule. Linear marginal model analysis with baseline included as a covariate did not reveal a consistent pattern of cognitive benefits following the GSPE relative to the placebo either acutely or chronically when considering all outcome measures. GSPE was associated with some improvements in reaction time (acutely) and psychomotor skill (chronically), however the placebo was also associated with some benefits to reaction time and memory. Therefore, a 400 mg GSPE did not consistently improve cognitive function in healthy young adults. These findings suggest that younger, healthy populations are perhaps less sensitive to polyphenol extract doses <400mg relative to older, or cognitively compromised populations.

Anthocyanins Promote Learning through Modulation of Synaptic Plasticity Related Proteins in an Animal Model of Ageing.

Anthocyanin-rich foods, such as berries, reportedly ameliorate age-related cognitive deficits in both animals and humans. Despite this, investigation into the mechanisms which underpin anthocyanin-mediated learning and memory benefits remains relatively limited. The present study investigates the effects of anthocyanin intake on a spatial working memory paradigm, assessed via the cross-maze apparatus, and relates behavioural test performance to underlying molecular mechanisms. Six-week supplementation with pure anthocyanins (2% w/w), administered throughout the learning phase of the task, improved both spatial and psychomotor performances in aged rats. Behavioural outputs were accompanied by changes in the expression profile of key proteins integral to synaptic function/maintenance, with upregulation of dystrophin, protein kinase B (PKB/Akt) and tyrosine hydroxylase, and downregulation of apoptotic proteins B-cell lymphoma-extra-large (Bcl-xL) and the phosphorylated rapidly accelerated fibrosarcoma (p-Raf). Separate immunoblot analysis supported these observations, indicating increased activation of extracellular signal-related kinase (ERK1), Akt Ser473, mammalian target of rapamycin (mTOR) Ser2448, activity-regulated cytoskeleton-associated protein (Arc/Arg 3.1) and brain-derived neurotrophic factor (BDNF) in response to anthocyanin treatment, whilst α-E-catenin, c-Jun N-terminal kinase (JNK1) and p38 protein levels decreased. Together, these findings suggest that purified anthocyanin consumption enhances spatial learning and motor coordination in aged animals and can be attributed to the modulation of key synaptic proteins, which support integrity and maintenance of synaptic function.

Improved metabolic function and cognitive performance in middle-aged adults following a single dose of wild blueberry.

PURPOSE: Research has demonstrated cognitive benefits following acute polyphenol-rich berry consumption in children and young adults. Berry intake also has been associated with metabolic benefits. No study has yet examined cognitive performance in middle-aged adults. We investigated the relationships among cognitive and metabolic outcomes in middle-aged adults following wild blueberry (WBB) consumption. METHODS: Thirty-five individuals aged 40-65 years participated in a randomized, double blind, cross-over study. Participants consumed a breakfast meal and 1-cup equivalent WBB drink or matched placebo beverage on two occasions. Participants completed cognitive tasks and had blood drawn before and at regular intervals for 8 h after each meal/treatment. Changes in episodic memory and executive function (EF) were assessed alongside plasma levels of glucose, insulin, and triglyceride. RESULTS: Analysis of the memory-related Auditory Verbal Learning Task (AVLT) word recognition measure revealed a decrease in performance over the test day after placebo intake, whereas performance after WBB was maintained. For the AVLT word rejection measure, participants identified more foils following WBB in comparison to placebo. Benefits were also observed for EF on the Go/No-Go task with fewer errors following WBB intake on cognitively demanding invalid No-Go trials in comparison to placebo. Furthermore, in comparison to placebo, response times were faster for the Go/No-Go task, specifically at 4 h and 8 h following WBB treatment. We also observed reduced post-meal glucose and insulin, but not triglyceride, concentrations in comparison to placebo over the first 2 h following ingestion. Though the addition of Age, BMI, glucose and insulin as covariates to the analysis reduced the significant effect of beverage for AVLT word rejection, metabolic outcomes did not interact with treatment to predict cognitive performance with the exception of one isolated trend. CONCLUSIONS: This study indicated acute cognitive benefits of WBB intake in cognitively healthy middle-aged individuals, particularly in the context of demanding tasks and cognitive fatigue. WBB improved glucose and insulin responses to a meal. Further research is required to elucidate the underlying mechanism by which WBB improves cognitive function.

Flavonoid-Rich Mixed Berries Maintain and Improve Cognitive Function Over a 6 h Period in Young Healthy Adults.

Research with young adults has previously indicated flavonoid-rich berry interventions facilitate improved executive function (EF) and positive affect 20 min-2 h post-dosing. There has been little consideration of the impact of a berry intervention over a working day and interventions have also tended to consider only a single berry type. This study investigated the temporal profile of EF and mood changes over a 6 h period following a mixed-berry intervention. We hypothesized berry-related benefits would be most evident when participants were cognitively compromised on demanding elements of the task or during periods of fatigue. The study employed a single-blind, randomized, placebo controlled, between-subjects design. Forty participants aged 20-30 years consumed a 400 mL smoothie containing equal blueberry, strawberry, raspberry, and blackberry (n = 20) or matched placebo (n = 20). Mood was assessed using the Positive and Negative Affect Schedule; EF was tested using the Modified Attention Network (MANT) and Task Switching (TST) Tasks. Testing commenced at baseline then 2, 4 and 6 h post-dosing. As expected, following placebo intervention, performance decreased across the day as participants became cognitively fatigued. However, following berry intervention, participants maintained accuracy on both cognitive tasks up to and including 6 h, and demonstrated quicker response times on the MANT at 2 and 4 h, and TST at 6 h. This study demonstrates the efficacy of flavonoid rich berries in maintaining or improving cognitive performance across the 6 h day.

Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol.

BACKGROUND: Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality. Extracts of Cannabis sativa, and analogues of the major phytocannabinoid Δ9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss. We recently established that the non-psychoactive phytocannabinoid cannabigerol (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin. METHODS: An acute cachectic phenotype was induced in adult male Lister-hooded rats by 6 mg/kg (i.p.) cisplatin. In total 66 rats were randomly allocated to groups receiving vehicle only, cisplatin only, or cisplatin and 60 or 120 mg/kg CBG (po, b.i.d.). Feeding behavior, bodyweight and locomotor activity were recorded for 72 hours, at which point rats were sacrificed for post-mortem analyses. Myofibre atrophy, protein synthesis and autophagy dysregulation were assessed in skeletal muscle, plasma metabolic profiles were obtained by untargeted 1H-NMR metabonomics, and levels of endocannabinoid-like lipoamines quantified in plasma and hypothalami by targeted HPLC-MS/MS lipidomics. RESULTS: CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Y=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Y=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment. CONCLUSIONS: Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models.

Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the TSC1 or TSC2 genes and is characterized by widespread tumour growth, intractable epilepsy, cognitive deficits and autistic behaviour. CBD has been reported to decrease seizures and inhibit tumour cell progression, therefore we sought to determine the influence of CBD on TSC pathology in zebrafish carrying a nonsense mutation in the tsc2 gene. CBD treatment from 6 to 7 days post-fertilization (dpf) induced significant anxiolytic actions without causing sedation. Furthermore, CBD treatment from 3 dpf had no impact on tsc2-/- larvae motility nor their survival. CBD treatment did, however, reduce the number of phosphorylated rpS6 positive cells, and their cross-sectional cell size. This suggests a CBD mediated suppression of mechanistic target of rapamycin (mTOR) activity in the tsc2-/- larval brain. Taken together, these data suggest that CBD selectively modulates levels of phosphorylated rpS6 in the brain and additionally provides an anxiolytic effect. This is pertinent given the alterations in mTOR signalling in experimental models of TSC. Additional work is necessary to identify upstream signal modulation and to further justify the use of CBD as a possible therapeutic strategy to manage TSC.

The effects of acute wild blueberry supplementation on the cognition of 7-10-year-old schoolchildren.

PURPOSE: Previous evidence suggests consumption of flavonoids, a sub-class of polyphenols, is associated with improved cognitive function across the lifespan. In particular, acute intervention of a flavonoid-rich wild blueberry (WBB) drink has been shown to boost executive function (EF), short-term memory and mood 2-6 h post-consumption in 7-10-year-old children. However, confirmation of the aspects of EF and memory susceptible to WBB ingestion is required, particularly during childhood, a critical period of neurological development. In addition, the child literature on berry flavonoid supplementation and cognition highlights the potential for such interventions to elicit positive benefits to real-world educational scenarios, such as reading, a complex ability which relies upon aspects of cognition already known to improve following WBB. METHODS: Here we examined which aspects of EF and memory are susceptible to acute WBB, as well as investigating whether acute WBB could further benefit reading ability. Fifty-four healthy children, aged 7-10 years, consumed a 200 ml WBB drink (253 mg anthocyanins) or a matched placebo according to a randomised, single-blind, parallel-groups design. Verbal memory (Auditory Verbal Learning Task; AVLT), EF (Modified Attention Network Task; MANT), and reading efficiency (Test of Word Reading Efficiency-2; TOWRE-2) were assessed at baseline and 2 h post-consumption. RESULTS: For the MANT, significantly quicker RTs were observed for WBB participants when compared to placebo participants on 120 ms trials, without cost to accuracy. Furthermore, WBB participants showed enhanced verbal memory performance on the AVLT, recalling more words than placebo participants on short delay and memory acquisition measures post-consumption. Despite these significant improvements in cognitive performance, no significant effects were observed for reading measures. CONCLUSION: Consumption of WBB was found to significantly improve memory and attentional aspects of EF. This indicates that a flavonoid-rich blueberry product, equivalent to 240 g or 1½ cups of fresh blueberries can provide acute cognitive benefits in children. These findings support accumulating evidence that flavonoid-rich products are beneficial for healthy brain function, particularly during critical developmental periods. However, the lack of findings relating to reading ability suggested acute WBB may not be sufficient to elicit benefits to reading. Chronic supplementation and other more sensitive reading measures should be considered for examining the effects of WBB on such a complex skill in the future.

A Randomized, Double-Blinded, Placebo-Controlled Study to Compare the Safety and Efficacy of Low Dose Enhanced Wild Blueberry Powder and Wild Blueberry Extract (ThinkBlue™) in Maintenance of Episodic and Working Memory in Older Adults.

Previous research has shown beneficial effects of polyphenol-rich diets in ameliorating cognitive decline in aging adults. Here, using a randomized, double blinded, placebo-controlled chronic intervention, we investigated the effect of two proprietary blueberry formulations on cognitive performance in older adults; a whole wild blueberry powder at 500 mg (WBP500) and 1000 mg (WBP1000) and a purified extract at 100 mg (WBE111). One hundred and twenty-two older adults (65⁻80 years) were randomly allocated to a 6-month, daily regimen of either placebo or one of the three interventions. Participants were tested at baseline, 3, and 6 months on a battery of cognitive tasks targeting episodic memory, working memory and executive function, alongside mood and cardiovascular health parameters. Linear mixed model analysis found intervention to be a significant predictor of delayed word recognition on the Reys Auditory Verbal Learning Task (RAVLT), with simple contrast analysis revealing significantly better performance following WBE111 at 3 months. Similarly, performance on the Corsi Block task was predicted by treatment, with simple contrast analysis revealing a trend for better performance at 3 months following WBE111. Treatment also significantly predicted systolic blood pressure (SBP) with simple contrast analysis revealing lower SBP following intervention with WBE111 in comparison to placebo. These results indicate 3 months intervention with WBE111 can facilitate better episodic memory performance in an elderly population and reduce cardiovascular risk factors over 6 months.

A cannabigerol-rich Cannabis sativa extract, devoid of [INCREMENT]9-tetrahydrocannabinol, elicits hyperphagia in rats.

Nonpsychoactive phytocannabinoids (pCBs) from Cannabis sativa may represent novel therapeutic options for cachexia because of their pleiotropic pharmacological activities, including appetite stimulation. We have recently shown that purified cannabigerol (CBG) is a novel appetite stimulant in rats. As standardized extracts from Cannabis chemotypes dominant in one pCB [botanical drug substances (BDSs)] often show greater efficacy and/or potency than purified pCBs, we investigated the effects of a CBG-rich BDS, devoid of psychoactive [INCREMENT]-tetrahydrocannabinol, on feeding behaviour. Following a 2 h prefeed satiation procedure, 16 male Lister-hooded rats were administered CBG-BDS (at 30-240 mg/kg) or vehicle. Food intake, meal pattern microstructure and locomotor activity were recorded over 2 h. The total food intake was increased by 120 and 240 mg/kg CBG-BDS (1.53 and 1.36 g, respectively, vs. 0.56 g in vehicle-treated animals). Latency to feeding onset was dose dependently decreased at all doses, and 120 and 240 mg/kg doses increased both the number of meals consumed and the cumulative size of the first two meals. No significant effect was observed on ambulatory activity or rearing behaviour. CBG-BDS is a novel appetite stimulant, which may have greater potency than purified CBG, despite the absence of [INCREMENT]-tetrahydrocannabinol in the extract.

Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats.

RATIONALE: The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, ∆(9)-tetrahydrocannabinol (∆(9)-THC). However, we have previously shown that a cannabis extract devoid of ∆(9)-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour. OBJECTIVES: The objective of the study was to assess the effects of CBG on food intake and feeding pattern microstructure. METHODS: Male Lister hooded rats were administered CBG (30-120 mg/kg, per ora (p.o.)) or placebo and assessed in open field, static beam and grip strength tests to determine a neuromotor tolerability profile for this cannabinoid. Subsequently, CBG (at 30-240 mg/kg, p.o.) or placebo was administered to a further group of pre-satiated rats, and hourly intake and meal pattern data were recorded over 2 h. RESULTS: CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120-240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased. CONCLUSIONS: Here, we demonstrate for the first time that CBG elicits hyperphagia, by reducing latency to feed and increasing meal frequency, without producing negative neuromotor side effects. Investigation of the therapeutic potential of CBG for conditions such as cachexia and other disorders of eating and body weight regulation is thus warranted.

A Review of the Cognitive Effects Observed in Humans Following Acute Supplementation with Flavonoids, and Their Associated Mechanisms of Action.

Flavonoids are polyphenolic compounds found in varying concentrations in many plant-based foods. Recent studies suggest that flavonoids can be beneficial to both cognitive and physiological health. Long term flavonoid supplementation over a period of weeks or months has been extensively investigated and reviewed, particularly with respect to cognitive ageing and neurodegenerative disease. Significantly less focus has been directed towards the short term effects of single doses of flavonoids on cognition. Here, we review 21 such studies with particular emphasis on the subclass and dose of flavonoids administered, the cognitive domains affected by flavonoid supplementation, and the effect size of the response. The emerging evidence suggests that flavonoids may be beneficial to attention, working memory, and psychomotor processing speed in a general population. Episodic memory effects are less well defined and may be restricted to child or older adult populations. The evidence also points towards a dose-dependent effect of flavonoids, but the physiological mechanisms of action remain unclear. Overall, there is encouraging evidence that flavonoid supplementation can benefit cognitive outcomes within an acute time frame of 0-6 h. But larger studies, combining cognitive and physiological measures, are needed to strengthen the evidence base.

The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial.

RATIONALE: There has recently been increasing interest in the potential of flavanols, plant-derived compounds found in foods such as fruit and vegetables, to ameliorate age-related cognitive decline. Research suggests that cocoa flavanols improve memory and learning, possibly as a result of their anti-inflammatory and neuroprotective effects. These effects may be mediated by increased cerebral blood flow (CBF), thus, stimulating neuronal function. OBJECTIVES: The present study employed arterial spin labelling functional magnetic resonance imaging to explore the effect of a single acute dose of cocoa flavanols on regional CBF. METHODS: CBF was measured pre- and post-consumption of low (23 mg) or high (494 mg) 330 ml equicaloric flavanol drinks matched for caffeine, theobromine, taste and appearance according to a randomized counterbalanced crossover double-blind design in eight males and ten females, aged 50-65 years. Changes in perfusion from pre- to post-consumption were calculated as a function of each drink. RESULTS: Significant increases in regional perfusion across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, particularly in the anterior cingulate cortex and the central opercular cortex of the parietal lobe. CONCLUSIONS: Consumption of cocoa flavanol improves regional cerebral perfusion in older adults. This provides evidence for a possible acute mechanism by which cocoa flavanols are associated with benefits for cognitive performance.

Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se.

Cannabidiol (CBD) is a non-psychoactive, well-tolerated, anticonvulsant plant cannabinoid, although its mechanism(s) of seizure suppression remains unknown. Here, we investigate the effect of CBD and the structurally similar cannabinoid, cannabigerol (CBG), on voltage-gated Na(+) (NaV) channels, a common anti-epileptic drug target. CBG's anticonvulsant potential was also assessed in vivo. CBD effects on NaV channels were investigated using patch-clamp recordings from rat CA1 hippocampal neurons in brain slices, human SH-SY5Y (neuroblastoma) cells and mouse cortical neurons in culture. CBG effects were also assessed in SH-SY5Y cells and mouse cortical neurons. CBD and CBG effects on veratridine-stimulated human recombinant NaV1.1, 1.2 or 1.5 channels were assessed using a membrane potential-sensitive fluorescent dye high-throughput assay. The effect of CBG on pentyleneterazole-induced (PTZ) seizures was assessed in rat. CBD (10µM) blocked NaV currents in SH-SY5Y cells, mouse cortical neurons and recombinant cell lines, and affected spike parameters in rat CA1 neurons; CBD also significantly decreased membrane resistance. CBG blocked NaV to a similar degree to CBD in both SH-SY5Y and mouse recordings, but had no effect (50-200mg/kg) on PTZ-induced seizures in rat. CBD and CBG are NaV channel blockers at micromolar concentrations in human and murine neurons and recombinant cells. In contrast to previous reports investigating CBD, CBG had no effect upon PTZ-induced seizures in rat, indicating that NaV blockade per se does not correlate with anticonvulsant effects.

A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats.

The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. We demonstrate that a 3-week intervention with two dietary doses of flavonoids (Dose I: 8.7 mg/day and Dose II: 17.4 mg/day) facilitates spatial memory acquisition and consolidation (24 recall) (p < 0.05) in young healthy rats. We show for the first time that these behavioral improvements are linked to increased levels in the polysialylated form of the neural adhesion molecule (PSA-NCAM) in the dentate gyrus (DG) of the hippocampus, which is known to be required for the establishment of durable memories. We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.

A low-Δ9 tetrahydrocannabinol cannabis extract induces hyperphagia in rats.

Appetite stimulation via partial agonism of cannabinoid type 1 receptors by Δtetrahydrocannabinol (ΔTHC) is well documented and can be modulated by non-ΔTHC phytocannabinoids. ΔTHC concentrations sufficient to elicit hyperphagia induce changes to both appetitive (reduced latency to feed) and consummatory (increased meal one size and duration) behaviours. Here, we show that a cannabis extract containing too little ΔTHC to stimulate appetite can induce hyperphagia solely by increasing appetitive behaviours. Twelve, male Lister hooded rats were presatiated before treatment with a low-ΔTHC cannabis extract (0.5, 1.0, 2.0 and 4.0 mg/kg). Hourly intake and meal pattern data were recorded and analyzed using one-way analyses of variance followed by Bonferroni post-hoc tests. The cannabis extract significantly increased food intake during the first hour of testing (at 4.0 mg/kg) and significantly reduced the latency to feed versus vehicle treatments (at doses ≥1.0 mg/kg). Meal size and duration were unaffected. These results show only the increase in appetitive behaviours, which could be attributed to non-ΔTHC phytocannabinoids in the extract rather than ΔTHC. Although further study is required to determine the constituents responsible for these effects, these results support the presence of non-ΔTHC cannabis constituent(s) that exert a stimulatory effect on appetite and likely lack the detrimental psychoactive effects of ΔTHC.

Cannabis constituents modulate δ9-tetrahydrocannabinol-induced hyperphagia in rats.

RATIONALE: The hyperphagic effect of Delta9-tetrahydrocannabinol (Delta9THC) in humans and rodents is well known. However, no studies have investigated the importance of Delta9THC composition and any influence other non-Delta9THC cannabinoids present in Cannabis sativa may have. We therefore compared the effects of purified Delta9THC, synthetic Delta9THC (dronabinol), and Delta9THC botanical drug substance (Delta9THC-BDS), a Delta9THC-rich standardized extract comparable in composition to recreationally used cannabis. METHODS: Adult male rats were orally dosed with purified Delta9THC, synthetic Delta9THC, or Delta9THC-BDS, matched for Delta9THC content (0.34-2.68 mg/kg). Prior to dosing, subjects were satiated, and food intake was recorded following Delta9THC administration. Data were then analyzed in terms of hourly intake and meal patterns. RESULTS: All three Delta9THC substances tested induced significant hyperphagic effects at doses >or=0.67 mg/kg. These effects included increased intake during hour one, a shorter latency to onset of feeding and a greater duration and consumption in the first meal. However, while some differences in vehicle control intakes were observed, there were significant, albeit subtle, differences in pattern of effects between the purified Delta9THC and Delta9THC-BDS. CONCLUSION: All Delta9THC compounds displayed classical Delta9THC effects on feeding, significantly increasing shortterm intake whilst decreasing latency to the first meal. We propose that the subtle adjustment to the meal patterns seen between the purified Delta9THC and Delta9THC-BDS are due to non-Delta9THC cannabinoids present in Delta9THC-BDS. These compounds and other non-cannabinoids have an emerging and diverse pharmacology and can modulate Delta9THC-induced hyperphagia, making them worth further investigation for their therapeutic potential.