Emma L. Wightman

Herbal Extracts and Phytochemicals: Plant Secondary Metabolites and the Enhancement of Human Brain function

Humans consume a wide range of foods, drugs, and dietary supplements that are derived from plants and which modify the functioning of the central nervous sytem (CNS). The psychoactive properties of these substances are attributable to the presence of plant secondary metabolites, chemicals that are not required for the immediate survival of the plant but which are synthesized to increase the fitness of the plant to survive by allowing it to interact with its environment, including pathogens and herbivorous and symbiotic insects. In many cases, the effects of these phytochemicals on the human CNS might be linked either to their ecological roles in the life of the plant or to molecular and biochemical similarities in the biology of plants and higher animals. This review assesses the current evidence for the efficacy of a range of readily available plant-based extracts and chemicals that may improve brain function and which have attracted sufficient research in this regard to reach a conclusion as to their potential effectiveness as nootropics. Many of these candidate phytochemicals/extracts can be grouped by the chemical nature of their potentially active secondary metabolite constituents into alkaloids (caffeine, nicotine), terpenes (ginkgo, ginseng, valerian, Melissa officinalis, sage), and phenolic compounds (curcumin, resveratrol, epigallocatechin-3-gallate, Hypericum perforatum, soy isoflavones). They are discussed in terms of how an increased understanding of the relationship between their ecological roles and CNS effects might further the field of natural, phytochemical drug discovery.

Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation

BACKGROUND The many putative beneficial effects of the polyphenol resveratrol include an ability to bolster endogenous antioxidant defenses, modulate nitric oxide synthesis, and promote vasodilation, which thereby improves blood flow. Resveratrol may therefore modulate aspects of brain function in humans. OBJECTIVE The current study assessed the effects of oral resveratrol on cognitive performance and localized cerebral blood flow variables in healthy human adults. DESIGN In this randomized, double-blind, placebo-controlled, crossover study, 22 healthy adults received placebo and 2 doses (250 and 500 mg) of trans-resveratrol in counterbalanced order on separate days. After a 45-min resting absorption period, the participants performed a selection of cognitive tasks that activate the frontal cortex for an additional 36 min. Cerebral blood flow and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated hemoglobin, were assessed in the frontal cortex throughout the posttreatment period with the use of near-infrared spectroscopy. The presence of resveratrol and its conjugates in plasma was confirmed by HPLC after the same doses in a separate cohort (n = 9). RESULTS Resveratrol administration resulted in dose-dependent increases in cerebral blood flow during task performance, as indexed by total concentrations of hemoglobin. There was also an increase in deoxyhemoglobin after both doses of resveratrol, which suggested enhanced oxygen extraction, that became apparent toward the end of the 45-min absorption phase and was sustained throughout task performance. Cognitive function was not affected. Resveratrol metabolites were present in plasma throughout the cognitive task period. CONCLUSION These results showed that single doses of orally administered resveratrol can modulate cerebral blood flow variables.

Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double-blind, placebo-controlled, cross-over investigation

Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.

Epigallocatechin gallate, cerebral blood flow parameters, cognitive performance and mood in healthy humans: a double-blind, placebo-controlled, crossover investigation.

The aim of the study was to assess the effects of oral ingestion of the ‘green tea’ polyphenol epigallocatechin gallate (EGCG) on cognitive performance, mood and localised cerebral blood flow (CBF) parameters in healthy human adults.

Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation☆ , ☆☆

Nitrate derived from vegetables is consumed as part of a normal diet and is reduced endogenously via nitrite to nitric oxide. It has been shown to improve endothelial function, reduce blood pressure and the oxygen cost of sub-maximal exercise, and increase regional perfusion in the brain. The current study assessed the effects of dietary nitrate on cognitive performance and prefrontal cortex cerebral blood-flow (CBF) parameters in healthy adults. In this randomised, double-blind, placebo-controlled, parallel-groups study, 40 healthy adults received either placebo or 450 ml beetroot juice (~5.5 mmol nitrate). Following a 90 minute drink/absorption period, participants performed a selection of cognitive tasks that activate the frontal cortex for 54 min. Near-Infrared Spectroscopy (NIRS) was used to monitor CBF and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated-haemoglobin, in the frontal cortex throughout. The bioconversion of nitrate to nitrite was confirmed in plasma by ozone-based chemi-luminescence. Dietary nitrate modulated the hemodynamic response to task performance, with an initial increase in CBF at the start of the task period, followed by consistent reductions during the least demanding of the three tasks utilised. Cognitive performance was improved on the serial 3s subtraction task. These results show that single doses of dietary nitrate can modulate the CBF response to task performance and potentially improve cognitive performance, and suggest one possible mechanism by which vegetable consumption may have beneficial effects on brain function.

Behavioural effects of compounds co-consumed in dietary forms of caffeinated plants

Research into the cognitive and mood effects of caffeine in human subjects has highlighted some fairly robust and well-accepted effects. However, the majority of these studies have focused on caffeine in isolation; whilst caffeine is normally consumed in the form of plant-derived products and extracts that invariably contain other potentially bioactive phytochemicals. The aim of the present review is to consider the possible mechanisms of action of co-occurring phytochemicals, and any epidemiological evidence suggesting that they contribute to potential health benefits ascribed to caffeine. Intervention studies to date that have been conducted to explore the effects on brain function of the non-caffeine components in caffeine-bearing plants (coffee, tea, cocoa, guaraná), either alone or in combination with caffeine, will also be summarised. Research is beginning to accumulate showing independent effects for several of the phytochemicals that co-occur with caffeine, and/or a modulation of the effects of caffeine when it is co-consumed with these naturally concomitant phytochemicals. The present review highlights that more research aimed at understanding the effects of these compounds is needed and, more importantly, the synergistic relationship that they may have with caffeine.

Cognitive and Mood Effects of a Nutrient Enriched Breakfast Bar in Healthy Adults: A Randomised, Double-Blind, Placebo-Controlled, Parallel Groups Study

Objectives: Few previous studies have assessed the effects of concomitant administration of multiple potentially psychoactive nutrients. Methods: 95 healthy adult participants consumed either a nutrient enriched breakfast bar (containing α-Linolenic acid, l-tyrosine, l-theanine, vitamins, minerals and 21.5 mg of caffeine) or an isocaloric, macronutrient matched control bar for 56 days. Cognitive function and mood were assessed pre-dose and at 40- and 160-min post-dose on the 1st and 56th day of the intervention period. Results: The results demonstrated acute effects of treatment across post-dose assessments on both assessment days in terms of alertness, and on tasks assessing attention, working and episodic memory and executive function, including cognitively demanding Serial subtraction and Rapid Visual Information Processing tasks. There were no evident chronic effects independent of the breakfast bars’ acute effects. Discussion: These results demonstrate that a nutrient enriched breakfast bar with low caffeine content can exert striking beneficial effects on acute cognitive function and alertness.

Chapter 27:Medicinal Plants, Phytochemicals and Alzheimer's Disease

Natural, plant-derived products have been used by humans for a number of millennia as medical treatments, including for CNS disorders such as cognitive decline. Plants are an important source of pharmacologically active chemical entities. Over the last 25 years a sizeable minority of new, registered drugs have been derived from, or mimic, phytochemicals. These include galantamine, an alkaloid used for the treatment of cognitive declines associated with Alzheimers disease (AD). The active components of plant based products are generally secondary metabolites, with the majority falling into the chemical structural groups of alkaloids, terpenoids and phenolics. Members of these chemical classes play differing roles in the ecological life of plants, and subsequently exert differing profiles of costs/benefits in terms of efficacy and tolerability in humans. Potential, novel plant based treatments for the symptoms or causes of AD that are reviewed here include the alkaloid-huperzine A, a number of extracts with terpenoid bioactives-including Gingko biloba, Salvia officinalis/lavandulaefolia, Melissa officinalis and Bacopa monniera, and a range of phenolics, including the single molecule polyphenols-resveratrol, curcumin and epigallocatechin gallate. This latter group, which are edible components of everyday foods, are particularly promising and have garnered substantial basic research. However, their potential beneficial properties require confirmation in human trials.Taken as a whole, the extant evidence regarding potential plant based treatments for AD suggests that extracts containing multiple terpenoids, and multiple or single phenolics that are found in common foodstuffs may have roles to play in treating or slowing the onset of AD.

The Acute and Chronic Cognitive and Cerebral Blood Flow Effects of a Sideritis scardica (Greek Mountain Tea) Extract: A Double Blind, Randomized, Placebo Controlled, Parallel Groups Study in Healthy Humans

Background: The presence of polyphenols such as hydroxy-cinnamic acids and flavonoids in Sideritis scardica (Greek mountain tea) are likely responsible for the cognitive and mood effects of its consumption and this could be underpinned by the ability of such polyphenols to prevent monoamine neurotransmitter reuptake and to increase cerebral blood flow (CBF). Objective: The current study extends the small amount of Sideritis scardica literature in humans by assessing both cognitive and mood outcomes in a sample of older adults, as well as blood pressure (BP) and CBF, in a subsample, utilizing near-infrared spectroscopy (NIRS). Design: This randomized, double-blind, placebo-controlled, parallel groups trial randomized N = 155, 50–70-year-old male and female participants who were assessed for the cognitive (N = 140), mood (N = 142), BP (N = 133) and CBF (N = 57) effects of two doses of Greek mountain tea (475 and 950 mg) as well as an active control of 240 mg Ginkgo biloba, and a placebo control, following acute consumption (Day 1) and following a month-long consumption period (Day 28). Results: Relative to the placebo control, 950 mg Greek mountain tea evinced significantly fewer false alarms on the Rapid Visual Information Processing (RVIP) task on Day 28 and significantly reduced state anxiety following 28 days consumption (relative also to the active, Ginkgo control). This higher dose of Greek mountain tea also attenuated a reduction in accuracy on the picture recognition task, on Day 1 and Day 28, relative to Ginkgo and both doses of Greek mountain tea trended towards significantly faster speed of attention on both days, relative to Ginkgo. Both doses of Greek mountain tea, relative to placebo, increased oxygenated haemoglobin (HbO) and oxygen saturation (Ox%) in the prefrontal cortex during completion of cognitively demanding tasks on Day 1. The higher dose also evinced greater levels of total (THb) and deoxygenated (Hb) haemoglobin on Day 1 but no additional effects were seen on CBF on Day 28 following either dose of Greek mountain tea. Ginkgo biloba led to lower levels of Ox% and higher levels of Hb on Day 1 and lower levels of both HbO and THb on Day 28. Conclusions: The significantly improved cognitive performance following Greek mountain tea on Day 1 could be due to significant modulation of the CBF response. However, these improvements on Day 28 are more likely to be due to the reductions in state anxiety and, taken together, suggests that the former mechanism is more likely to facilitate acute cognitive effects and the latter more likely to underpin more prolonged cognitive improvements.

Volatile terpenes and brain function : investigation of the cognitive and mood effects of Mentha × Piperita l. essential oil with in vitro properties relevant to central nervous system function.

Background: Extracts of several members of the monoterpene-rich Lamiaceae sub-family Nepetoideae, including those from the Salvia (sage), Melissa (Lemon balm) and Rosmarinus (rosemary) genera, evince cognitive and mood effects in humans that are potentially related to their effects on cholinergic and GABAergic neurotransmission. To date, despite promising in vitro properties, the cognitive and mood effects of the closely related Mentha spicata (spearmint) and Mentha piperita (peppermint) remain unexplored. This study therefore assessed the human cognitive/mood effects of the M. spicata/piperita essential oil with the most promising, brain-relevant in vitro properties according to pre-trial in vitro screening. Design: Organic spearmint and peppermint (Mentha spicata/piperita) essential oils were pre-screened for neurotransmitter receptor binding and acetylcholinesterase (AChE) inhibition. In a double-blind, placebo-controlled, balanced cross-over study, 24 participants (mean age 25.2 years) consumed single doses of encapsulated placebo and 50 µL and 100 µL of the most promising essential oil (peppermint with nicotinic/GABAA receptor binding and AChE inhibitory properties, that increased calcium influx in a CAD cell neuronal model). Psychological functioning was assessed with mood scales and a range of standardised, cognitively demanding tasks pre-dose and at 1, 3 and 6 h post-dose. Results: The highest (100 µL) dose of essential oil improved performance on the cognitively demanding Rapid Visual Information Processing task (RVIP) at 1 h and 3 h post-dose and both doses attenuated fatigue and improved performance of the Serial 3 s subtraction task at 3 h post-dose. Conclusion: Peppermint (Mentha piperita) essential oil with high levels of menthol/menthone and characteristic in vitro cholinergic inhibitory, calcium regulatory and GABAA/nicotinic receptor binding properties, beneficially modulated performance on demanding cognitive tasks and attenuated the increase in mental fatigue associated with extended cognitive task performance in healthy adults. Future investigations should consider investigating higher doses.