David O. Kennedy

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.

Glucose administration, heart rate and cognitive performance: effects of increasing mental effort

Abstract  Rationale: It is known that glucose administration is capable of improving performance on tests of declarative verbal memory and non-mnemonic tasks requiring high ”mental effort”. At the same time, cognitively demanding tasks are associated with elevated heart rate, a response that could feasibly be part of a physiological mechanism serving to increase the delivery of glucose to active brain substrates. Objective: The present placebo-controlled, double-blind, balanced, crossover study examined the interaction between glucose administration, cognitive performance and heart rate during three tasks of differing mental demand and somatically-matched control tasks. Methods: The effects of a glucose drinkon participants’ performance on two serial subtraction tasks (Serial Threes and Serial Sevens) and a Word Retrieval (Verbal Fluency) task were assessed. Heart rates were monitored throughout the experiment, and participants rated each task in terms of its perceived mental demand. Results: Serial Sevens was rated as the most mentally demanding task, followed by Word Retrieval, then Serial Threes. Glucose consumption significantly improved performance on Serial Sevens, with a trend for improved performance on Word Retrieval. Both Serial Sevens and Serial Threes were associated with significant heart rate elevation above that seen in somatically matched control tasks (ruling out the possibility that accelerated heart rate was due to peripheral mechanisms alone). Unexpectedly, participants in the glucose condition had higher heart rates during cognitive processing. Additionally, individuals whose baseline heart rates were below the median performed better on Serial Threes and Serial Sevens. Conclusion: We suggest that supplemental glucose preferentially targets tasks with a relatively high cognitive load, which itself (through unknown mechanisms) mobilises physiological reserves as part of a natural response to such tasks. Furthermore, baseline heart rate and responses to cognitive demand and glucose administration may represent important physiological individual differences.

Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort

Cocoa flavanols (CF) positively influence physiological processes in ways that suggest their consumption may improve aspects of cognitive function. This study investigated the acute cognitive and subjective effects of CF consumption during sustained mental demand. In this randomized, controlled, double-blinded, balanced, three period crossover trial 30 healthy adults consumed drinks containing 520 mg, 994 mg CF and a matched control, with a three-day washout between drinks. Assessments included the state anxiety inventory and repeated 10-min cycles of a Cognitive Demand Battery comprising of two serial subtraction tasks (Serial Threes and Serial Sevens), a Rapid Visual Information Processing (RVIP) task and a ‘mental fatigue’ scale, over the course of 1 h. Consumption of both 520 mg and 994 mg CF significantly improved Serial Threes performance. The 994 mg CF beverage significantly speeded RVIP responses but also resulted in more errors during Serial Sevens. Increases in self-reported ‘mental fatigue’ were significantly attenuated by the consumption of the 520 mg CF beverage only. This is the first report of acute cognitive improvements following CF consumption in healthy adults. While the mechanisms underlying the effects are unknown they may be related to known effects of CF on endothelial function and blood flow.

Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm).

Objective: Melissa officinalis (lemon balm) is contemporaneously used as a mild sedative and/or calming agent. Although recent research has demonstrated modulation of mood in keeping with these roles, no studies to date have directly investigated the effects of this herbal medication on laboratory-induced psychological stress. Methods: In this double-blind, placebo-controlled, randomized, balanced crossover experiment, 18 healthy volunteers received two separate single doses of a standardized M. officinalis extract (300 mg, 600 mg) and a placebo, on separate days separated by a 7-day washout period. Modulation of mood was assessed during predose and 1-hour postdose completions of a 20-minute version of the Defined Intensity Stressor Simulation (DISS) battery. Cognitive performance on the four concurrent tasks of the battery was also assessed. Results: The results showed that the 600-mg dose of Melissa ameliorated the negative mood effects of the DISS, with significantly increased self-ratings of calmness and reduced self-ratings of alertness. In addition, a significant increase in the speed of mathematical processing, with no reduction in accuracy, was observed after ingestion of the 300-mg dose. Conclusion: These results suggest that the potential for M. officinalis to mitigate the effects of stress deserves further investigation.

Modulation of Mood and Cognitive Performance Following Acute Administration of Single Doses of Melissa Officinalis (Lemon Balm) with Human CNS Nicotinic and Muscarinic Receptor-Binding Properties

Melissa officinalis (Lemon balm) is a herbal medicine that has traditionally been attributed with memory-enhancing properties, but which is currently more widely used as a mild sedative and sleep aid. In a previous study it was demonstrated that a commercial Melissa extract led to dose-specific increases in calmness, and dose-dependent decrements in timed memory task performance. However, the extract utilized in that study did not exhibit in vitro cholinergic receptor-binding properties. The current study involved an initial screening of samples of M. officinalis for human acetylcholinesterase inhibition and cholinergic receptor-binding properties. The cognitive and mood effects of single doses of the most cholinergically active dried leaf were then assessed in a randomized, placebo-controlled, double-blind, balanced crossover study. Following the in vitro analysis, 20 healthy, young participants received single doses of 600, 1000, and 1600 mg of encapsulated dried leaf, or a matching placebo, at 7-day intervals. Cognitive performance and mood were assessed predose and at 1, 3, and 6 h postdose using the Cognitive Drug Research computerized assessment battery and Bond–Lader visual analog scales, respectively. In vitro analysis of the chosen extract established IC50 concentrations of 0.18 and 3.47 mg ml−1, respectively, for the displacement of [3H]-(N)-nicotine and [3H]-(N)-scopolamine from nicotinic and muscarinic receptors in the human cerebral cortex tissue. However, no cholinesterase inhibitory properties were detected. The most notable cognitive and mood effects were improved memory performance and increased ‘calmness’ at all postdose time points for the highest (1600 mg) dose. However, while the profile of results was overwhelmingly favorable for the highest dose, decrements in the speed of timed memory task performance and on a rapid visual information-processing task increased with decreasing dose. These results suggest that doses of Melissa officinalis at or above the maximum employed here can improve cognitive performance and mood and may therefore be a valuable adjunct in the treatment of Alzheimers disease. The results also suggest that different preparations derived from the same plant species may exhibit different properties depending on the process used for the sample preparation.

A low glycaemic index breakfast cereal preferentially prevents children's cognitive performance from declining throughout the morning

This study investigated whether the glycaemic index (GI) of breakfast cereal differentially affects childrens attention and memory. Using a balanced cross-over design, on two consecutive mornings 64 children aged 6-11 years were given a high GI cereal and a low GI cereal in a counterbalanced order. They performed a series of computerised tests of attention and memory, once prior to breakfast and three times following breakfast at hourly intervals. The results indicate that childrens performance declines throughout the morning and that this decline can be significantly reduced following the intake of a low GI cereal as compared with a high GI cereal on measures of accuracy of attention (M=-6.742 and -13.510, respectively, p<0.05) and secondary memory (M=-30.675 and -47.183, respectively, p<0.05).

DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial

BACKGROUND Docosahexaenoic acid (DHA) is important for brain function, and its status is dependent on dietary intakes. Therefore, individuals who consume diets low in omega-3 (n-3) polyunsaturated fatty acids may cognitively benefit from DHA supplementation. Sex and apolipoprotein E genotype (APOE) affect cognition and may modulate the response to DHA supplementation. OBJECTIVES We investigated whether a DHA supplement improves cognitive performance in healthy young adults and whether sex and APOE modulate the response. DESIGN Healthy adults (n = 176; age range: 18-45 y; nonsmoking and with a low intake of DHA) completed a 6-mo randomized, placebo-controlled, double-blind intervention in which they consumed 1.16 g DHA/d or a placebo. Cognitive performance was assessed by using a computerized cognitive test battery. For all tests, z scores were calculated and clustered into cognitive domains as follows: episodic and working memory, attention, reaction time (RT) of episodic and working memory, and attention and processing speed. ANCOVA was conducted with sex and APOE as independent variables. RESULTS RTs of episodic and working memory improved with DHA compared with placebo [mean difference (95% CI): -0.18 SD (-0.33, -0.03 SD) (P = 0.02) and -0.36 SD (-0.58, -0.14 SD) (P = 0.002), respectively]. Sex × treatment interactions occurred for episodic memory (P = 0.006) and the RT of working memory (P = 0.03). Compared with the placebo, DHA improved episodic memory in women [0.28 SD (0.08, 0.48 SD); P = 0.006] and RTs of working memory in men [-0.60 SD (-0.95, -0.25 SD); P = 0.001]. APOE did not affect cognitive function, but there were some indications of APOE × sex × treatment interactions. CONCLUSIONS DHA supplementation improved memory and the RT of memory in healthy, young adults whose habitual diets were low in DHA. The response was modulated by sex. This trial was registered at the New Zealand Clinical Trials Registry (http://www.anzctr.org.au/default.aspx) as ACTRN12610000212055.

Salvia lavandulaefolia (Spanish Sage) enhances memory in healthy young volunteers

Sage (Salvia) has a longstanding reputation in British herbal encyclopaedias as an agent that enhances memory, although there is little evidence regarding the efficacy of sage from systematized trials. Based on known pharmacokinetic and binding properties, it was hypothesised that acute administration of sage would enhance memory in young adult volunteers. Two experiments utilised a placebo-controlled, double-blind, balanced, crossover methodology. In Trial 1, 20 participants received 50, 100 and 150 microl of a standardised essential oil extract of Salvia lavandulaefolia and placebo. In Trial 2, 24 participants received 25 and 50 microl of a standardised essential oil extract of S. lavandulaefolia and placebo. Doses were separated by a 7-day washout period with treatment order determined by Latin squares. Assessment was undertaken using the Cognitive Drug Research computerised test battery prior to treatment and 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were immediate and delayed word recall. The 50 microl dose of Salvia essential oil significantly improved immediate word recall in both studies. These results represent the first systematic evidence that Salvia is capable of acute modulation of cognition in healthy young adults.

Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults

It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax ginseng, and a combination of the two extracts can improve different aspects of cognitive performance in healthy young volunteers. The present study directly compared the effects of single doses of G. biloba, ginseng, and a product combining the two on aspects of mood and cognitive performance in the same cohort of healthy, young adult volunteers. The study followed a randomised placebo-controlled, double-blind, balanced, cross-over design. Twenty participants received 360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts, and a matching placebo. Treatment order was dictated by random allocation to a Latin square, with a 7-day wash-out period between treatments. Cognitive testing comprised completion of the Cognitive Drug Research (CDR) computerised assessment battery and two serial subtraction mental arithmetic tasks. Mood was assessed with Bond-Lader visual analogue scales. Following a baseline cognitive assessment, further test sessions took place 1, 2.5, 4, and 6 h after the days treatment was taken. The results largely supported previous findings. All three treatments were associated with improved secondary memory performance on the CDR battery, with the ginseng condition evincing some improvement in the speed of performing memory tasks and in the accuracy of attentional tasks. Following ginkgo and the ginkgo/ginseng combination performance of both the Serial Threes and Serial Sevens, subtraction tasks was also improved at the later testing sessions. No modulation of the speed of performing attention tasks was evident. Improvements in self-rated mood was also found following ginkgo and to a lesser extent the combination product.