Bacopa monniera Wettst. (Water hyssop)

Bacopa monniera has been used in Ayurvedic medicine for some 3000 years. Its traditional and contemporary indications include anxiety and cognitive performance and the active constituents are thought to be triterpenoid saponins, of which the most prevalent are known as bacoside A and B.

Potential CNS-relevant mechanisms include an enhancement of protein kinase activity in the hippocampus, interactions with the cholinergic and monoaminergic neurotransmitter systems, and antioxidant properties.

Bacopa monniera extracts have been shown in animal models to protect cognitive function in the face of a number of challenges and exert anxiolytic effects in stress paradigms.

In humans the behavioural effects have received little methodical attention. However, several double-blind, placebo-controlled studies have assessed the cognitive and mood effects of Bacopa monniera extracts. In the first of these Stough et al. (2001a) investigated the effects of 5 and 12 weeks’ administration of 300 mg of a standardised (55% bacosides) extract in 46 healthy adult participants. By the 12-week endpoint, self-ratings of ‘anxiety state’, and cognitive tasks assessing speed of early information processing, verbal learning rate and memory consolidation were beneficially modulated in the group taking extract.

A second study using the same extract, involving 76 middle-aged participants, demonstrated a lack of any cognitive or mood effect following 3 months’ administration of 300 or 450 mg extract (depending on body weight). However, an assessment 6 weeks after the end of the trial showed that the group taking extract had outperformed placebo on a single task, a ‘delayed recall of word pairs’ task. The authors tentatively interpret this as a possible attenuation of ‘forgetting’, but allow for the effect being a statistical anomaly. Given the lack of a clear effect from these two studies, Bacopa monniera requires further research.

Ginkgo biloba L. (Gingko)

Ginkgo biloba extract contains a number of species-specific flavonoids and the terpenoids: bilobalide and ginkgolides A, B, C and J. Potential CNS-relevant mechanisms of action include:

• a potential antagonism of platelet activating factor

• enhanced nitric oxide bioavailability

• scavenging and inhibition of free radicals

• modulation of a number of neurotransmitter systems

• beneficial effects on blood viscosity and circulation

• both in-vitro and in-vivo protection against hypoxic challenges

• in-vivo neuro-protective properties

• increased cerebral perfusion in humans.

There is also some evidence of cognitive enhancement in both younger and older ‘cognitively intact’ populations administered 120 mg or 180 mg of gingko extract for 7 days or longer, although evidence in this respect is not unequivocal.

Several placebo-controlled, balanced crossover experiments, with relatively small sample sizes have also demonstrated improved cognitive performance in young adults following single doses of GBE. In the last of these studies, Kennedy et al. (2000) demonstrated linear, dose-dependent speeding of attention task performance for the two highest doses under investigation (240 mg, 360 mg gingko extract), and improved memory following the lowest dose (120 mg) in 20 participants. A later re-analysis of the data for the lowest dose not only confirmed this memory enhancement effect but also suggested modest but significant slowing on attention tasks following this typical daily dose.

A large number of studies have assessed the efficacy of chronic administration of Ginkgo biloba in the amelioration of the cognitive declines associated with ageing and dementia. In this respect a comprehensive Cochrane review meta-analysed the 33 extant studies involving cohorts with dementia or age-related cognitive impairment that met their inclusion criteria. The authors concluded that ‘Overall there is promising evidence of improvement in cognition and function associated with Ginkgo‘. However, in a recent update and re-analysis, Birks and Grimley-Evans (2007) added a further three studies and deleted two studies and, in terms of cognitive function, fractionated their analyses by the length of treatment and the instrument employed. While there was evidence of improvement either following some treatment durations or dependent on the cognitive assessment instrument utilised, their revised overall conclusion was that the evidence with regards overall efficacy in dementia or cognitive impairment is ‘inconsistent and unconvincing’.

Two potentially interesting randomised, controlled trials have also been published recently. Napryeyenko and Borzenko (2007) investigated the effects of ginkgo in 400 patients with mild-to-moderate dementia who also had concomitant neuropsychiatric symptoms (who would be expected to show more rapid decline than average) and demonstrated significant improvements in cognitive functioning and neuropsychiatric symptoms following 6 months’ treatment with the extract Egb 761. A single trial has also assessed the effects of two doses of Egb 761 in people with anxiety disorders. Results showed a significant dose-related improvement in Hamilton Rating Scale for Anxiety and a number of clinical measures. With regards safety, Birks and Evans (2007) conclude that Ginkgo biloba appears to be safe and comparable with placebo in terms of negative side-effects across studies.

Panax ginseng C.A. Mey. (Ginseng)

‘Ginseng’ is generally taken to refer to the dried root of several species in the plant genus Panax (Araliaceae family). The most widely used family member is Panax ginseng, which has a medicinal history stretching back more than 5000 years.

The major active constituents of the Panax genus are thought to be the species-specific saponins, also known as ginsenosides, of which over 30 have been identified.

Ginsenosides have a number of effects relevant to general health, including bolstering of the immune system, anti-inflammatory, antihepatotoxic and anti-carcinogenic effects. With regards to brain function, ginseng exerts a number of central and peripheral physiological effects that are potentially relevant. These include a host of neuro-protective properties, cardiovascular effects, modulation of the hypothalamic-pituitary-adrenal axis, neurotransmission, and glucoregulation. While ginsenosides are known to exert a plethora of effects at a cellular level, a number of authors have suggested that the modulation of nitric oxide synthesis contributes to many of their wider effects including those within the CNS.

Animal behaviour models suggest that ginsenosides have antistress and anxiolytic effects, moderate fatigue, improve memory in impaired rodents and improve learning and memory in several hippocampal/amygdala-dependent behavioural tasks in intact rodents. Potential mechanisms of the latter include the ability to foster neurogenesis and modulate long-term potentiation in the hippocampus.

In humans there is no clear evidence from controlled studies of ergogenic or antifatigue effects. Similarly, while a number of studies have demonstrated improvements in subjective ‘wellbeing’ or ‘quality of life’ attributable to ginseng monotherapy, a number of other studies have failed to find this effect. However, it should be noted that the lack of clear efficacy in these domains may reflect methodological shortcomings.

A number of randomised, double-blind, placebo-controlled, balanced-crossover studies investigating single doses of Panax ginseng have identified positive cognitive effects in healthy young adults. The most consistent finding is of improved secondary memory performance following standardised ginseng extract G115 alone, and in combination with both Ginkgo biloba and guarana (Paullinia cupana). Improvements have also been noted in the speed of performing attention tasks and significantly shortened latency of the P300 component of auditory evoked potentials measured by EEG, along with overall topographical modulation of electrical activity.

Two studies have also concomitantly measured glucoregulatory effects and cognitive performance during ‘glucose sensitive’, mentally demanding task performance. In the first of these, Reay et al. (2005) demonstrated significantly reduced fasted blood glucose levels and concomitant improvements in performance and reductions in self-ratings of mental fatigue in healthy young participants following 200 mg or 400 mg of G115. In the second study, Reay et al. (2006) used the same methodology and the most effective dose from the previous study (200 mg) but added a further factor: presence or absence of glucose 75 g. The results directly replicated the cognitive improvements, attenuation of mental fatigue and reduced blood glucose levels seen following ginseng alone in the previous study, but showed that these effects were largely abolished by coadministration with glucose.

The cognitive effects of longer-term dosage with ginseng has not been investigated to a great extent. In two early, double-blind, placebo-controlled studies, D’ Angelo et al. (1986) and Sorensen and Sonne (1996) demonstrated improvements restricted to one or two task outcomes from within a large selection of tasks following ginseng 200 mg and 400 mg/day. Similarly, a recent double-blind, placebo-controlled pilot study (n = 16) using a balanced crossover design in an investigation of 8 weeks’ treatment with 200 mg Korean Panax ginseng demonstrated improvements that were limited to two working memory tasks from within a larger battery, and one (social relations) of four scales from within the World Health Organization – Quality of Life scale.

Panax ginseng monopreparations are rarely associated with adverse events or drug interactions.

Salvia officinalis L. and Salvia lavandulifolia Vahl (Sage)

The most commonly consumed species of the large genus Salvia are Salvia officinalis (garden sage) and Salvia lavandulaefolia (Spanish sage). Indications have traditionally included beneficial central nervous system effects, principally with regards mood and memory.

It has been suggested that the monoterpenoid constituents of sage, e.g. 1,8-cineole, contribute to the physiological activity of the whole herb. Extracts also contain a number of polyphenolic compounds, most notably rosmarinic acid and methyl carnosate. Concentration-dependent inhibition of acetylcholin-esterase in postmortem human brain homogenates was demonstrated by essential oils of both herbs and alcoholic extracts of both fresh and dried Salvia officinalis leaf and dose-dependent inhibition of human acetylcholinesterase by Spanish sage essential oil has also been shown and in vivo in the striatum and hippocampus of aged rats following oral administration.

Acetylcholinesterase inhibition has been shown to involve synergistic interactions and antagonisms. Two studies have also demonstrated inhibition of butyrylcholinesterase in human erythrocytes and others have shown the antioxidant and free-radical scavenging properties of both sages. This latter study also demonstrated anti-inflammatory actions by the extract and its geraniol and α-pinene monoterpenoid constituents.

Several other potentially CNS-relevant properties have also been demonstrated including an oestrogenic activity of Spanish sage and the monoterpenoid component geraniol and benzodiazepine receptor binding by fractions of a methanol extract of Salvia officinalis.

Five double-blind, placebo-controlled, randomised, balanced-crossover studies in healthy humans have assessed the behavioural effects of single doses of sage with in-vitro cholinesterase-inhibiting properties (the number of participants was 20, 24, 20, 30, 36 respectively). Tildesley et al. (2003) assessed the effects of three doses of S. lavandulaefolia essential oil and showed significant memory improvements in 20 healthy young participants following the two lowest doses (50 µL, 100 µL). In a subsequent study, Tildesley et al. (2005) examined the effects of 25 and 50 µL of the same oil in 24 participants and demonstrated that improved memory performance was most marked for the lowest dose of 25µL. Both doses also resulted in significantly increased ratings of ‘contentedness’ and ‘calmness’.

The memory-enhancing effects in a healthy young population have also been confirmed in a recent study into the effects of 50 µL Salvia officinalis essential oil. This study also demonstrated improved mood (alertness) and reduced ratings of mental fatigue during an extended period of cognitive demand. A further study assessed the effects of four separate single doses of an ethanolic extract of Salvia officinalis in an elderly cohort. Once again the results showed clear improvements in memory performance, with this most marked for the lower two doses.

In one further study, Kennedy et al. (2006) also assessed the effects of two doses (300, 600 mg) of dried Salvia officinalis leaf with both acetylcholinesterase and butyrylcholinesterase-inhibitory properties on mood and performance of a psychological stressor multitasking battery. The results showed that the lower dose reduced anxiety and the higher dose increased ratings of ‘alertness’, ‘calmness’ and ‘contentedness’. Task performance was also improved for the higher dose at both post-dose sessions, but reduced for the lower dose at the later testing session.

A single, double-blind, placebo-controlled trial has also assessed the effects of 16 weeks’ administration of an Salvia officinalis alcoholic tincture in 30 patients with Alzheimer’s disease. Those in the verum group were shown to have significantly improved scores on the Alzheimer’s Disease Clinical Assessment Scale cognitive subscale (ADAS-cog) at the study endpoint at 16 weeks. Clinical dementia rating scores were also significantly improved at the end of the study.

Related posts:

1. DEMENTIA   Weitbrecht and Jansen (1986) studied the effects of Ginkgo Biloba Extract 761 (120mg/day) compared with placebo and ergot alkaloids (5.94mg/day) in patients suffering from mild to moderate primary degenerative dementia. This randomized trial was double-blind with respect to Ginkgo Biloba Extract 761 and placebo, and the reference substance was given to a third treatment...