Ginkgo biloba

Extracts of G. biloba leaf contain a number of bioactive components, which include diterpenes, ginkgolides A, B, C, J and M, the sesquiterpene bilobalide and a range of flavonoids. The synergistic effects of these phytochemicals results in interactions with a number of CNS systems, which would be expected to attenuate neurocognitive decline. These include an up-regulation of the vasorelaxatory neurotransmitter nitric oxide and a resulting increase in cerebral blood flow, a down-regulation in the enzymatic deamination of monoaminergic neurotransmitters, free radical scavenging and neuroprotection, which includes reduced amyloid-β neurotoxicity⁽ Reference Fehske, Leuner and Müller ^{29 –} Reference DeFeudis and Drieu ^{31 )}. These interactions support the prescription of ginkgo for millennia in traditional Eastern forms of medicine for disorders of old age including AD⁽ Reference Berger ^{32 )} and the beneficial effects seen in vitro and in vivo animal models of AD; where attenuation of cognitive decline has been observed in the AD mouse⁽ Reference Stackman, Eckenstein and Frei ^{33 )}; often reported to be due to protection against amyloid-β-induced oxidative stress⁽ Reference Smith and Luo ^{34 )}. Modern, controlled intervention trials in human subjects have also yielded some positive results.

In 2002, a Cochrane review concluded that ‘overall there is promising evidence of improvement in cognition and function associated with ginkgo’⁽ Reference Birks and Grimley Evans ^{35 )} but, in 2009, this message had changed to one blighted by ‘inconsistent’ and ‘unconvincing’ results⁽ Reference Birks and Evans ^{36 )}. This is despite a study conducted in the same year where cognitive decline, as assessed by the Alzheimer's disease assessment scale (ADAS-cog), was attenuated by ginkgo⁽ Reference Snitz, O'Meara and Carlson ^{37 )} but perhaps represents the influence of several small, heterogeneous studies on a research area still in its infancy. Nevertheless, since this review, a handful of larger scale reviews have reported more promising results of ginkgo. In 2010, a review of nine studies, comprising 2372 patients with various dementias, found that ginkgo attenuated declines in cognitive performance across all dementia groups tested and additional improvements in activities of daily living were seen in the AD groups⁽ Reference Weinmann, Roll and Schwarzbach ^{38 )}. In the same year a review of six studies found that 6 months administration of ginkgo resulted in significant improvements on the ADAS-cog⁽ Reference Wang, Wang and Song ^{39 )}. Importantly, this result was evinced when baseline risk was taken into account and might represent an important methodological consideration in AD research. In support of this, a separate review⁽ Reference Janßen, Sturtz and Skipka ^{40 )} found that improvements seen in daily living, cognitive function and amelioration of neuropsychiatric symptoms (such as psychosis, agitation, aggression, anxiety, euphoria/dysphoria or disordered motor behaviour), in a review of six studies comprising 1800 participants with AD, were most striking in those suffering significant levels of neuropsychiatric symptoms; thus individual differences in risk levels and severity of symptoms likely has an impact on response to ginkgo and overall study findings; especially if small cohorts are utilised in individual trials.

Ginseng

Ginseng has a 5000-year history of medicinal consumption⁽ Reference Yun ^{41 )} and comprises forty or more bioactive saponins (known as ginsenosides), which exert anti-fungal/viral/bacterial/feeding effects within the plant⁽ Reference Osbourn ^{42 ,} Reference Sparg, Light and van Staden ^{43 )}. Again, this terpene-derived nutritional supplement demonstrates efficacy in interacting with numerous physiological systems, including acting as an antioxidant, stimulating nitric oxide production and acting as a ligand for glucocorticoid and androgen receptors; interactions which, among others, are seen to increase immune function, enhance CNS function and prevent CVD and other diseases in animal models⁽ Reference Lu, Yao and Chen ^{44 )}. Specific neurocognitive interactions with neurotransmitter function and the processes of neurogenesis and long-term potentiation are also observed to exert anti-stress, antidepressant, and anxiolytic effects, to moderate fatigue and improve memory in impaired rodents⁽ Reference Attele, Wu and Yuan ^{45 ,} Reference Dang, Chen and Liu ^{46 )}.

Research in young healthy participants is still in its infancy and buoyed by heterogeneous methodology but, on the whole, provides promise in terms of cognitive enhancement⁽ Reference Kennedy, Scholey and Wesnes ^{47 –} Reference Reay, Scholey and Kennedy ^{50 )}. In vitro and animal data supports the potential for ginseng to be of specific benefit to AD-induced cognitive decline where ginsenosides have been observed to minimise the inhibitory effect of amyloid-β protein on cholinergic transmission⁽ Reference Lee, Shiao and Chen ^{51 )} and, in turn, prevent the resulting amnesiac effects in rats⁽ Reference Wang, Wang and Ng ^{52 )}. To the best of current knowledge, however, only two trials exist, which investigate whether these cognitive benefits also extend to AD in human subjects. The first of these reports on the 12-week consumption of 9 g/d Korean ginseng in fifteen patients with dementia where scores on the ADAS-cog and clinical dementia rating were significantly improved⁽ Reference Heo, Lee and Chu ^{53 )}. The second trial is a follow-up of patients in this same trial after 24 weeks where a significant improvement on the Korean Mini Mental State Exam was evinced following 4·5 and 9 g/d ginseng and maintained at 48 and 96 weeks⁽ Reference Heo, Lee and Oh ^{54 )}.

Melissa officinalis (lemon balm)

Melissa is another terpene with a centuries-long history for treating disorders, which modern research has confirmed efficacy for; including as a memory and mood enhancer⁽ Reference Kennedy and Scholey ^{55 )}. The bioactives underpinning these effects include monoterpenes and sesquiterpenes; which include 1, 8 cineole⁽ Reference Tittel, Wagner and Bos ^{56 )}, and the CNS-relevant effects of these compounds includes antioxidant activity⁽ Reference Ferreira, Proença and Serralheiro ^{57 ,} Reference Pereira, Fachinetto and de Souza Prestes ^{58 )}, activation of the cholinergic system (including cholinesterase inhibition)⁽ Reference Ferreira, Proença and Serralheiro ^{57 ,} Reference Perry, Court and Bidet ^{59 –} Reference Dastmalchi, Ollilainen and Lackman ^{61 )} and up-regulation of γ-aminobutyric acid (GABA) ergic neurons⁽ Reference Awad, Muhammad and Durst ^{62 )}.

These interactions would suggest benefit to AD sufferers and, indeed, one of the only two controlled trails, which has investigated Melissa here observed reduced agitation and improved cognitive (ADAS-cog) and behavioural function (as assessed by the Cognitive Drug Research test battery) following 16 weeks administration of an alcoholic-Melissa tincture in a group of mild–moderate sufferers⁽ Reference Akhondzadeh, Noroozian and Mohammadi ^{63 )}. The other of the two studies, however, failed to find statistically significant differences in AD symptoms with Melissa⁽ Reference Ballard, O'Brien and Reichelt ^{64 )}. This study, though, administered Melissa in the form of an aromatherapy spray (dispersed once in the morning and afternoon in patient rooms) or essential oil hand massage (with a third group receiving a combination), which also contained lavender. This novel approach to administration presents an unknown quantity in terms of subsequent plasma levels of Melissa and time needed for the bioactives to reach the CNS and, as such, makes it difficult to compare with the above study and related studies, which administer phytochemicals orally. It could also be the case that the alcoholic matrix in the initial study in some way enhanced, or indeed was solely responsible for, the significant effects seen there. Nevertheless, it is important to note that the latter study did observe clinical benefit to some participants and this may indicate the very important role of individual differences in response to terpene phytochemicals; a consideration also noted with ginkgo studies described earlier. Here too it may be the case that pre-AD differences and current symptom severity influence the role that terpenes play and, with the Melissa essential oil study specifically, it could be that the response to scent (including lavender; which contains the active terpene linalool) and the pleasant sensation of being massaged, interact to produce effects which are of benefit to some and not others.

Salvia lavandulaefolia and Salvia officinalis (sage)

Sage has a history stretching back as far as the ancient Greeks where it was used as a cognitive enhancer and to prevent age-related decline; hence the derivation of the word sage in relation to wisdom. The two most abundant bioactive monoterpenes in sage are 1, 8 cineole and camphor and, of interest here, these monoterpenes have demonstrated potent cholinesterase-inhibiting properties⁽ Reference Savelev, Okello and Perry ^{65 –} Reference Perry, Houghton and Jenner ^{68 )}; with 1, 8 cineole alone evincing the greatest effects⁽ Reference Savelev, Okello and Perry ^{65 )}. These CNS effects produce enhanced secondary memory, accuracy and attention in healthy aged (over 65 years) participants⁽ Reference Scholey, Tildesley and Ballard ^{69 )} and consumption of this terpene, in the form of an essential oil, is reportedly well tolerated in a small group (n 11) of patients aged 76–95 years with mild–moderate AD following 6 weeks of 50–150 µl daily consumption of S. officinalis ⁽ Reference Perry, Bollen and Perry ^{70 )}. The latter study did not observe any statistically significant cognitive benefit but this was not the a priori aim of the study and this is reflected in the sample size. Nevertheless the authors do report positive indications on the cognitive test battery used (Cognitive Drug Research) and this is in line with the only other trial investigating the benefit of sage in AD⁽ Reference Akhondzadeh, Noroozian and Mohammadi ^{71 )}. Here nineteen participants (65–80 years), with mild–moderate AD, consumed an S. officinalis-alcoholic tincture for 16 weeks and better outcomes on the ADAS-cog, compared with the placebo controls, was observed. This study also demonstrated a trend towards reduced agitation in the S. officinalis group.

Resveratrol

Resveratrol derives from a sub-class of non-flavonoid polyphenols termed stilbenes and is found in limited sources, which include grapes and, as a result, wine. Resveratrol has received much research attention regarding its potential to benefit a number of disease states, including CVD⁽ Reference Zordoky, Robertson and Dyck ^{79 )}, cancer⁽ Reference Carter, D'Orazio and Pearson ^{80 )} and even life extension in a range of animal models⁽ Reference Hector, Lagisz and Nakagawa ^{81 )}. The many and varied health effects attributed to resveratrol are likely underpinned by the multifarious biological targets that it interacts with. These include, but are not limited to, cyclooxygenase 1 and 2, the sirtuins and various kinases and DNA/RNA and lipoproteins. These specific interactions explain how resveratrol is able to exert anti-inflammatory effects, to interact directly with cell signalling and its links to cardiovascular health, respectively⁽ Reference Britton, Kovoor and Brown ^{82 )}. Interaction with these targets, and others such as up-regulation of cerebral blood flow ⁽ Reference Kennedy, Wightman and Reay ^{6 ,} Reference Wightman, Reay and Haskell ^{7 )}, and the ability of resveratrol to attenuate amyloid-β-induced cell death in vitro ⁽ Reference Han, Zheng and Bastianetto ^{83 )}, suggests that this polyphenol should be capable of beneficial therapeutic potential in AD. Indeed, results from animal models supports the function of resveratrol here with reduced markers of pathology, e.g. amyloid-β plaques⁽ Reference Karuppagounder, Pinto and Xu ^{84 )}, and behavioural deficits, e.g. improved learning and memory⁽ Reference Ma, Sun and Liu ^{85 )}, in response to resveratrol exposure and consumption (25 mg/kg per d) of resveratrol, respectively.

However, to the best of current knowledge, only one study exists, which investigates resveratrol in human volunteers with AD. Here a phase-2 randomised, placebo-controlled, double-blind 12-month trial of 500 mg/d (escalating to 1000 mg twice daily) resveratrol was conducted in participants with mild–moderate AD⁽ Reference Turner, Thomas and Craft ^{86 )}. Unfortunately the therapeutic measures of the present study were limited and, whilst amyloid-β markers were reduced by resveratrol, this was not more significant than in the placebo group, and brain volume loss was not attenuated. Resveratrol consumption was generally well tolerated, but participants did report significant gastrointestinal problems and weight loss, which is likely due to the high dose being received after escalation as these side effects are not seen often in the literature with doses at or lower than 500 mg.