The clinical efficacy of salvia officinalis

The clinical cap top executive of salvia officinalisAn evaluation of the clinical efficacy of salvia officinalis, salvia lavandulaefolia and genus genus Melissa officinalis for the prophylaxis, management and amelioration of cognitive dys function with particular reference to Alzheimers distemper and non-Alzheimer-type senile deliriums.1. Introduction madness is a collection of symptoms ca r knocked out(p)ined by a chronic, global deterioration of cognitive function. It terminate occur at any age save is nigh universal in the elderly and increases with age (Beers et al. 2006 1811). Around 5% of heap everywhere 65, 25% everyplace 80 and 45% all over 85 rich person some form of insanity (Knapp et al. 2007 10 Collins 1997 185). The population is maturation and whereas today thither is an estimated 700,000 people in the UK suffering from derangement, this follow is plume to increase to to a greater extent than a million by 2025. The huge force mania has on society, devastating families and costing around 17-18 million every year bottomland non be overstated (Knapp et al. 11). Early identification and safe, legal, intervention is therefore important. dementedness may be classified as Alzheimers or non-Alzheimer-types (Beers et al. 2006 1811). The most unwashed madness is Alzheimers disease (AD) (Grossman et al. 2006 985), affecting around 20 million people worldwide (Akhondzadeh et al. 2003 53) and accounting for around 62% of madnesss (Knapp et al. 2007 11). Non-Alzheimer-type monomanias typically affecting those over 60 include vascular dementia (27%), Lewy body dementia and fronto-temporal dementia (Knapp et al. 29).Cognitive disorders atomic number 18 treated allopathically with drugs that call for yet to show of import benefits and have a number of side- centres and contraindications. The need for safer, more effective treatments has conduct to increasing interest in the use of herbs for their management (Akhondzadeh and Abb asi 2006 117). A frame of herbs, for example Salvia officinalis, Rosmarinus officinalis, Mellissa officinalis, Ginkgo biloba (Heinrich et al 2004 234), Withania somnifera (Howes et al. 2003 12), Centella asiatica (Chevallier 1996 78) and Panax nin-sin (Mantle et al. 2000 207) have long-standing tralatitious use as wargonhousing-enhancing herbs. Consequently a number of clinical studies have been conducted to assess the efficacy of some of these herbs, most nonably Ginkgo biloba, Salvia spp. and Mellissa officinalis, in the treatment of cognitive disorders. Of these, only clinical trials of Gingko biloba have been extensively followed (Birks and Grimley Evans 2002 Ernst et al. 1999 Oken et al. 1998). This present re image aims to fill this hatchway by providing up-to-date information on whether clinical studies of Salvia spp. and Mellissa officinalis corroborate their traditional use as cognition enhancers. To inform herbal do it will evaluate clinical studies to assess whet her the results have determined safe, effective herbal strategies and prescription for prophylaxis, management and amelioration of cognitive decline.2. The literature canvas2.1. Background clinical presentation and pathologyAlthough much scientific progress has been make since 1907 when Alois Alzheimer first described a case of dementia with peculiar patches disseminated throughout the cerebral cortex (Collins 1997 185), there is still much to influence soundly-nigh the aetiology and pathogenesis of Alzheimers disease and new(prenominal) dementias (Knapp et al. 2007 11). The onrush of dementia is insidious, a good deal stemma as mild cognitive impairment (MCI) and progressing to severe dementia over time (Loveman et al. 2006 4). In the early stages, episodes of mild forgetfulness or misplacing possessions ar often attri unlessed to normal aging. Patients plebeianly suffer from anomic aplasia and agnosia moreover retain spoken language information (Collins 1997 186). Demen tia becomes more apparent when sufferers are unable to learn late information, to register the content of a conversation, or to recall juvenile events or the names of family members. Unlike those with benign forgetfulness, dementia patients are oblivious(predicate) of their amnesia. Frequently, there are mood trans dos, depression and other psychologic disturbances. Language comprehension fails (aphasia) and eventually patients may simply repeat what they hear or be unable to speak at all. Visuospacial deficits commonly occur at a late stage (Collins 1997 186). Those bear upon have bar in reduplicate drawing simple objects.Differential diagnosis between MCI subtypes of various and hard aetiologies is challenging (Kidd 1999 145). As some MCI subtypes are reversible (Levey et al. 2006 992) prophylaxis for dementia could voltage droply encompass a range of varied or unknown aetiologies and pre work factors. Knowledge of these and an awareness of differing clinical presentat ions are therefore important (Levey et al 991). Additionally, an understanding of current orthodox treatment strategies and key neurochemical impairments in dementia burn down inform herbal practice of the most likely redress actions of herbs.2.1.1. Alzheimers diseaseAs clinical studies have indicated that mild to moderate Alzheimers disease (AD) responds better to allopathic drugs than severe AD (Levey et al 2006 993), to prevent rebirth of MCI to AD early diagnosis is important. shew apprizes that MCI associated with memory loss most commonly leads to AD (Levey et al. 991) and results of a clinicopathologic bailiwick of 80 subjects with MCI through to promethium suggest that depression is one of the first features of AD (Galvin et al. 2005 763). Formation of sink in neuritic senile plaques in the adept is characteristic of AD but as these can only be determined from biopsy (Collins 1997 186) probable diagnosis is make by clinical neuropsychological testing (Grossman et al. 2006 986) much(prenominal) as the mini Mental state Examination (MMSE) (Alzheimers Society 2002 436), while magnetic reverberance imaging can corroborate diagnosis by identifying areas of temporal neural loss (Vandenberghe and Tournay 2004 347).Progression of AD is unremitting for around 5-10 days until expiration ensues. In the final stages sufferers may develop apraxia, with difficulty in execute familiar tasks. A common cause of death is pneumonia when patients eventual difficulty with eating results in aspiration pneumonia (Collins 1997 186). The loss of faculties has been ascribed to both structural and neurochemical abnormalities (Perry et al. 1996 1063). gray plaques in the originators of AD patients confine amyloid and tau protein (microtubule associated protein) (Collins 1997 188). Since isolation of b-amyloid peptide from cerebral vessels in AD patients (Wong et al. 1984 8729), the accepted hypothesis for the pathogenesis of AD has been the amyloid hypothesis, wh ich proposes that AD is cod to excessive formation of extracellular b-amyloid (Ab?) from amyloid precursor protein (APP), a membrane protein in neurons (Grossman et al. 2006 986). It is thought that Ab molecules initiate a toxic shower long before plaque forms by causing an inflammatory reaction, disrupting synaptic function and causing neurons to degenerate (Grossman et al. 986) with a loss of cholinergic fibres in the basal forebrain. In vitro results suggest that Ab enters mitochondria and induces impeccant al-Qaida aggrieve (Reddy 2006 9). Intracellular neurofibrillary tangles are believed to be formed by abnormal phosphorylation of tau proteins (Tanzi and Bertram 2005 545), curiously in the hippocampus and neocortex, areas of the brain involved in memory (Mantle et al. 2000 202). To date, thirteen genes have been implicated in AD (Bertram et al. 2007 17). Of sporadic late attempt Alzheimers up to 40% of cases may be payable to a untimely gene on chromosome 21, ApoE4, a n isoform of the ApoE gene that encodes for apolipoprotein, an astrocytic protein that may play a role in the reparative process in the brain. ApoE4s patho catching mechanism may be to enhance amyloid deposits wi edit out tissue paper by accelerating cleavage of b-peptide (Collins 1997 189). self-denial of a gene implicated in AD does not unavoidably result in its development, the likelihood of which is further complicated by the capability role of environmental factors much(prenominal) as viruses and toxins in combination with genetic factors (Bird 2005 864).2.1.2. Vascular dementiaVascular dementia (VaD) is any type of dementia caused by cerebral blood vessel disease (Micieli 2006 S37). Onset of VaD is usually abrupt. Imaging may reveal areas of multiple infarcts (Collins 1997 191) but their presence does not necessarily imply dementia (Grossman 2006 987). fit to Looi and Sachdev (1999) it is not possible to brand between AD and VaD with neuropsychological testing. Speech an d language difficulties associated with vascular dementia may be mild or there may be a more pronounced aphasia as in multi-infarct VaD (Collins 1997 191). 2.1.3. Frontal lobe dementiaFrontal lobe dementia or Picks disease is uncommon and is characterised by neuronal loss and gliosis. Rarely, there are fibrillary inclusion bodies in the neurons. Presentation of frontage lobe dementia differs from AD in that the first symptoms are a change in personality rather than memory loss (Collins 1997 193).2.1.4. Lewy body dementiasDementia with Lewy bodies may differ to AD in its presentation in that patients suffer from marked visual hallucinations. Additionally, cognition tends to fluctuate between normality and confusion. Parkinsonian features much(prenominal) as shuffling gait, tremor, bradykinesia and rigidity are prevalent. Sleep behaviour disorder, such(prenominal) as acting out attacking themes, may appear days before other signs of the disease (Grossman et al. 2006 989).2.2. Risk factorsFactors believed to pose a guess for developing dementia include cardiovascular disease, being female, a family record of dementia, Downs syndrome, older age, issueroom trauma, diabetes and lower educational standards (Collins 1997 186, 188 Lebson et al. 1997 301). 2.2.1. Cardiovascular disease Patients may have more than one type of dementia concurrently (Beers et al. 2006 1811). This is heighten by results of a number of epidemiological studies suggesting that cardiovascular disease increases the lay on the line of developing AD (Stampfer 2006 12). Using transcranial Doppler ultrasonography Sun et al. (2007 152) demonstrated minor cerebral blood flow velocities in MCI patients who also carried the ApoeE4 allele.Risk factors for VaD are believed to include artherogenic factors such as hypertension, hyper lipoidaemia, diabetes, and cigarette smoking (Micieli 2006 S38). Conversely, there are indications from clinical trials that nicotine has a protective effect for AD (Breteler et al. 1992 71). Results of a randomised, double-blind, multicentred trial in which subjects with hypertension were treated with antihypertensives or placebo suggest that hypertension is a try factor for developing both AD and VaD. Antihypertensives reduced risk by 55%. The results were noteworthy as subjects had similar characteristics, the sample sizing was large (3228) and equally divided into placebo and treatment groups. Median follow-up was 3.9 years (Forette et al. 2002 2047).2.2.2. Head trauma A meta-analysis by Fleminger et al. (2003 858) replicated earlier findings by Mortimer et al. (1991) that head injuries pose a risk for AD but only in males, thought to be receivable to an early protective effect of oestrogens in females (Fleminger et al. 860). Bias may have been introduced into both studies as informants recalled the injuries. 2.2.3. Diabetes mellitus Given that diabetes mellitus (DM) is a known risk factor for vascular disease it is not impress that mos t studies on the development of vascular dementia in DM patients have shown a positive association (Biessels 2004 10). Studies on DM as a risk factor for AD, however, have yielded conflicting results, possibly due to study limitations such as small sample sizes and selection crook (Leibson et al. 1997 301). Large longitudinal studies may be more reliable. A population-based historic cohort study of 1,455 cases followed over 9,981 person years fix a statistically significant positive association (Leibson et al. 304). According to results from the Framlingham Study, diabetes may not be an in regardent risk factor for developing AD but risk is brawnyly associated with possession of the ApoE4 genotype (Akomlafe et al. 2006 1551).2.2.4. Hormones Women are twice more likely than men to suffer from AD. Although this may be partly due to women having a longer life expectancy (Beers et al. 2006 1814) there is evince to suggest that a decline in endogenous oestrogen in later life plays a role in its pathogenesis. Oestrogen is believed to stimulate cholinergic performance, reduce oxidative stress related cell damage, reduce vascular risks, reduce Ab formation and promote synaptic activity (Zandi et al. 2002 2123 Hoskin et al. 2004 141). Evidence from studies to determine whether oestrogen-containing hormone replacement therapy (HRT) in women has a protective effect on the brain, however, is conflicting (Colucci et al. 2006 1376) but this may be due to differences in methodology and confounding factors (Resnick and Henderson 2002 2171). For example, in one large prospective study that found a positive correlation between HRT use and a significant reduction in AD development, patients with dementia were asked questions regarding preliminary use of HRT (Zandi et al. 2124) yet accurate recall in a dementia sufferer cannot be guaranteed. Results of a retrospective case-control study suggesting the likelihood of women developing AD increases with number of pregnancies ( Colucci et al. 2006 1375) could be of little value. Cases with previous head injuries, low educational standards, both considered risk factors for AD (Collins 1997 186 Fleminger et al. 2003 858), and those who had used HRT, were not excluded from the study.There is evidence to suggest testosterone may delay AD onset in men. Men over 32 years of age who were free from AD at baseline (n = 574) were followed for a mean of nineteen years (Moffat et al. 2004 188). Long-term free testosterone levels were significantly lower in men who positive AD.Due to conflicting results and confounding factors in the re seem the clinical evidence for risk factors for dementia is inconclusive. However, although more research is needed the results can assistant in informing herbal practice.2.3. Orthodox treatment strategiesAs cholinergic neurotransmitters are believed to have a role in memory function (Grossman et al. 2006 985) symptomatic treatment for subtypes of dementia is similar and focuses on ac etylcholinesterase ( offend) inhibition with drugs such as donepezil, rivastigmine and galantamine (Loveman et al. 2006 8). According to Delagarza (2003 1366) loss of cholinergic neurons causes a decrease in acetylcholine and subsequent drop in stand with a compensatory rise in butylcholinesterase (BChE). Nicotinic receptors also decrease. Rivastigmine also inhibits BChE galantamine also acts on nicotinic receptors. Depression in dementia is treated with non-anticholinergic antidepressants as anticholinergic drugs exacerbate symptoms (Beers et al. 2006 1814). Another drug, memantine, a N-methyl-D-aspartic sultry (NMDA) receptor antagonist (Grossman et al. 987), licensed to treat moderate to severe AD, acts by modulating the action of the neurotransmitter glutamate, which is believed to be associated with cholinergic damage and neurodegeneration when secreted in excess (Loveman et al. 2006 8).Dizziness, diarrhoea, headaches, illness and vomiting were found by a meta-analysis of de mentia drugs to be common adverse events with anti-cholinesterases and memantine (Loveman et al. 2006 49). Furthermore, their long-term benefits are inconclusive (Loveman et al. 145). Similarly, their use for vascular or Lewy body dementia is controversial as a review of clinical trials data deems there is insufficient evidence for their efficacy. Trials were of generally poor fictitious character and with inconsistent findings (Maggini et al. 2006 457).Other potential drugs for AD include 70 new compounds formulated to interfere with the toxic amyloid cascade or to place inflammation, oxidation or apoptosis (Grossman et al 2006 987). As g-aminobutyric acid (gamma aminobutyric acid) agonists can impair memory GABA antagonists are also being real (Association of the British Pharmaceutical Industry). 2.4. Potential herbal treatment strategiesIn view of the hypothesised diseased sequelae, risk factors and current orthodox treatment of dementias, efficacious herbs for these condition s could potentially have one or more of AChE-inhibiting or cholinergic, antidepressant, hypotensive, hypoglycaemic, antioxidant, anti-inflammatory, GABA modulator, nicotinic agonist, testosterogenic and oestrogenic actions. According to Kennedy and Scholey (2006 4614) orthodox AChE inhibitors are not well tolerated by patients as they are toxic alkaloids and European plants traditionally used for cognitive sweetening may therefore depict non-alkaloid safer alternatives. To this end Salvia officinalis, Salvia lavandulaefolia and Melissa officinalis, members of the Labiatae family (Lamiaceae), have been extensively investigated in vitro.2.4.1. Salvia spp.Salvia is the largest genus in the Labiatae family with over 700 species. The most common European species are Salvia officinalis L (garden or common sage) (Figure 1) and Salvia lavandulaefolia Vahl (Spanish sage), both of which originate on the shores of the Mediterranean (Kennedy and Scholey 2006 4614). S. officinalis is an aromat ic, evergreen shrub up to 75 cm in height with greyish-green oblong to lanceolate opposite leaves covered in a fine down. It has bluish-violet, two-lipped flowers arranged in whorls (Wildwood 1998 202). S. lavandulaefolia has narrower leaves and a lower spreading wont (Sergei Savelevs Database).Sage was used in medieval Europe as a tisane for prolonging life and is a traditional spring tonic for strengthening wearied constitutions (Lipp 1996 63). According to Culpepper (1826 147) Sage is of excellent use to help the memory, warming and accelerate the senses and an old country remedy, which indicates its efficacy for inflammation A sunburnt expression is eased by washing with sage tea (Page 1978 41). Other traditional uses are for headaches and migraine (Page 34).The major active constituents of the leaves of both species are believed to be the volatile anoints (1.0-2.8%), containing monoterpenes such as a-pinene, b-pinene, 1-8-cineole, camphor, geraniol and thujone (Kennedy and Scholey 2006 4615). S. officinalis contains around 50% a- and b- thujone whereas only traces have been found in S. lavandulaefolia. As thujone, a terpenoid ketone, is potentially neurotoxic, S. lavandulaefolia may provide a safer alternative than S. officinalis to orthodox dementia drugs (Perry et al. 1999 530). However, S. officinalis is toxic only at doses of over 15 g (Grainger-Bissett and Wichtl 2001 441) but the oil should not be ingested. Both species contain polyphenolic compounds including rosmarinic acid, methyl carnosate, luteolin, luteolin-7-0-glucoside and caffeic acid (Kennedy and Scholey 4615), triterpenes eg oleanic acid and the flavonoids 5-Methoxysalvagenin (Barnes et al. 2002 408) and hispidulin (Johnston and Beart 2004 809).2.4.2. Melissa officinalisM. officinalis L (balm, lemon balm) (Figure 2) originates from the eastern Mediterranean region and western Asia and is now astray cultivated in the west (Grainger Bissett and Wichtl 2001 329). It is a bushy perennia l, about 60 cm high with bright green, lemon-scented leaves in opposite pairs. Small liplike flowers grow in whorls and change colour from pale yellow to sporty or pale blue. Fresh leaves should be collected when young (Wildwood 1998 175). It has been in medicinal use as a nervous system revitalising for over 2000 years (Kennedy and Scholey 2006 4617). The London Dispensary (1696 cited in Grieve 1931) states An essence of Balm, prone in Canary wine every morning will revitalize youth, strengthen the brain John Evelyn wrote Balm is sovereign for the brain, strengthening the memory and powerfully chasing away melancholy (cited in Grieve 1931). There are no known contraindications or adverse personal effects (Barnes et al. 2002 339).M. officinalis contains 0.2-0.3% essential oil (EO) consisting of over 70 components including around 60% monoterpenoid aldehydes and over 35% sesquiterpenes. The regulation monoterpenes include citronellol, neral, geranial, methyl citronellate, ocime ne major sesquiterpenes include b-caryophylene and germacrene D. The herb also contains flavonoids, caffeic and chlorogenic glycosides, polyphenolic acids such as rosmarinic acid, and triterpenes (Granger Bissett and Wichtl 2001 330). 2.5. Possible mode of action of phytochemical constituents in dementia2.5.1. Antioxidant propertiesnumerous studies have been conducted on Salvia officinalis in a search for infixed antioxidants to use in the food industry. Consequently, results of chemical tests on purified buy foods of the herb have suggested that phenolic compounds rosmarinic acid, carnosic acid, carnosol, carnosoic acid, rosmadiol, rosmanol, epirosmanol, isorosmanol, galdosol methyl carnosate, 9-erythrosmanol and luteolin-7-0-glucopyranoside have significant antioxidant activity (Bertelsen et al 1995 1272 Cuvelier et al. 1994 665 Pizzale et al. 2002 1651 Miura et al. 2002 1848 Wang et al. 1998 4869).S. lavandulaefolia dehydrated hitchhike extracts in ethanol, chloroform and wat er, and various EO monoterpenes were assayed for antioxidant properties in phospho lipid microsomes. The extracts and monoterpenes a-pinene, b-pinene, 1-8-cineole, camphor and geraniol and thujone all showed significant antioxidant activity (Perry et al. 2001 1351). The extracts showed greater antioxidant activity than any individual monoterpenes, which suggested a interactional effect (Perry et al. 1352). Ferreira et al. (2006 35) measured the antioxidant properties of EOs, decoctions and ethanolic extracts of M. officinalis and S. officinalis relative to b-carotene. The EO and decoctions of both herbs showed significant antioxidant activity. Lima et al (2007) found methanolic and aqueous extracts of S. officinalis prevented lipid peroxidation in hepatoma cells. As there were more phenolics in the methanol extract it was thought there were other antioxidant compounds in the aqueous extract.Ethanolic EO extract from dried M. officinalis investigated for its ability to inhibit lip id peroxidation in vitro showed a dose-dependent (10-20 mg) 80-90% protection of linoleic acid from peroxyl radical attack. As no rosmarinic acid was detected in the EO the antioxidant action was attributed to squalene (Marongiu et al. 2004 790). Considering there are potentially 70 constituents in the EO it is unlikely that this would have been the only active phytochemical but composition of the oil varies according to harvesting, origin and climate (Grainger-Bissett and Wichtl 2001 329). Interestingly, M. officinalis prepared as a tea demonstrated significant antioxidant capacity, which corresponded to high phenolic content, when assayed with the ABTS (2,2/-azinobis 3-ethylbenzothiazoline-6-sulfonic acid) radical decolourisation assay (Ivanova et al. 2005 147).2.5.2. Anti-inflammatory activityChloroform, aqueous and ethanol extracts and monoterpenes of S. lavandulaefolia, were tested for their ability to inhibit formation of pro-inflammatory eicosanoids thromboxane B2 (TXB2) and leukotriene B4 (LTB4) in leucocytes (Perry et al. 2001 1348). The chloroform and ethanol extracts showed significant inhibition of LTB4. Alpha-pinene and geraniol showed weak selectivity for LTB4 and TXB2 respectively (Perry et al. 1351). The results support the traditional use of S. lavandulaefolia as an anti-inflammatory herb but indicate that it is the sum of the whole plant phytochemicals acting in synergy that are likely to contribute to this action. A standardised ethanolic extract containing 9.9% rosmarinic acid (RA) from the leaves of S. officinalis reduced Ab-induced neuronal cell death, Ab-induced lipid peroxidation, reactive oxygen species formation, DNA fragmentation and tau protein hyperphosphorylation in vitro (Iuvone et al. 2006 1143). Kimura et al (1987) found rosmarinic acid (RA) had the ability to inhibit pro-inflammatory cytokines in tender polymorphonuclear leucocytes (PMNs) in vitro. As both species contain RA these results suggest antioxidant, anti-inflammator y and neuroprotective properties of M. officinalis and the Salvia spp. against Ab-induced neurotoxicity. 2.5.3. Oestrogenic activityA range of concentrations of EO, ethanolic, chloroform and aqueous extracts and isolated monoterpenes of S. lavandulaefolia were assayed in yeast culture for oestrogen-binding properties. The EO showed weak oestrogenic activity at low concentrations. The aqueous and ethanolic fractions and geraniol showed significant oestrogenic activity (Perry et al. 2001 1352). The results of this experiment support S. lavandulaefolias use as an oestrogenic herb. The effects of S. officinalis in combination with Medicago sativa were assessed on menopausal symptoms related to oestrogen deprivation. Hot flushes and night sweats were completely eliminated in 20 out of 30 women (De Leo et al. 1998 207). These effects were attributed to dopaminergic actions but it is not clear for which herb. S. officinalis does, however, contain geraniol found to be oestrogenic in vitro ( Perry et al. 2001 1352).2.5.4. Acetylcholinesterase inhibitory activityM. officinalis EO demonstrated strong AChE inhibition in homogenised human brain tissue but ethanolic extract of the dried leaf had no effect. Ethanolic perfumed leaf extract showed a weak effect (Perry et al. 1996 1064). Conversely, when EOs and ethanolic extracts of M. officinalis were assayed in solution with AChE negligible results were obtained for its inhibition by EO and significant results for its ethanolic extract (Ferreira et al. 2006 34). Dried, reconstituted ethanolic, ethyl acetate rayon or aqueous extracts of M. officinalis, yielding 10mg/ml, demonstrated weak AChE inhibitory activity when assayed in a chemical system using thin layer chromatography (Salah and Jger 2005 146). The herbs were purchased from local suppliers in the Lebanon so their quality is unknown.S. officinalis EO and ethanolic extract assayed in solution with AChE showed moderate AChE inhibitory activity (Ferreira et al. 2006 34 ). Moderate (dose-dependent) AChE and weak BChE inhibition was demonstrated by ethanolic extracts of fresh and dried S. officinalis and S. lavandulaefolia in human brain homogenates. The EOs had significant effects but not the individual constituents (camphor, thujone, cineole, caffeic acid and borneol) (Perry et al. 1996 1066). The findings suggest a major synergistic effect of the constituents (Perry et al. 2000 895), which was later confirmed by Savelev et al. (2003 667). The results for camphor conflict with another experiment in which S. lavandulaefolia EO and isolated monoterpenes a-pinene, 1-8-cineole and camphor demonstrated AChE inhibitory activity in human erythrocytes.Ethanolic extracts of dried S. officinalis, S. lavandulaefolia and M. officinalis were assayed for acetylcholine (ACh) receptor activity in human brain homogenate. All plants demonstrated ACh receptor activity and M. officinalis had the highest nicotinic displacement value (Wake et al. 2000 108). 2.5.5. GABA modulationMethanol extract from S officinalis leaves revealed the flavonoids apigenin, hispidulin and cirsimaritin functioning as benzodiazepine receptor-active components (Kavvadias et al. 2003 113), suggesting a potential calming effect for the herb, which may be relevant to AD.2.6. military rank of in vitro studiesAccording to the results all three herbs may have AChE inhibitory, anti-inflammatory and antioxidant properties, and S. lavandulaefolia and S. officinalis may have and oestrogenic properties (Appendix I, Table 1, page 36) and a tranquilising effect for S. officinalis.Although these results are interesting in vitro systems cannot be extrapolated to humans and clinical evidence is necessary to support findings. For example, they cannot determine effective human venereal disease or mode of administration. They largely do not account for potential synergistic effects of the herbs nor do they provide an indication of in vivo physiological, pathological and genetic, or en vironmental, influences. Furthermore, the extent to which phytochemicals in herbs are effective in dementia may depend upon their bioavailability in the brain (Anekonda and Reddy 2005 371). It is worth noting, however, that as terpenoids tend to be lipophilic they are able to cross the blood brain barrier (Houghton and Howes 2005 12). Some results are conflicting but they may depend on methodological quality and design. The experiments cited above vary widely in their approach with regard to extraction methods and assay methods. Savelev (2003 667) has demonstrated how two disparate methods used for exploring interactions between the same agents may give different results when use to the same set of data. Consistency of results may also be affected by differences in harvesting times and quality of herbs. Results for M. officinalis are oddly inconsistent but, according to Perry et al. (1996 1068) most commercial sources of the EO are adulterated. Additionally, variation in media com position is known to affect the outcome of in vitro tests (Maurer and Kuschinsky 2006 73). Consequently, in vitro experiments can only provide an indication of the clinical efficacy of therapeutic interventions. However, notwithstanding the inherent difficulties of in vitro research with herbs, there is considerable consistency with their potential value in dementia prophylaxis and management (Appendix I, Table I, page 36). bright results in vitro of constituents of plants traditionally used to enhance memory, and subsequent interest in their potential actions in the brains of human patients, has generated clinical trials of M. officinalis and Salvia spp. for dementia. These will be reviewed. 3. MethodA computerised literature search was conducted on the Allied and complementary color Medicine Database (AMED) including CINAHL Database, EMBASE, Pascal Biomed, Biological Abstracts, RCN Journals Database and IPA (International Pharmaceutical Abstracts) PubMed, the Cochrane Collabora tion, Bandolier, the NHS Centre for Reviews, The National look into Register, ADEAR (Alzheimers Disease Education and Referral Centre database), PLoS (Public Library of Science), Herbalgram and Alt HealthWatch as well as hand-searching in books and journals. Literature searches dated back to 1985 and the final search was in April 2007.Key words in medical subject headings (MeSH) for an initial search in various Boolean combinations were memory, cognitive dysfunction, dementia, Alzheimers, herbal, botanicals, phytotherapy, complementary and alternative. Also, in a second search these MeSh terms were entered with key herbs Salvia, sage, Melissa and lemon balm.Inclusion criteriaControlled clinical trials, observational studies and case reports. Herbs for which there are at least two clinical studies in relation to cognitive enhancement. Exclusion criteriaDue to the limitations and ethical considerations of animal experiments the review is restricted to human trials.Trials with combine d preparations are excluded.Due to time constraints and a restriction to text file in the English language a complete systematic review is not viable at this time. To eliminate