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natural medicines, nutraceuticals and neurocognition include seafood is likely to have “…rendered humans more resilient to natural pres- sures and the increasingly packed social environments of late pleistocene europe.” dietary imbalance of efas humans have evolved consuming an almost equal balance of omega-3 to omega-6 fatty acids in the diet [65]. while some argue this balance was 1:1, others maintain that the paleolithic diet had a proportion of omega-6 to omega-3 of 5:1. in japan and greenland, this balance is approximately 3:1. however, in europe this ratio is esti- mated in the range of 10–50:1, while in the united states, this range is estimated in the range 30–50:1 [124]. after the agricultural and industrial revolutions the balance was dramatically shifted to a predominance of omega-6 fatty acids. inventions such as the seed drill dramatically increased the availability of seed oils in the food supply; multiplied by the feeding of an omega-6 rich seed diet to domesticated animals. the pufa composition of the meat reflects the changes in feeding: omega-6 is the main pufa in domesti- cated meat and eggs, but omega-3 fatty acids are predominant in free-range cattle and poultry allowed to forage for grass, the terrestrial relative of marine algae [15]. the substantial rise in western consumption of meat from domesticated livestock in the last century was linked, through observational studies in the 1960s, to the western epidemic of coronary heart disease. blood cholesterol was subsequently identified as major risk factor for heart disease, resulting in public health policy recommendations to reduce dietary cholesterol, particularly by replacing dietary saturated fatty acids with pufas [125]. as the omega-6 rich pufa sources, such as sunflower oil, were the most readily available, these recommendations effectively worsened the conditions required for optimal omega-3 metabolism. further, as pufas are readily oxidized, manufactur- ers developed products by partial hydrogenation to increase shelf life, such as marga- rines, despite the fact that commercial hydrogenation produced trans-isomers, rarely found in nature. in addition to saturated fats, domesticated meat also contains higher proportions of omega-6 fatty acids in their pufa fractions, which are passed through consump- tion to humans [5]. hibbeln et al. [126] argue that in fact saturated fatty acids and cholesterol were not significantly increased during the twentieth century at all, but the amount of the omega-6 la consumption was increased threefold in the u.s. diet from an average of 11.7–34.3 g/person/day from 1909 to 1999. in the same period, estimated pl levels of aa levels rose from 64% to 75%. this change in resulted in a displacement of the long chain omega-3 fatty acids (epa + dha) from the cell membranes [29]. this new pl profile has been asso- ciated through observational and clinical intervention studies with many chronic inflammatory and autoimmune diseases, such as coronary vascular disease, rheu- matoid arthritis, mental health and psychiatric problems, and neurodegenerative diseases [127,128]. in a remarkable multinational study published in the lancet, hibbeln [127] demon- strated an extremely high inverse correlation between the prevalence of depression in a country and the fish consumption per capita for that country (r = −0.84, p < 0.005).

omega-3 fatty acids moreover, in a sample of 20 moderately to severely depressed patients, adams [129] correlated the severity of the symptoms of depression with the imbalance of omega-3 to omega-6 fatty acids in red blood cell pls (r = 0.729, p < 0.01). although the cor- relations are strong, causality cannot be inferred from observational studies alone. however, these data contribute to the mounting evidence demonstrating a protective effect of the preformed dietary long chain omega-3 fatty acids in mental health. omega-3 fatty acids were recently shown in a prospective, intervention study to help prevent psychosis in at-risk young people. in a clinical trial of a 12 week supple- mentation period of 1.2 g/day of epa + dha in 81 young people (13–25 years old) with ultrahigh risk of developing schizophrenia, the supplement was significantly better than placebo at reducing risk of transitioning to psychosis. where 27.5% of the control group transitioned to psychosis, only 4.9% of the omega-3 group (p = 0.007) had developed psychosis within the 40 week follow-up period [130]. a high ratio of omega-6 to omega-3 fatty acids has been associated with violent and aggressive behavior. hibbeln et al. [131] directly correlated intakes of omega-6 fatty acids with homicide rates in five western countries, including australia (r = 0.94, p < 0.00001). in a sample of habitually violent and impulsive male offenders with antisocial personality, plasma pl dha were significantly lower than controls (p < 0.05), while the omega-6 fatty acid, aa, metabolites pge2, and txb2 levels were elevated (p < 0.01) [132]. in a randomized, placebo-controlled double blind trial involving 231 young adult male prisoners, supplementation of a combination of fish oil with gamma-linolenic acid and multivitamins led to a 23% (p = 0.03) reduction in violent and antisocial behavior compared with those taking the placebo. after 2 weeks of supplementation, violence and antisocial behavior were reduced by 35% (p < 0.001) in those taking the active supplement where the placebo group was unchanged [133]. in summary, humans have evolved with a rich dietary source of dietary preformed epa and dha. consumed as seafood or as capsules, these nutrients are readily incor- porated into lipid transport mechanisms and distributed around the body where they are taken up into the pl membranes of cells in a dose-dependent manner [134]. brain and retinal tissue rely on dha, in particular, for optimal functioning and are sensi- tive to dietary fluctuations [135]. dha can theoretically be converted from ala in the liver, but the conversions are rate-limited by many known and unknown factors. recommended daily intakes there is no longer any disparity in the literature with regards to the essentiality of pufas. widespread discussions, however, are canvassing the optimal levels of essential fatty acid intakes required for health and well-being. there are consider- able differences of opinion regarding the practicalities of providing recommenda- tions on a dietary ratio of omega-6 to omega-3 fatty acids. it is argued that a recommendation regarding the ratio of n-6 to n-3 fatty acids would not be useful as the different omega-3 fatty acids have different biological effects and a reduction in omega-6 fatty acids is not equivalent to an increase in omega-3 fatty acids. therefore most health authorities focus on absolute intakes of the individual fatty acids [136]. nevertheless, the argument is maintained that because

omega-3 fatty acids of the omega-3 fatty acid dpa from red meat. the australian average daily intake was reestimated to be 246 mg but the median daily intake was 121 mg [154]. the average was believed to be skewed to the right because a subgroup of people supple- ment with high doses of fish oil. therefore, most people in australian are consuming around a quarter (25%) of the daily intake recommended to prevent chronic diseases. for the prevention of coronary heart disease, most western countries around the word recommend that individuals should consume an average of 500 mg/day from epa + dha, the equivalent of approximately two oily fish meals per week [155]. france is the only country which specifically recommends preformed dha at 120 mg/day. curiously, the average intake of dha is 448 mg/day in france, which is much higher than other western countries. compare this with approxi- mately 70 mg/day in the united states, 106 mg/day in australia, and 170 mg/day in germany [9,156]. during pregnancy and breastfeeding, there is an increased requirement; some recommend 200 mg/day dha, while intakes up to 3 g/day of dha have been shown to be safe [157]. the current australian nhmrc recommendation ais (adequate intakes) have been estimated on the median population intakes as estimated from the 1995 national nutrition survey. these are for men 13 g/day la, 1.3 g/day ala, and 160 mg/day combined epa + dpa + dha. for women, they are 8 g/day la, 0.8 g/day ala, and 90 mg/day combined lc omega-3 fatty acids. these values for the omega-3 fatty acids are comparable with those given in the united states by the institute of medicine; 1.6 g/day ala for men and 1.1 g/day for women, 10% of which can be consumed as epa + dha, which represents the current mean intake of epa + dha in the american diet, approximately 100 mg/day [155]. many in the population require increase levels of long chain omega-3 fatty acids, such as during pregnancy and lactation. in addition, requirements are increased dur- ing inflammation, as more epa and dha are used up in the conversions to rvs. the optimal dose for treating inflammatory symptoms in rheumatoid arthritis has been estimated through meta-analysis to be 3 g/day [158]. a recent review found that the amount required to reduce blood pressure in people with hypertension is in the range of 3–9 g/day of epa and dha [124]. a large sample (n = 11,324) open label, randomized controlled italian study, known as the gissi-p trial, demonstrated that 875 mg (0.88 g) epa + dha per day was sufficient to reduce the risk of all-cause mortality in survivors of myocardial infarction [159]. modern nutraceuticals when nutrients are consumed, as nutritional supplements or fortified foods, in order to treat or prevent diseases, they come under the relatively new banner of the so- called nutraceuticals [160]. omega-3 fatty acids, particularly dha, are increasingly being added back to the food supply in the form of individual supplementation, direct fortification of foods and fortification of animal feed in order to confer beneficial health benefits. driven by consumer demand, dha and epa are increasingly incor- porated directly into industrial food production, despite increased production costs. ala-rich foods, such as linseeds, are being added to animal feed and are increasing the epa and dha levels of the eggs, dairy products, and meat produce.

natural medicines, nutraceuticals and neurocognition milk, bread, and eggs are frequently being fortified with algal oil and fish oil [161]. these new functional foods have the potential to positively benefit both indi- viduals and whole societies without any change to dietary habits. for instance, a recent review of the fortification of milks established that inclusion of an average of 300 mg of epa + dha increased plasma pl levels of the nutrients by 25%–50% within 6 weeks accompanied by beneficial health effects such as the reduction of ldl cholesterol and serum triglycerides [162]. domestic animal feed that has been enriched with epa + dha has been shown to enrich both red meat and eggs [163]. similarly feeding ala to farmed animals produces health benefits in human consumers of the produce. in livestock where extruded linseed replaced 5% of other oil sources, the butter had reduced n-6/n-3 ratio by 54%, the meat by 60%, and the eggs by 86% [164]. the beneficial ratio in animals fed linseed supplementation transferred to con- sumers, where those that ate the linseed-fed animal produce had a reduction of in blood lipids to an n-6/n-3 ratio of 10.2 compared with 14.3 in controls. these benefi- cial blood lipid alterations coincided with increased epa and dha in erythrocyte pls and reduced la and aa, bringing the pl n-6/n-3 ratio down from 4.2 to 3.8 [164]. thus, without changing dietary habits, supplementation of animal fodder has the potential to effect health benefits in the population. novel gm (genetically modi- fied) oilseeds are also being patented for future use in domestic animal feed [165]. the meat and eggs from pasture-fed animals naturally contain significantly higher omega-3 fatty acids than those from farm intensive methods that incorporate omega-6-rich feeding of animals [166,167]. however, wild animals have substan- tially higher omega-3 fatty acids in their produce than free-range or organic animals [168]. in a remarkable recent study, crawford et al. [168] bought 12 samples of meat from a western supermarket and compared it with 12 matched samples of african buffalo, using meat from skeletal muscle (the semitendinosis muscle). in the western meat, 97.8% of the total fatty acids were saturated and monoun- saturated, so that just 2.2% on the fatty acid content consisted of essential pufas. in african meat, this ratio was 78.7% saturated and monounsaturated to 21.9% pufas. interestingly, when the buffalo were further categorized into in parkland buffalo (n = 5) or woodland buffalo (n = 7), there was a huge difference in pufa content of the pls in the meat of the skeletal muscle; parkland consisted of 10% pufa content, while wood- land consisted of 30% pufa. the difference between parkland and woodland buffalo was compared by crawford et al. with the difference in available grazing diversity between the first type of historic animal enclosures for domesticated animals and the modern pasture-limited monoculture available to so-called “free-range” livestock. crawford et al. also present data on the fatty acid content in a range of modern meats, including organic and wild game, and consistently show a dramatic loss of epa and dha from the meat of domesticated livestock. for instance, the epa fraction (percentage per total fatty acids) = 0.14 in a beef sirloin steak, 0.32 in organic beef steak, 2.52 in venison and 3.8 in wetlands buffalo. similarly dha = trace (<0.1%) in the conventionally and organically reared beef, 0.7 in venison, and 0.9 in buffalo. although the organic meat had twice the epa content as conventionally farmed meat, neither had any dha, and the differences were negligible when compared with the epa and dha content of wild meats, the type of meat with which humans have evolved and adapted.

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part iv herbal medicines, nutraceuticals and neurocognition

natural medicines, nutraceuticals and neurocognition examination [mmse] and activities of daily living [adls]). a recent cochrane systematic review conducted in china, which included six clinical trials with a total of 454 patients, also suggested that hupa may improve general cognitive function, global clinical status, behavioral disturbance, and functional performance with minimal side effects in ad patients (li et al., 2009). a similar cochrane review investigated hupa for vad, but only identified one small study involving 14 par- ticipants in which hupa proved no better than placebo (hao et al., 2009). however, as noted in these reviews, the lack of quality data, small sample sizes of individual clinical trials, and short intervention periods limit firm conclusions about hupa’s clinical efficacy and highlight the need for rigorous randomized controlled trials with large sample sizes. curcuma longa the perennial herb curcuma longa (turmeric) has been applied in therapeutic prepara- tions for centuries in different parts of the world, and is a well-documented treatment for various disease conditions including asthma, bronchial hyperactivity and respiratory allergy, liver disorders, anorexia, rheumatism, diabetic wounds, runny nose, cough, and sinusitis, as well as for neurodegenerative disorders (goel et al., 2008). turmeric contains three structurally closely related chemical components—curcumin, deme- thoxycurcumin, and bisdemethoxycurcumin, which together are commonly referred to as “curcumin” or “curcuminoids” (goel et al., 2008). commercially available “curcumin” extracts are often claimed to contain either 70% or 95% curcuminoids. data from various animal and/or in vitro studies suggest that curcuminoids possess antioxidant, anti-inflammatory, and cholesterol-lowering properties, all of which are key processes involved in pathogenesis of ad (ringman et al., 2005). it has also been suggested that curcuminoids directly bind small beta-amyloid spe- cies to block aggregation and fibril formation, supporting the rationale for curcumi- noids to be used therapeutically for ad (yang et al., 2005). however, evidence from rigorous clinical trials to support this therapeutic claim is still generally lacking. in a large, population-based study, the relationship between consumption of curry (often contains turmeric) and cognitive function was investigated in 1010 elderly non- demented asians (singaporeans). the data demonstrated that consumption of curry containing turmeric was associated with significantly better cognitive performance measured by mmse than those who “never or rarely” consumed curry containing turmeric (ng et al., 2006). a randomized, double-blind, placebo-controlled trial was recently undertaken in 34 ad patients in hong kong to evaluate curcumin’s effect on ad. six months treatment of one or four grams of curcumin did not significantly change the mmse scores or other pathological parameters, although a trend toward increase in serum aβ40 emerged, which may represent an increase in disaggregation of aβ deposits by curcumin treatment. this study was one of the earliest attempts to evaluate the clinical effectiveness of curcumin for ad, in which several factors including small sample size, relatively short invention period, and lack of cognitive decline in the placebo group significantly limited the generalization of the findings. several larger-scale clinical trials are currently underway or soon to be completed, and their results will no doubt help determine the therapeutic value of curcumin for the treatment and prevention of age-related dementia.

chinese medicine used to treat dementia panax ginseng panax ginseng (ginseng) root has been used for the management of ad in many asian countries. most of the cognition-enhancing effects of ginseng have been stud- ied in animals and healthy individuals. the relevant principal bioactive components of ginseng are ginsenosides, which have been suggested to have antioxidant, anti- inflammatory, and anti-apoptotic effects (radad et al., 2006). a recent in vitro study also demonstrated that ginsenoside rg3 promotes beta-amyloid peptide degradation via enhancing gene expression (yang et al., 2009). data from human studies suggest that ginseng modestly improves thinking and secondary and working memory in healthy volunteers (kennedy et al., 2003; reay et al., 2006). two recent small, open-label trials demonstrated the potential therapeutic benefits of ginseng for ad (heo et al., 2008; lee et al., 2008). in the former study, 12 week treatment of low-dose (4.5 g/day; n = 15) and high-dose (9 g/day; n = 15) korean ginseng showed significant effects on alzheimer’s disease assessment scale- cognitive subscale (adas-cog) and clinical dementia rating (cdr) when compared with those in the control group (n = 31) (heo et al., 2008). in the latter study, in which 87 ad patients (n = 58 in the ginseng group; n = 39 in the control group) were involved, 12 weeks’ treatment with ginseng powder (4.5 g/day) produced significant improvements in adas-cog and mmse scores (lee et al., 2008). ginseng has also demonstrated clinical benefits when combined with ginkgo in improving cognitive function in humans (wesnes et al., 2000; kennedy et al., 2001). large-scale, long- term studies using standardized extracts are now required to confirm the clinical efficacy of ginseng therapy in ad. panax notoginseng panax notoginseng (san qi) is commonly used in chinese medicine to treat athero- sclerosis, hypertension, various thrombosis, external injury, and pain. in addition, san qi has been suggested to provide therapeutic benefits for dementia. in ng108- 15 cells senile dementia model induced by amyloid beta-peptide (aβ), san qi sig- nificantly increased the survival rate, differentiation, and growth rate of ng108-15 cells, suggesting that the herb can minimize the neural toxic effects of aβ (liu et al., 2004). san qi has also been shown to enhance learning and memory ability as well as to increase ach content in hippocampus in aβ and ibotenic acid-induced demen- tia models in rats (guo et al., 2004; sun et al., 2007). saponins (e.g., ginsenoside rb1, rd, re, notoginsenoside r1, r2, r3, etc.) are the key bioactive components respon- sible for the neuroprotective effects of san qi (chen and chen, 2004). salvia miltiorrhiza salvia miltiorrhiza (dan shen) is one of most popular chinese herbs and has been used for the management of various diseases, especially cardiovascular diseases such as coronary artery disease, ischemic strokes, and cerebral thrombosis. animal studies demonstrated that dan shen extracts produced neuroprotective effects and reversed learning and memory deficits in ad animal models (mice and rats) induced by beta-amyloid peptide treatment (zhang et al., 2001; liu and li, 2007). in vad models in rats, dan shen extracts have also markedly increased the content of ach and 5-ht and decreased ache activities in the brain tissue (yuan et al., 2002).

natural medicines, nutraceuticals and neurocognition in addition, it is reported that dan shen decreased the number of apoptosis of cranial nerve cells (huang, 2002). the mechanisms of action underpinning these effects have been suggested to attribute to antioxidant, anti-inflammation, anti-cholinesterase, and cns-sedatives effects, all of which are relevant to ad (chen and chen, 2004). tanshinone has been suggested to be the key biomarker (he et al., 2009). crocus sativus crocus sativus (xi hong hua) is commonly used in tcm as an antidepressant, antispasmodic, and anticatarrhal. data from in vivo and in vitro studies demon- strated that xi hong hua possesses neuroprotective properties. xi hong hua extract has shown to improve learning and memory function in ethanol-induced memory impairment in mice and to ameliorate cerebral ischemia–induced oxidative dam- age in rat hippocampus (abe and saito, 2000; hosseinzadeh and sadeghnia, 2005). crocitin, the principal constituent of xi hong hua, which has a strong antioxidant, is suggested to be largely responsible for saffron’s protective effect on the central nervous system (abe and saito, 2000). camellia sinensis data from animal and epidemiological studies suggested that drinking green tea (camellia sinensis) may help to protect the brain against the aging process. there is evidence that suggests a probable inverse correlation between tea consumption and the incidence of ad and other neurodegenerative diseases (e.g., parkinson’s disease) (sharangi, 2009). the chief bioactive components of tea are polyphenols, caffeine, and amino acids. polyphenols are responsible for tea’s well-known antioxidant properties (sharangi, 2009). in particular, its main catechin polyphenol constituent, epigallocat- echin gallate (egcg), has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders (mandel et al., 2008). in a human cross-sectional study assessing the effect of green tea on cognitive functions in elderly japanese participants, it was reported that green tea consumption of two or more cups (100 ml per cup) per day reduced the prevalence of cognitive function impairments in the participant cohort (kuriyama et al., 2006). more recently, nurk and his colleagues (2009) examined the relationship between intake of three flavonoid-rich foods (chocolate, wine and tea) in the elderly participants aged between 70 and 74 years. the results showed that the consumption of these foods (especially tea) is associated with enhanced cognitive function in a dose-dependent manner (nurk et al., 2009). herbal formulation and synergistic effects combination therapy underpins the philosophy of chinese herbal medicine, where patients are generally treated with multi-herbal formulations. there is preliminary evidence that complex chemical mixtures enhance therapeutic efficacy by facilitat- ing synergistic action and/or ameliorating/preventing potential side effects (kroll and cordes, 2006; wagner and ulrich-merzenich, 2009). synergistic effects can occur in many ways, including for example, where constituents from herbal extracts interact with one another to improve their solubility and hence the bioavailability (wagner and ulrich-merzenich, 2009). furthermore, constituents of complex herbal extracts can

chinese medicine used to treat dementia affect different targets, which make them ideal therapies for disorders such as demen- tia, which have multifactorial/multisystem pathophysiological components (kroll and cordes, 2006). for example, clinical studies in healthy volunteers have found that the cognitive effects of a ginkgo–ginseng combination are significantly greater than those of either extract delivered alone, suggesting the possibilities of synergistic interactions between the extracts (kennedy et al., 2001; scholey and kennedy, 2002). over hundreds of years of tcm clinical practice, numerous complex herbal formulations have been used for managing dementia-like symptoms. for example, guipi decoction is a multi-herbs herbal formulation (atractylodes macrocephala, astragalus henryi, arillus longan, semen zizyphi spinosae, radix ginseng, radix aucklandiae, radix glycyrrhizae, radix angelicae sinensis, and radix polygalae), which was first used back in 1253 in china. data from animal studies suggest that guipi decoction can significantly improve learning and memory function in ad animal models in mice and rats (hou and xu, 2006; qian et al., 2006; zou et al., 2006). in the following section, research on a three-herb, standardized herbal for- mulation, wnk (which the authors have been partially involved) will be discussed to provide an example of the development of new herbal medicine formulations. using modern chemistry, pharmacognosy, and pharmacology techniques, wnk’s chemical and pharmacological profiles were clearly defined. the data from these experiments demonstrate significant improvements in learning and memory func- tions, pathogenic biochemical parameters in blood and brain tissue, and antioxidant capacity in various experimental dementia models. in an in vivo study, wnk (11, 22, and 44 mg/kg/day over 15 days) was adminis- tered to dysmnesia models in mice induced by scopolamine, reserpine, chlorderazin, sodium nitrite, and alcohol, respectively. compared with the control, the middle- and high-dose treatment of wnk markedly decreased the error numbers and prolonged the latencies of dysmnesia in all active groups in step-through or step-down tests (xu et al., 2007). in a chronic cerebral hypoperfusion model induced by bilateral common carotid artery ligation in rats, 8 weeks treatment of wnk (i.g.) significantly shortened the persistent time of finding the platform in morris water maze (xu et al., 2008). activity of cholinesterase was also significantly decreased while the ach level was markedly increased in the brain tissue. in addition, the activity of superoxide dismutase (sod) was significantly enhanced. the effects of wnk on ach were also investigated in an amyloid β-protein-induced dementia model in rats (liu et al., 2004). after 30 days treatment of wnk (15.5 and 31.0 mg/kg/day, i.g.), ach levels in the brain tissue increased significantly by 18.56% and 19.97%, respectively, when com- pared with the model group. similarly, in a pdappv7171 transgenic dementia model in mice, wnk treatment at 31 and 62 mg/kg/day i.g. over 12 weeks significantly increased ach in both treatment groups, while serotonin (5-ht) levels in the brain tis- sue decreased significantly in the high-dose wnk group only (cong et al., 2007). the effects of crocin alone (one of the principal active components of wnk) on ischemia/ reperfusion (i/r) injury were investigated using a global or bilateral common carotid artery occlusion (bccao) model in mice (zheng et al., 2006). transient global cere- bral ischemia (20 min) followed by 24 h of reperfusion significantly increases the production of nitric oxide (no) and malondialdehyde (mda) in cortical microvas- cular homogenates and decreases the activities of superoxide dismutase (sod) and

natural medicines, nutraceuticals and neurocognition glutathione peroxide (gsh-px). pretreatment with crocin at 20 mg/kg, on the other hand, resulted in a significant decrease in mda content and a significant elevation in total antioxidant capacity (increased sod and gsh-px activities). a pilot randomized, double-blind, placebo-controlled clinical trial of wnk for vad in humans demonstrated some promising results (liu et al., 2007). sixty- two patients (32 in active group, 30 in placebo group) with probable or possible vad according to the national institute for neurologic disease and stroke and the association internationale pour la recherche et l’enseignement en neurosciences (ninds-airen) criteria were recruited. patients received 16 weeks treatment of either active or identical placebo after randomization. at completion of treatment, the mean scores of the primary efficacy parameter (adas-cog) reduced from 24.5 to 20.3 (mean reduction, 4.18 ± 0.75) in patients receiving wnk and from 18.98 to 17.81 (mean reduction, 1.18 ± 0.58) in patients receiving the placebo. while the minor dif- ferences in baseline adas-cog scores were not significantly different, the improve- ment of adas-cog scores following wnk treatment was significantly greater than that of the placebo group. wnk also significantly reduced the degree of impairment in quality of life caused by vad as evidenced by the significant improvement in sf36 scores. out of eight domains, significant improvements were observed in “role emo- tion,” “mental health,” “role physical,” and “social functioning” in patients receiving wnk while significant trends toward improvement were also noted in two other domains (“physical functioning” and “bodily pain”). importantly, the results for adas-cog are consistent with the finding from a single photon emission computed tomography (spect) sub-study of 18 patients (n = 7 wnk; n = 11 placebo) within this trial. the spect scan results showed that when compared to the placebo, wnk treatment appeared to increase blood flow in the inferior frontal and anterior tempo- ral lobes, an effect which was more marked in the left hemisphere. these regions are known to be associated with cognitive, memory, auditory, and speech functions. no serious adverse events were reported within this trial. acupuncture acupuncture is one of the main modalities of tcm and has gained popularity over the past decade in the western world. in tcm, acupuncture is viewed as complex intervention comprising diagnosis, needling, lifestyle advice, therapeutic alliance, and adjunctive treatments such as moxibustion, cupping, and sometimes even chinese herbs. acupuncture is practiced widely by not only tcm practitioners but also medical doctors and other allied health practitioners including physiotherapists, chiropractors, nurses, and osteopaths; however, the latter groups tend to focus on the needling component. acupuncture needling normally involves inserting fine needles into specific points on the body surface (acupoints) to promote circulation of qi and blood through the meridian channel systems and to restore the balance of yin and yang and, in doing so, to treat illness and promote health. acupuncture has been used to treat various diseases including, pain, musculoskeletal injuries, and depression. there is also some evidence to suggest that acupuncture might provide therapeutic benefits in the management of dementia and associated symptoms (e.g., agitated and aggressive behaviors).

chinese medicine used to treat dementia clinical trials of acupuncture acupuncture treatment has been found to improve cognitive and memory function in patients with dementia (especially vad). in a study by zhao et al. (2009), 90 vad patients were randomized to receive electro-acupuncture, nimodipine, or electro- acupuncture plus nimodipine for 6 weeks. significant improvements in mmse scores were reported in all three groups compared with baseline. a similar finding was reported in a study that evaluated the effects of long-term retention of scalp needle on mmse, hastgawa dementia scale (hds), activity of daily living (adl), and latency and amplitude of event-related potential p300 of eeg in vad patients (chu et al., 2008). here, 65 patients were randomly allocated to acupuncture (n = 33) and almi- trine bismesylate (duxil). the total effective rates (compared to baseline) of mmse, hds, adl, and the latency of p300 were significantly greater in the acupuncture group than those in the medication group. the results suggest that the scalp acupunc- ture treatment can improve cognitive function and activity of daily living in vad. in another study by lin et al. (2009), the combination of acupressure (a special acupunc- ture technique in which pressure is applied to acupoints, rather than needle insertion) and montessori-based activities was found to be effective in relieving agitated and aggressive behaviors in 133 institutionalized residents with dementia in taiwan. in a positron emission tomography (pet) study, huang et al. (2005) investigated whether acupuncture improved cerebral glucose metabolism in 10 patients with vad. half of the patients received acupuncture at li15, sj5, li4, sp10, st36, sp6, and lr3 (standard hemiplegia needling) whereas the other half received acupuncture at these same points plus du20, du26, and ht7 (vad specific needling). the acupunc- ture was administered every weekday for four weeks, i.e., 20 sessions. compared with baseline, standard hemiplegia needling increased glucose metabolism in the len- tiform nucleus of the affected hemisphere and the temporal lobe of the non-affected hemisphere. the addition of vad-specific needling increased glucose metabolism in the frontal lobes and thalami bilaterally as well as in the temporal lobe and the lentiform nucleus of the non-affected hemisphere, which is consistent with the results of a study using the same cohort of participants that showed a significant increase in blood circulation in response to acupuncture to the respective areas of the brain (huang et al., 2006). despite the encouraging results from the aforementioned clinical trials, there are significant methodological limitations to most of these studies. perhaps most importantly, these studies did not include placebo comparators, making it difficult to determine if the observed effects of acupuncture reflect its efficacy or some other processes, such as the placebo effect. further, most of the studies had relatively small sample sizes. weina et al. (2007) recently conducted a cochrane review of acupunc- ture for vad. the authors identified 95 relevant studies of which improvement was reported in up to 71%–90% of the treatment group. however, none of these trials met their inclusion criteria due to inadequate methodology. of the 95 trials, only 17 were randomized controlled trial and these were limited due to combining interventions or providing pharmaceutical treatment to the control groups. this led to a conclu- sion that the effectiveness of acupuncture for vad is uncertain and that high-quality randomized placebo-controlled trials of acupuncture are needed.

natural medicines, nutraceuticals and neurocognition animal studies there has been substantial research into acupuncture needling on animals, most of which has been published in the chinese literature. these studies attempt to determine mechanistic actions of acupuncture and are generally consistent with findings from clinical trials in terms of the potential cognition enhancing effects of acupuncture. for example, in vad rats, animals given acupuncture needling performed better in subsequent tasks in a morris water maze when compared with those in the control groups (lai et al., 2000; wang, 2002; meng et al., 2009). the following mechanistic pathways have been postulated based on the existing animal studies. effects on neurotransmitter: acupuncture is reported to reduce the activity of cholinesterase and hence slow down the ach metabolism in the brain of vad mice (tian et al., 2002). an increase in expression of chat mrna and chat protein– positive cells in the hippocampus of vad rats was observed after acupuncture treatment, implying enhanced cholinergic neuron function (ma and tang, 2009). acupuncture is also found to be able to reverse the dementia-induced reduction of 5-ht, dopamine, and noradrenalin in cortex, hippocampus, and hypothalamus (lai et al., 1999). electro-acupuncture can also increase the level of arginine vasopressin, an important neuropeptide closely related to memory and learning (mo et al., 2002). effects on oxygen free radicals: electro-acupuncture has been shown to increase the activity of superoxide dismutase (sod) and decrease malondialdehyde (mda), suggesting that the intervention promotes free-radical scavenging abilities and hence minimizes the tissue damage caused by the free radicals (lai et al., 2000; zhao et al., 2000). effects on vasoactive substances: electro-acupuncture treatment was associated with an increase in nitric oxide (no) content in hippocampus in vad rats. this change correlated well with the improvement of learning and memory observed in the same animals (lai and yu, 2001). acupuncture is also shown to increase 6-keto-pgf1 in plasma and this may be, at least partially, responsible for the beneficial antiplatelet aggregation and vasodilation effects of acupuncture in vad (tian et al., 2002). anti-apoptotic effects: bcl-2 is an important anti-apoptotic gene. ear acupuncture has shown to significantly increase expression of the anti-apoptotic bcl-2 protein in ca1 region of hippocampus. the result suggests that acupuncture can provide protective effects to hippocampal neurons against apoptosis in vad, and hence con- tribute to the improvement of learning and memory function (zhang et al., 2001). other mechanisms: it is reported that electro-acupuncture increased the number and density of the neurons in ca1 area of hippocampal gyrus in vad model in mice (zhao et al., 2001). a study investigating the effect of electro-acupuncture on the cerebral circulation revealed that the treatment at du20, du14, and st36 increased the regional cerebral blood flow in the parietal lobe and hippocampus in vad rats (he, 2002). ear acupuncture has also shown to cause increased expression of c-fos mrna and protein-positive cell in ca1 area of the hippocampus in vad rat model (zhang et al., 2001).

chinese medicine used to treat dementia while these animal studies are suggestive of potential anti-dementia effects of acupuncture needling, it is unclear if and how these findings might generalize to humans and this needs to be investigated empirically. other chinese medicine interventions for dementia other chinese medicine modalities that have been used in clinical practice to treat dementias and/or alleviate associated symptoms include (but are not limited to): qigong exercise, tai chi, tuina, nutritional or food therapies. the direct scientific evidence to support the use of these interventions for dementia is currently lacking, although there is some preliminary evidence regarding qigong and tai chi, which is described in the following. qigong exercise qigong is an ancient and widely practiced chinese meditation exercise combining meditation, controlled breathing, and gentle physical movements aimed at directing mental attention to specific area of the body (posadzki et al., 2010). qigong has been suggested to be able to control the vital energy (qi) of the body and consequently to improve spiritual, physical, and mental health (jones, 2001). medical qigong can be divided into two parts: internal and external. the former is developed by individual practice of qigong exercise. the latter refers to experienced qigong practitioners emitting qi to a patient for the purpose of healing/curing diseases (sancier, 1996). preliminary evidence suggests that qigong practice can help to relieve stress and anxiety. for example, a clinical trial involving 24 generally healthy male par- ticipants found that qigong significantly improved anxiety, alertness, depression, fatigue, and tension (jung et al., 2006). it has also been reported that qigong could normalize, stabilize, and sustain positive and pleasant emotional states of human mind and as a result improve the well-being and quality of life in humans (posadzki et al., 2010). in a randomized controlled trial by lee et al. (2005), heart-rate vari- ability (hrv) was compared in 40 subjects receiving external qigong or placebo. here, qigong significantly reduced heart rate and increased hrv, suggesting that the treatment stabilizes the sympathovagal function when compared with the placebo (lee et al., 2005). eeg topographic mapping also revealed some unique eeg pat- terns in response to qigong practice, which were clearly different from that of resting status with eyes closed (zhang, 1988). the alpha activity occurred predominantly in the anterior half of brain during qigong state. there were also significant increased alpha1 component and decreased alpha2 component, suggesting significant slowing of alpha peak frequency. the mechanisms of action underpinning the observed physiological/psychological effects of qigong are not clear. however, acute qigong training has been associated with a significant increase in the levels of human endogenous opioids peptides (e.g., beta-endorphin) and a decrease in stress-related hormones including adrenocortico- trophic hormone (acth), cortisol, and dehydroepiandrosterone-sulfate (dhea-s) (ryu et al., 1996; jones, 2001). these indicate that qigong, when used as a stress cop- ing method, can affect hormonal regulation to maintain neurological homeostasis.

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natural medicines, nutraceuticals and neurocognition examined flavonoid intake in relation to cognitive function over 10 years (letenneur et al., 2007). the mmse, benton’s visual retention test and isaacs set test were used to assess cognitive function. after adjustments for participant demograph- ics, flavonoid intake was significantly associated with better cognitive function over time. positive effects on cognitive function in healthy volunteers as well as those with cognitive deficits (mohsen et al., 2002) have been found using treat- ment with gingko biloba extract, known to contain flavonoids (cotman et al., 2002; mandel et al., 2004b). burns and nettelbeck (2003) conducted a 12 week, placebo- controlled study assessing the effects of g. biloba on cognitive abilities. long- term memory assessed by associational learning tasks and tested in immediate and delayed-recall forms showed significant improvement in those consuming the g. biloba. a similar 30 day, randomized, double-blind, placebo-controlled clinical trial found significant improvements in speed of information processing working memory and executive processing in participants consuming g. biloba (stough et al., 2001). according to the authors these improvements are likely to be due to the antioxidant and flavonoid characteristics of the extract (burns and nettelbeck, 2003; stough et al., 2001). methodological limitations of epidemiological studies investigating antioxidant and flavonoid consumption most of the studies investigating the relationship between antioxidant/flavonoid con- sumption and cognitive function are epidemiological. unfortunately, epidemiologi- cal studies have several methodological limitations. finding the time and equipment needed for assessing the cognitive function of large groups of people is difficult. therefore, most studies use short cognitive questionnaires (e.g., mmse), or small subsets of tests within much larger test batteries, rather than comprehensive cogni- tive assessments. furthermore, in most cases no rationale was provided to validate the combination of tests used. studies using more accurate and specific methods of assessment would provide a clearer understanding of the relationship between cogni- tive function and antioxidant consumption. epidemiological studies also have no control over participants’ antioxidant/ flavonoid consumption. there are various factors that could influence the effects of supplement consumption. these include “the length of time taking the supple- ment, the constancy, amount, purity and type of preparation, and the composition of the mixture” (martin and mayer, 2003, p. 71). this makes it difficult to examine the effects of individual antioxidants on cognitive function (gray et al., 2003), given the wide variety of antioxidant preparations publicly consumed in supplements and in everyday diet. another limitation of epidemiological study designs is that they do not allow researchers to fully exclude the possibility of confounding by unmeasured factors (kuriyama et al., 2006). for example, supplement intake may indicate a healthier diet or different social and lifestyle factors in those consuming supplements, which independently affect cognitive function. furthermore, epidemiological designs do not enable researchers to make causal associations between antioxidant/flavonoid consumption and cognitive function. even if it is possible to successfully adjust the

epigallocatechin gallate (egcg) and cognitive function findings for covariates, it is impossible to ensure there is not any hidden unmeasured covariates that could affect the results (little and rubin, 2000). animal studies several animal studies have investigated the relationship between antioxidants/ flavonoids and cognitive function. milgram et al. (2004) investigated the long-term effects of antioxidant supplementation on cognitive function, specifically learning, in a longitudinal study of aged dogs. dogs administered the antioxidant supplement for 1 year presented with significantly improved learning ability on a size discrimi- nation learning task and on a size discrimination reversal learning task. in a similar study, the consumption of an antioxidant-enriched supplement for 6 months resulted in a significant improvement in the ability of aged dogs to perform difficult learn- ing tasks (cotman et al., 2002). the dogs’ cognitive ability improved most on tasks involving oddity discrimination. the authors attributed these results to the cognitive enhancing effects of the flavonoids in the supplements. this is supported by studies on flavonoids. joseph et al. (1999) found that aged rats fed flavonoid-rich supple- mented food (including blueberry, spinach, and strawberry) for 8 weeks significantly improved in spatial learning and memory as assessed by the working memory ver- sion of the morris water maze. green tea and cognitive function only four studies have investigated the relationship between tea and cognitive func- tion in humans. the first study analyzed data collected from the tsurugaya project, an extensive health assessment of elderly japanese people (kuriyama et al., 2006). they found a higher consumption of green tea was associated with a lower preva- lence of cognitive impairment. there was no association between the consumption of black tea, oolong tea, or coffee and cognitive function. the lower prevalence of cognitive impairment was attributed to the unique effects of egcg. the second study analyzed the association between tea consumption and cognitive function using a cross-sectional and longitudinal methodological design (ng et al., 2008). participants were a cohort of chinese older adults from the singapore longitudinal aging study (slas). statistical analysis supported an association between green tea consumption and lowered cognitive impairment. however, this association cannot be separated from the influence of black or oolong tea, given only 10 participants in the study consumed green tea exclusively (ng et al., 2008). another limitation is both kuriyama et al. and ng et al. used the mmse as their primary measure of cognitive function. as mentioned earlier, the mmse was designed as a screening instrument for dementia (cress, 2006), consequently it does not comprehensively evaluate cog- nitive function. there are two more studies that have investigated the relationship between tea and cognitive function in humans. both of the studies assessed cognitive function using comprehensive batteries of tests. nurk and associates (2009) found a positive association between flavonoid-enriched foods (including wine, tea, and chocolate) and improved cognitive test performance. participants who consumed tea performed

natural medicines, nutraceuticals and neurocognition significantly better on tests assessing attention, perceptual speed, visuospatial skills, and global cognition than those who did not. several mechanisms by which flavonoid consumption might protect against cognitive impairment were proposed with major emphasis on the antioxidant actions of flavonoids (nurk et al., 2009). however, the type of tea consumed was not recorded; therefore, it is impossible to determine the unique influence of green tea in comparison to black or oolong tea. the fourth study, a continuation of the study conducted by ng et al. (2008), analyzed the relation- ship between tea consumption and cognitive function in a subsample of participants from the slas cohort (feng et al., 2010). tea consumption was associated with improved memory, executive function, and information processing speed. coffee consumption and cognitive function were not related, indicating the cognitive effects observed were due to a component specific to tea consumption. both black/oolong tea consumption and green tea consumption were associated with better cognitive performance. however, of the 716 participants only four participants consumed green tea exclusively, making it difficult to examine the unique effects of green tea. the studies conducted by kuriyama et al. (2006), ng et al. (2008), nurk et al. (2009), and feng et al. (2010) are methodologically limited due to the limitations of epidemiological designs. as mentioned earlier, epidemiological studies do not allow researchers to fully exclude the possibility of confounding by unmeasured factors. tea intake may indicate a healthier diet or more favorable social and lifestyle factors in those consuming tea, which independently improve cognitive function. there is also large intersubject and intrasubject variability in the consumption of tea polyphe- nols (chow et al., 2001). as only epidemiological studies have been conducted on this topic, it is impossible to determine a causal relationship between tea consump- tion and cognitive function. egcg and cognitive function several animal studies have examined the relationship between egcg and cogni- tive function. a recent study found ec consumption improves spatial memory in mice (praag et al., 2007). the mice were trained in a water maze for 2 weeks with four trials per day for 8 days. learning was faster and retention longer in ec-treated mice. praag et al. attributed the memory-enhancing benefits of ec to its ability to increase cortical blood flow. the relationship between catechin consumption and cognitive function has also been investigated in rats. haque et al. (2006) investi- gated the effect of long-term oral administration of green tea catechins (60% egcg) on the spatial learning ability of young rats. rats administered green tea catechins presented with improved memory-related learning ability as measured by comple- tion of the eight-arm radial maze. the authors attributed this improvement to the antioxidative activity of green tea catechins (haque et al., 2006). similarly, another study investigated the effects of green tea extract administration (30% egcg) on cognitive function, as measured by passive avoidance and an elevated maze task, in young and old rats (kaur et al., 2008). the extract significantly improved learning and memory in older rats. egcg has also been implicated in preventing cognitive decline in cognitively impaired animals. unno and associates (2006) found the usual decline of memory

epigallocatechin gallate (egcg) and cognitive function in senescence-accelerated (samp10) mice was significantly slowed when the mice consumed green tea catechins (31.7% egcg) on a daily basis for 1 year. memory was assessed using the passive avoidance task. samp10 mice are a model of brain senescence with cerebral atrophy and cognitive dysfunction. the administration of green tea polyphenols (60% egcg) has also been found to reduce cognitive impair- ments induced by psychological stress in rats (chen et al., 2009). the animal model of psychological stress was developed by restraint where the rats’ movement was limited periodically for 3 weeks. the rats’ cognitive function, as measured by per- formance in an open-field test, step-through test, and water maze, was improved by the consumption of the green tea polyphenols. egcg has also been found to enhance long-term potentiation (ltp). in a study conducted by xie et al. (2008), ltp in ts65dn mice was significantly enhanced when hippocampal slices were pre-incubated with egcg for 1 h prior to the experi- ment. this is important because ltp is a “well-characterized form of synaptic plasticity that fulfils many of the criteria for a neural correlate of memory” (cooke and bliss, 2006, p. 1659), and is widely considered the major cellular mechanism that influences learning and memory (abraham and williams, 2003). furthermore, xie et al. investigated ts65dn mice, a down syndrome mouse model with deficits in ltp and spatial learning and memory, further implicating the potential of egcg in influencing organisms with cognitive impairments. acute cognitive effects of egcg of the studies reviewed, the majority have involved the administration of antioxi- dants, flavonoids, green tea, or egcg for at least 2 weeks. however, there is evi- dence that egcg may also have an acute effect (pietta et al., 1998; xie et al., 2008). several studies have investigated the absorption of egcg. the time to maximum absorption of catechins has been reported to be approximately 2 h (duffy et al., 2001; pietta et al., 1998), with the plasma elimination half-life of approximately 2–3 h (collie and morley, 2007; mckay and blumberg, 2007). in line with these findings, the highest concentrations of catechins in humans have been reported to occur around 1 h after ingestion (kimura et al., 2002). several studies have investigated the effect of egcg consumption on acute anti- oxidant activity. in one study a sample of 12 participants were supplemented with single doses of green tea catechins equivalent to 400 mg egcg, both in free and in phospholipid complex forms (pietta et al., 1998). blood samples were collected before and 60, 120, 180, 240, 300, and 360 min after ingestion. a single dose of both forms of egcg produced an increase in total radical antioxidant parameter, with a peak at 2 h after ingestion (pietta et al., 1998). similarly, kimura and associates (2002) investigated the consumption of a single (164 mg) and double (328 mg) dose of egcg on ferric-reducing antioxidant power. in contrast to pietta and associates, there were no significant differences in either dose from baseline 30, 60, or 180 min after ingestion. however, kimura et al. had a sample of five participants, which may have been insufficient to detect an effect. furthermore, the studies measured anti- oxidant activity using different assays that differ in their chemistry and their mecha- nisms in detecting differences in activity (pellegrini et al., 2003).

natural medicines, nutraceuticals and neurocognition given its acute physiological effects, two recent studies have examined the acute neurocognitive effects of egcg administration (scholey et al., 2012; wightman et al., 2012). scholey and colleagues found increased self-rated calmness and reduced stress 2 h following a 300 mg dose of egcg (teavigo). the behavioral effects were coupled with treatment-related changes in overall eeg activity—and increases in alpha, beta, and theta waveform activity localized to frontal regions. wightman et al.’s (2012) results also indicate changes in frontal activity, with decreased blood flow to this region as measured using near infrared spectroscopy following 135 mg of the same extract. the wightman study found no change in mood or cognitive per- formance (repeated cycles of cognitively demanding tasks) following 135 or 270 mg of the extract. the acute effects of flavonoids, more specifically the consumption of g. biloba and bacopa monniera, on cognitive function have been investigated. kennedy et al. (2000) investigated the cognitive effects of an acute administration of g. biloba. their results showed acute g. biloba administration enhances cognitive perfor- mance in healthy young adults. this cognitive enhancement was most noticeable in tasks assessing attention. the effect was time-dependent, with significant improve- ments found at 150, 240, and 360 min following ingestion. contrastingly, a similar study conducted by nathan et al. (2001) found no relationship between a single dose of b. monniera, known to have similar antioxidant activities to egcg, and cognitive function. the authors suggested a chronic administration of b. monniera may be required to significantly improve cognitive function. biological mechanisms of egcg related to cognitive function antioxidant properties although the mechanisms underlying the cognitive effects of egcg are not fully understood, its benefits are commonly attributed to its antioxidant properties (zaveri, 2006). egcg is a more powerful antioxidant than vitamins c and e (kimura et al., 2002; kuriyama et al., 2006). several studies have investigated the antioxidant power of egcg. kimura and associates (2002) investigated the consumption of a single dose of egcg on ferric-reducing antioxidant power. they found no signifi- cant differences from baseline 30, 60, or 180 min after the ingestion of 328 mg of egcg. conversely, other studies have found a single dose of green tea causes an increase in ferric-reducing ability of plasma assay (leenan et al., 2000) and total radical antioxidant parameter (pietta et al., 1998), measuring antioxidant power. however, in the later studies participants ingested a larger than normal amount of tea catechins (400–900 mg vs. a normal value of 300 mg), suggesting larger amounts of egcg may need to be consumed to exert its antioxidant power. the regular con- sumption of green tea catechins, as evidenced in a 30 day study conducted by pietta and simonetti (1998), has also been found to provide antioxidant protection. the antioxidative effect of egcg may also influence cognitive function by ameliorating the effects of oxidative stress. oxidative stress refers to the damages in cellular structure and functions that occur due to the increased production of

epigallocatechin gallate (egcg) and cognitive function free radicals, reactive species, and oxidant-related reactions (yu and chung, 2006). research has shown the brain is particularly vulnerable to oxidative stress over time because of its high oxygen consumption, 20% of the total body oxygen, and its deficiency in free radical protection (joseph et al., 1999; kaur et al., 2008). antioxidants, in particular egcg, may improve cellular functioning and minimize oxidative stress in aged organisms (blokhina et al., 2003; yu and chung, 2006). the antioxidant properties of egcg have also been found to promote the inhi- bition of xanthine oxidase, which can lower the production of oxygen-free radi- cals in the brain (lee et al., 2004; pietta and simonetti, 1998). furthermore, unno and associates (2006) found oxidative damage in dna was suppressed in aged mice fed egcg. the consumption of egcg has been suggested as a treatment for alzheimer’s disease due to its ability to reduce the effects of oxidative stress (engelhart et al., 2002). the metal-chelating properties of green tea catechins are also important con- tributors to their antioxidative activity (zaveri, 2006). although egcg is a rela- tively selective chelator of iron (mandel et al., 2007), it also chelates other metals (reznichenko et al., 2006). metal chelators are compounds that bind to metals con- sequently rendering them motionless and unable to participate in neurodegenerative progression (chaston and richardson, 2003). it has been suggested in neurodegen- eration metals accumulate in the brain where neuronal death occurs (mandel and youdim, 2004). however, the causal direction is unclear. the metal-chelating char- acteristic of egcg has been associated with its ability in treating parkinson’s dis- ease and alzheimer’s disease (mandel et al., 2006). researchers have proposed several other explanations for the improvements in cognitive function seen after antioxidant consumption. the consumption of antioxi- dants may result in reduced inflammatory responses (joseph et al., 1999) and ace- tylcholinesterase activity (kaur et al., 2008), which is part of the central cholinergic system involved in regulating cognitive functions (kim et al., 004). while some have also proposed an increase in cortical blood flow (pragg et al., 2007) and in the production of neurons (spencer, 2009) may explain the effects. this is supported by recent research that has shown flavanol-enriched foods can increase cerebral blood flow velocity (sorond et al., 2008). furthermore, the oral administration of ec has been found to enhance angiogenesis, the development of new blood vessels from pre- existing blood vessels (pragg et al., 2007). cerebral blood flow has been found to be correlated with cognitive function (ruitenberg et al., 2005). neuroprotective effects data from several studies indicate the antioxidant properties of green tea catechins are unlikely to be the sole explanation for their effects (mandel et al., 2005). both in vivo and in vitro studies have demonstrated green tea catechins exert a neuropro- tective role, and several researchers attribute this to their diverse pharmacological activities (mandel et al., 2004b, 2005; mandel and youdim 2004). bastianetto et al. (2006) showed that egcg is the sole catechin to contribute to the neuroprotective effects of green tea. this characteristic of egcg could be involved in the preven- tion of cognitive decline. over the last 5 years research has demonstrated green

natural medicines, nutraceuticals and neurocognition tea catechins, through their neuroprotective properties, have the ability to effect cell survival or death genes and signal transduction (kalfon et al., 2006; lee et al., 2004; levites et al., 2003; mandel and youdim, 2004; mandel et al., 2004a, 2006; weinreb et al., 2004; youdim et al., 2002). these effects have been reported in a variety of models of toxicity (bastianetto et al., 2006) including that induced by ischemia (lee et al., 2004), n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (levites et al., 2001), glutamate (lee et al., 2004), and β-amyloid peptides (levites et al., 2003). it is important to note it is still unclear whether these neuroprotective effects are due to antioxidant activities or due to the unique activities of egcg on a range of molecular targets. furthermore, most of the mechanisms that have been proposed are based on in vitro studies with amounts of egcg much higher than those achievable in vivo (zaveri, 2006). plasma tea catechin concentrations determined in humans after the oral consumption green tea catechins have been found to be 5–50 times less than the concentrations shown to exert biological activities (chow et al., 2005). whether the neuroprotective mechanisms of egcg can be replicated in vivo is still unknown (zaveri, 2006). bioavailability of egcg understanding the biological effects of tea consumption in humans is made dif- ficult by inadequate information on the bioavailability and biotransformation of tea catechins. there is evidence egcg can cross the blood–brain barrier and has access to the brain after oral ingestion (bastianetto et al., 2006; mohsen et al., 2002). suganuma et al. (1998) found after 3 h 33% of the total amount of catechin absorbed was found in the mouse brain from a single administration of egcg. human studies on the pharmacokinetics of tea catechins have been limited in scope. however, the studies that have been done indicate the bioavailability of egcg in humans to be limited. levels in plasma up to a maximum of 7.3 μmol/l (±3.6) have been reported, but more often are in the submicromolar range (howells et al., 2007; yang et al., 2008). higher plasma concentrations have been found in fasting patients compared to those consuming egcg with food (naumovski, 2010). peperine, derived from black pepper, has also been found to enhance the bioavailability of egcg in mice (lambert et al., 2004). however, oral consumption of egcg in humans results in high plasma clearance levels and volume distribution, suggesting the bioavailability of egcg in the blood may be low (howells et al., 2007). in addition, a large variabil- ity between people in the pharmacokinetics of green tea catechins has been reported (chow et al., 2005). although green tea extracts have been marketed as nutritional supplements, it appears large doses may need to be used because of the limited phar- macokinetic mechanisms of the catechin (zaveri, 2006). future research research investigating the relationship between egcg and cognitive function is in its infancy. the effect of egcg consumption on cognitive function in humans has not been adequately investigated. positive associations between antioxidants,

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natural medicines, nutraceuticals and neurocognition that of people under 65 (bryant and sonerson, 2006). the same report concludes that 33% of these increased costs could be offset by measures aimed at maintaining improved health, which of course also involves brain and cognitive processes. a time-honored and much empirically supported method of promoting optimal health throughout the life span has been through the adoption and maintenance of an appropriate, healthy diet. recent research suggests that this principle not only applies to protection from “physical ailments” such as cardiovascular problems, but may also extend to ameliorating the effects of cognitive decline associated with increased age. the maintenance of brain health underpinning intact cognition is a key factor to maintaining a positive, engaged, and productive lifestyle. in the light of this, the role of diet including supplementation with nutritional and even pharmaco- logical interventions capable of ameliorating the neurocognitive changes that occur with age constitutes vital areas of research. what is cognitive aging? individual age-related changes in cognition vary greatly. however, research in cognitive aspects of aging (typically in 60–90 year-olds) has identified consistent deficits in reasoning and decision making, spatial abilities, perceptual-motor and cognitive speed, and, most robustly, memory (e.g., christensen and kumar, 2003). longitudinal studies of aged populations illuminate the time course of cognitive deterioration. using 5–10 year retest intervals, significant decrements across most cognitive capacities become evident. a recent review of longitudinal aging stud- ies concludes that crystallized intelligence (e.g., factual knowledge) remains intact until late aging whereas measures of speed, information processing, and aspects of memory (e.g., working memory) are more sensitive to decline from age 60 (christensen and kumar, 2003). brain aging and oxidative stress neuroimaging studies reveal that increasing age is reliably associated with ventricu- lar enlargement, reduction in gross brain volume, reductions in frontal and temporo- parietal brain volume, higher levels of cortical atrophy, and increased white-matter hyperintensities (looi and sachdev, 2003). ultimately, shrinkage of cortical vol- ume reduces cognitive capacity (maclullich et al., 2002), and age-related increases in neuropathological events such as β-amyloid protein deposition and formation of neurofibrillary tangles represent significant risk factors. neuropathological events such as β-amyloid deposition are not exclusive to neurodegenerative disorders such as ad, in fact occurring in a large proportion of cognitively intact individuals. for example, in one study, the proportion of nonclinical subjects with β-amyloid deposits ranged from 3% in a 36–40 age group to 75% in an 85+ age group (braak and braak, 1997). alongside age-associated cortical degeneration (maclullich et al., 2002), there exist numerous microscopic insults related to oxidative stress. free radicals formed in the brain produce significant cellular damage and mediate processes that result in neural cell death on large scales (packer, 1992). between 95% and 98% of free radicals and reactive oxygen species (ros), o2 −, ho, and h2o2 are formed by

bacopa monnieri and cognitive aging mitochondria as by-products of cellular respiration. studies of mitochondria isolated from the brain show that 2%–5% of total oxygen consumed yields ros, and these highly reactive molecules make a significant contribution to the peroxidation of prin- cipal cell structures (e.g., membrane lipids) (papa and skulachev, 1997). brain tissue is particularly susceptible due to its disproportionately high metabolic rate and levels of oxygen, the cytotoxic actions of glutamate, and its high concentrations of peroxi- dizable unsaturated fatty acids (packer, 1992). aging decreases the brain’s ability to combat the actions of free radicals. aging is associated with increased levels of pro- oxidant mediators and decreases in antioxidants (artur et al., 1992). the relationship between cognition and oxidative stress is evident in the extensive damage caused by free radicals in age-related neurological conditions (coyle and putfarcken, 1993; smith et al., 1996) and animal models of age-related oxidative injury with central cognitive and behavioral impairments (forster et al., 1996). concurrent with the normal age-related cognitive changes are increases in the formation of brain ros resulting in significant damage to dna, proteins, and in particular membrane lipids (smith et al., 1991). although multiple factors precipitate oxidative stress throughout the body, the brain is particularly vulnerable, and its cumulative effects may account for the delayed onset and progressive nature of alzheimer’s and parkinson’s demen- tias as well as normal age-related mental deterioration (coyle and putfarcken, 1993). antioxidants and cognition the central role of oxidative stress in age-related cognitive decline and neurode- generative diseases has driven numerous studies examining the potential benefits of antioxidants in altering, reversing, or forestalling neuronal and behavioral changes (e.g., sano et al., 1997). antioxidant supplementation results in improved cognition and behavior in aged animals and concurrent decreases in oxidative insult to neural structures (socci et al., 1995). human research in this area is largely limited to epi- demiological studies. these have identified positive associations in aged individuals between biological levels of dietary antioxidants (vitamins e and c) and working memory measures including the wechsler memory test (goodwin et al., 1983). less reliable than biological measures, large-scale studies (3000+ participants) have also identified positive relationships between dietary intake of vitamins c and e and stan- dardized memory measures (masaki et al., 2000). while these nonclinical trials do not demonstrate causality, the consensus that memory is the main cognitive vari- able affected by antioxidant status is consistent with patterns of age-related cogni- tive decline and the in vivo neuroanatomy of lipid peroxidation (sram et al., 1993). three controlled studies of active antioxidant supplementation in aged individuals over periods of 1 year or longer reported improved performance on tests of short- term memory, verbal learning, and nonverbal memory (sram et al., 1993; la rue et al., 1997; chandra, 2001). however, these studies did not incorporate indicators of oxidative stress, making it impossible to determine the role of antioxidants in the cognitive changes. despite the great promise that antioxidant supplementation holds for understanding age-related mental deterioration, studies published in the area have been methodologically inadequate. in particular, human studies have thus far been severely limited by inappropriate cognitive measures, lack of biochemical

natural medicines, nutraceuticals and neurocognition indicators, uncontrolled subject populations, and unspecific antioxidant supplemen- tations. one particular herbal medicine that may have some utility in treating patho- logical changes in the brain associated with age-related cognitive decline and that has been used in our laboratory is bacopa monnieri (bm). bacopa monnieri bacopa monnieri (bm) is a botanical medicine from india that has been used for over 3000 years as a traditional ayurvedic treatment for asthma, insomnia, epi- lepsy, and as a “memory tonic” (russo and borrelli, 2005). bm has been used in traditional ayurvedic medicine for various indications including memory decline, inflammation, pain, pyrexia, epilepsy, and as a sedative (russo and borrelli, 2005). bm contains bacoside a and bacoside b that are steroidal saponins believed to be essential for the clinical efficacy of the product. while bm has been reported to have many actions, its memory enhancing effects have attracted most attention and are supported by the psychopharmacology literature. behavioral studies in animals have shown that bm improves motor learning, acquisition, retention, and delay extinction of newly acquired behavior (singh and dharwan, 1997). although the exact mechanisms of action remain uncertain, evidence suggests that bm may modulate the cholinergic system and/or have antioxidant and metal-chelating effects (agrawal, 1993; bhattacharya et al., 1999). bm may also have antiinflammatory (jain, 1994), anxiolytic and antidepressant actions (bhattacharya and ghosal, 1998), relaxant properties in blood vessels (dar and channa, 1999), and adaptogenic activ- ity (rai et al., 2003). chronic administration of bm inhibits lipid peroxidation in the prefrontal cortex, striatum, and hippocampus via a similar mechanism to ­ vitamin e (bhattacharya et al., 2000). in an animal model of ad, there was a dose-related reversal by bm of cognitive deficits produced by the neurotoxins colchicine and ibotenic acid (bhattacharya et al., 1999). in rodents, bm inhibited the damage induced by high concentrations of nitric oxide in astrocytes (russo et al., 2003). memory deficits following cholinergic blockade by scopolamine were reversed by bm treatment. in animal studies, bm reduced lipid peroxidation induced by feso4 and cumene hydroperoxide, indicating that, similarly to the chelating properties of edta, it acts at the initiation level by chelating fe++ (tripathi et al., 1996). more recently, in transgenic mice, bm supplementation reduced specific amyloid peptides by up to 60% while also improving memory performance (holcomb, 2006). thus, bm appears to have multiple modes of action in the brain all of which may be useful in ameliorating cognitive decline in the elderly. these include (1) direct procholiner- gic action, (2) antioxidant (flavonoid) capacity, (3) metal chelation, (4) antiinflamma- tory effects, (5) increased blood circulation, (6) adaptogenic activity, and (7) removal of β-amyloid deposits. extracts of bm extracts of bm contain significant levels of saponic bacosides a, b, and c; and bacosapoinins d, e, and f, in addition to other chemical constituents including alka- loids, flavonoids, and phytosterols (pengelly, 1997; heinrich et al., 2004). the main

natural medicines, nutraceuticals and neurocognition or similar (stough et al., 2001; roodenrys et al., 2002; calabrese et al., 2008; stough et al., 2008; morgan and stevens, 2010). in roodenrys’ (2002) study, an increased dose of 400 mg/day was given to participants weighing over 90 kg. however, lower (250 mg/day) (raghav et al., 2006) and higher doses of 450 mg/day (barbhaiya et al., 2008) have been used chronically. the human studies reviewed by pase et al. (2012) provide evidence of highly promising results in areas of cognition, memory, and speed of processing tasks. some studies used a healthy young adult population (stough et al., 2001; nathan et al., 2004; stough et al., 2008), and others used “middle aged” (roodenrys et al., 2002) or “elderly” populations (calabrese et al., 2008). progressively, aging popula- tions will be targeted for bm supplementation, given current evidence for mode of action on the brain. regardless of the age of the population, bm consistently improved selected cog- nitive functions. for example, bm was shown to improve working memory (stough et al., 2008), learning rate and memory consolidation, and other components of the rey auditory verbal learning test (stough et al., 2001; calabrese et al., 2008; morgan and stevens, 2010) as well as improvements in memory measured by the wechsler memory scale found in the raghav et al. (2006) study. furthermore, exec- utive functioning tasks, such as the stroop (calabrese et al., 2008) and inspection time (stough et al., 2001), have also shown to be improved by intervention with bm. the effect sizes on many domains were moderate to strong. bm on various out- come measures consistently improved cognition, memory, and speed of processing in older adults with an overall moderate effect on all measure of memory (mean d = 0.58). bm was also found to improve learning and memory (mean d = 0.61), working memory and executive function (mean d = 0.54), and visual processing and attention (mean d = 0.28). bm has also been studied in the context of age-associated memory impairment (aami). raghav et al. (2006) tested a sample of middle aged to elderly participants with aami. participants receiving a standardized bm extract (250 mg/day) showed statistically significant improvement across subtests of the wechsler memory scale from week 4 onward. tasks of mental control, logical memory, and paired associated learning showed the greatest improvement. clearly, these data are preliminary and need to be replicated. however, they support and reinforce the memory and cognitive enhancing effects of bm as well as an appropriate age-related target for intervention. to date, only one study has been reported to assess the efficacy of bm in a sample of participants with dementia. a small 6 month pilot study has been carried out by morgan and colleagues (see morgan and stevens, 2010) on participants diagnosed with mild–moderate dementia using bm (300 mg daily) as an adjunct intervention to their standard treatment. participants (n = 5) were tested using the mini mental state examination (mmse) and alzheimer’s disease assessment scale (adas-cog; cogni- tive subscale) at baseline and 6 months. both scales are valid measures of ad decline (folstein et al., 1975; kolibas et al., 2000). the bm intervention improved scores on both scales with 4/5 patients improving on the mmse and 3/5 improving on the adas-cog (although there was a dissociation between the patient who improved on the two scales). these results are an indication that bm may have potential as an adjunct treatment for ad.

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bacopa monnieri and cognitive aging russo, a. and borrelli, f. (2005). bacopa monniera, a reputed nootropic plant: an overview. phytomedicine, 12(4), 305–317. russo, a. et al. (2003). life science, 73(12), 1517–1526. sano, m. et al. (1997). a controlled trial of selegiline, alpha-tocopherol, or both as treatment for alzheimer’s disease. new england journal of medicine, 336(17), 1216–1222. singh, h.k. and dharwan, b.n. (1997). neuropsychopharmacological effects of the ayurvedic nootropic bacopa monniera linn (brahmi). indian journal of pharmacology, 29, s359–s365. smith, c.d. et al. (1991). proceedings of the national academy of sciences, 88, 10540–10543. smith, m.a. et al. (1996). oxidative damage in alzheimer’s. nature, 382, 120–121. socci, d.j., crandall, b.m., and arendash, g.w. (1995). chronic antioxidant treatment improves the cognitive performance of aged rats. brain research, 693(1–2), 88–94. sram, r.j. et al. (1993). effect of antioxidant supplementation in an elderly population. basic life sciences 1993, 61: 459–477. basic life sciences, 61, 459–477. stough, c., downey, l.a., lloyd, j., silber, b., redman, s., hutchison, c., wesnes, k., and nathan, p.j. (2008). examining the nootropic effects of a special extract of bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled ran- domized trial. phytotherapy research, 22(12), 1629–1634. stough, c., lloyd, j., clarke, j., downey, l.a., hutchison, c.w., rodgers, t., and nathan, p.j. (2001). the chronic effects of an extract of bacopa monniera (brahmi) on cognitive function in healthy human subjects. psychopharmacology, 156(4), 481–484. stough, c. et al. (2012). a randomized controlled trial investigating the effect of pycnogenol and bacopa cdri08 herbal medicines on cognitive, cardiovascular, and biochemical functioning in cognitively healthy elderly people: the australian research council longevity intervention (arcli) study protocol (anzctr12611000487910). nutrition journal, 11, 1–9. tripathi, y.b. et al. (1996). indian journal of experimental biology, 34(6), 523–526.

memory-enhancing and associated effects of beseb—cdri-08 of learning. should this requirement imply that all memories are permanent or that some are transient? various theories of learning are usually silent on this vital ques- tion. there does not seem to be any logic to assume that all consequences of experi- ence are permanent. in fact, there are several overriding reasons to suggest that this cannot be the case. many of the stimuli surrounding an individual and evoking a specific functional reaction have little or no adaptive significance. it makes very little sense in terms of economy or adaptation that all stimuli should produce enduring consequences in the brain. on the other hand, it is of adaptative value to be able to store long-term representation of experiences that are either particularly meaningful (in terms of consequences) or are frequently repeated. this plausible theory, supported in the daily experience of life, has been succinctly explained in a study in scarlet by sir arthur conan doyle. dr. james watson was astonished that sherlock holmes was supremely unaware of the copernican theory and the composition of the solar system. “you appear to be astonished” he (sherlock holmes) said, smiling at my (watson’s) expression of surprise. “now that i do know it i shall do my best to forget it.” “to forget it!” (watson) “you see” he (holmes) explained, “i consider that a man’s brain originally is like a little empty attic, and you have to stock it with such furniture as you choose. a fool takes in all the lumber of every sort that he comes across, so that the knowledge which might be useful to him gets crowded out, or at best is jumbled up with a lot of other things, so that he has a difficulty in laying his hands upon it. now the skilful workman is very careful indeed as to what he takes into his brain-attic. he will have nothing but the tools which may help him in doing his work, but of these he has a large assort- ment, and all in the most perfect order. it is a mistake to think that little room has elastic walls and can distend to any extent. depend upon it there comes a time when for every addition of knowledge you forget something that you knew before. it is of the highest importance, therefore, not to have useless facts elbowing out the useful ones.” “but the solar system!” i (watson) protested. “what the deuce is to me?” he (holmes) interrupted impatiently: “you say that we go round the sun. if we went round the moon it would not make a pennyworth of difference to me or to my work.” (emphasis added) (doyle, 1984) this prescient description by doyle bears testimony when we consider the ­ currently accepted concept of executive function. in understanding the executive function, the import of the “working memory” (the ability to hold a goal or ­ relevant information, not allowing any distraction and interference from other sources) has to be considered. the efficiency of executive function is closely related to the ­ converse ability to keep interfering information out of working memory and also out of the set response options. implicit in this postulation is the ability to withhold or ­ suppress such responses that would become incompatible with the goal when the context changes dynamically. such ability is also termed as “response suppression” and is emphasized, for instance, in various theories of attention deficit/hyperactivity disor- der (barkley, 1997; schachar et al., 1993). the individual memorizes only those information that are useful in life and that help him to survive. thus, the ability to suppress unwanted memories and also

natural medicines, nutraceuticals and neurocognition to avoid distractive memory through executive control, as postulated by ­ several researchers (anderson and grew, 2001; anderson et al., 2004), assumes a very significant importance in efficient functioning of day-to-day life. this is one vital aspect that one has to methodologically evolve to study either the drugs ­ influencing or the various mechanisms underlying the processes of learning and memory in experimental animals or human beings. bacopa: historical background bacopa monniera (linn) wettst [synonyms: herpestis monniera (linn) hb&k; grahola monniera linn; monniera cunerfolia michx (vernacular: brahmi)]; ­ family: scorphulariacae is a perennial herb found throughout india in wet and marshy regions. it is frequently mentioned in the religious, social, and medical trea- tises of india since the time of vedic civilization. its antiquity can be traced to the time of the athar-veda (science of well-being) written in 800 bce. the various treatises of ancient and medieval india have laid emphasis on the ability of bacopa in curing various diseases, particularly its unique ability to improve memory, sharpen intellect, facilitate acquisition of newer information, and promote learning. because of its unique properties many eminent indologists (roy, chandra, personal commu- nication) and modern researchers (russo and borrelli, 2005) believe that the word bra ˉhmi originates from lord brahma ˉ, the creator of the universe and the originator of áyurveda in hindu mythology. bacopa is an extremely important plant of the indian system of medicine, viz., a ˉyurveda. in the classical a ˉyurvedic text of çaraka (sharma, 2009), bacopa has been classified as medhya-rasa ˉyan (medhya: memory enhancing and rasa ˉyan: rejuvenating). çaraka has described the most unique features of the efficacy of bacopa in alleviating old age and age-related diseases, promoting memory and intellect, enhancing life span, providing nourishment, excellence, clarity of voice, complexion and luster (sharma, 2009). çaraka has also described a disease that he has termed as atathvabhe ˉne ˉvesha ˉm and has also diagnosed it to be the most dreadful ­ mental illness. the symptoms of the disease resemble a combination of hallucination, schizophrenia, obsessive com- pulsive disorder, and severe psychosis (sharma, 2009) and can be cured only by taking expressed juice of bacopa. the bacopa juice has also been prescribed as cure for epi- lepsy (sharma, 2009). in another treatise, viz., sus 'ruta-samhita, it has been mentioned that a 3 week course of bacopa juice will produce photographic memory and a person can retain hundred words uttered only twice daily (singhal et al., 2009). bacopa with clarified butter has been prescribed to be highly beneficial for leprosy, intermittent fever, epilepsy, and insanity (singhal et al., 2009). a bacopa-based drink has been pre- scribed for uroliathiasis (singhal et al., 2009) and a bacopa-based liquor to cure skin disorder (singhal et al., 2009). earlier investigations because of the traditional importance and unique therapeutic claims of bacopa, it attracted the early attention of chemists in india. some rudimentary investigations were done earlier by the chemists of banaras hindu university (bhu), varanasi

memory-enhancing and associated effects of beseb—cdri-08 (bose and bose, 1931; sastri et al., 1959). the initial neuropharmacological investi- gations were also done in bhu. malhotra and das (1959) reported a sedative effect of glycosides named hersaponins by them. aithal and sirsi (1961) found that the alcoholic extract and to a lesser extent the aqueous extract of the whole plant and chlorpromazine improved the performance of rats in motor learning. sinha (1971) had reported that a single dose of the glycoside hersaponin is better than pentobar- bitone in facilitating acquisition and retention of brightness discrimination reactive. it is difficult, however, to interpret these results in the context of the known tradi- tional claims of improving learning and memory. investigations done at central drug research institute, lucknow chemical investigations rastogi and dhar (1960) at the central drug research institute (cdri) were the first to undertake a systematic chemical examination of the plant. the following constitu- ents were isolated (chatterjee et al., 1963): name of the constituent m.p. (0°c) yield (on the weight of dry plant) % bacoside a 250–1 1.54 64.28 bacoside b 203 0.65 27.11 betulic acid 315 0.11 4.58 d-mannitol 166 0.02 0.83 stigmasterol 170 0.013 0.54 β-sitosterol 137 0.014 0.58 stigmastanol 141 0.05 2.08 the activity of the ethanolic extract was traced to a mixture of triterpenoid saponins, designated as bacosides a and b. both the bacosides showed single spots on tlc on silica gel, while bacoside a was obtained as colorless needles (chatterjee et al., 1965) and bacoside b was colorless powder (basu et al., 1967). bacoside a is levo- rotatory and bacoside b is dextro-rotatory. bacoside a was the major component of the plant and comprised two sets of saponins. one set was derived from pseudojujubogenin as the genuine aglycone. the pseudojujubogenin on acid hydrolysis furnished four triterpenoid transforma- tion products, viz., bacogenins a1, a2, a3, and a5 (kulshreshtha and rastogi, 1973). the jujubogenin on acid hydrolysis yielded two triterpenoids with triene side chains as transformation products. these triterpenoids were designated as bacogenins a4 (trans) and (cis). seasonal variations to monitor the seasonal variations of bacosides, fresh plant materials were collected every month, extracted with ethanol and fractionated. it was carried over a period of

memory-enhancing and associated effects of beseb—cdri-08 energy of humans since the inception of civilization. the experiments of lashley (1917) demonstrating the facilitation of maze learning by low dose of strychnine sulfate is perhaps the first recorded scientific investigation on a drug affecting learn- ing and memory. ever since then, there has been a tremendous upsurge in the study of drugs influencing learning and memory. with a greater widening of horizon, tech- nological advancement of laboratory research equipments, easy availability of target pharmacological tools, the refinement of conceptual framework has also signifi- cantly improved. all these have resulted in the study of drugs facilitating, impairing, and neuromodulating learning and memory in greater depth and detail. however, it will not be wise to overlook the fact that the evaluation of a new drug affecting learning and memory is still beset with several methodological problems. even though these have been dealt in detail elsewhere (singh and dhawan, 1992), it would still be pertinent to summarize some of the overriding issues. at the outset, one important issue is to distinguish the drug effect on learning vis-a-vis its effect on performance. a performance in the absence of a reward or motivation would only reflect latent learning. a true measure of the actual learning can only be witnessed when the experimental animals are motivated or when the reward is introduced (blodget, 1929). it is also important to dissociate the effect of a drug under the conditions when the learning by the experimental animals takes place in the drugged state. such learning performance is not reflected during the normal state when the influence of the drug wears off. generally, any drug having a depressant effect, for example, chlordiaz- epoxide, chlorpromazine, and pentobarbital, will produce such dissociation effects. similarly, it is of great theoretical significance to consider that the effect of a given drug on learning and memory will also depend upon the fact whether the primary action of the drugs is on the receptor or effector systems. any drug having only peripheral effects will still indirectly alter the cns function by modifying the inputs to the cns. conversely, any centrally acting drug will also alter the functions of peripheral nervous system. the type of apparatus chosen to study the effect of a drug on learning and memory is also a serious consideration. small differences in the design of a maze can produce discrepant results in the studies of the effects of drugs on learning. for example, the addition of retracing doors has been shown to increase the reliability of mazes (silverman, 1978). certain conceptual considerations apart from these methodological considerations, our endeavor to formulate a strategy to elucidate the memory-enhancing effect of beseb was also substantially influenced by different conceptual and experimental postulates available in the 1970s. if the classical idea of ivan petrovich pavlov about the formation of temporary connection provided an excellent starting point, the hypothesis of hebb (1949) of convergence of pathways and the coactivity of neurons resulting in modifiable synapses provided the additional fillip. an extremely important consideration was the result obtained by mcgaugh (1966), who taking a cue from the consolidation hypothesis evolved from the studies of electroconvulsive shock (ecs) induced amnesia (dunccan, 1949; glickman, 1961), suggested that the memory formation is a time-dependent process.

memory-enhancing and associated effects of beseb—cdri-08 cold (5°c), and low-oxygen tension (428 mm hg pressure, equivalent to an altitude of 15,000 ft) in a vertical decompression chamber. under such stressful conditions, the core temperature of the experimental animals starts falling. the treatment is termi- nated when a core temperature of 23° ± 1°c is attained. the modulatory effects of beseb cdri-08 on stress-induced changes in expression of hsp70 and activities of superoxide dismutase (sod) and cytochrome p450-dependent 7-pentoxyresorufin- d-alkylase (prod) and 7-ethoxy-resorufin-o-deethylase (erod) were estimated. the data clearly demonstrated the potential of beseb cdri-08 in reducing stress by modulating the expression of hsp70 and the activities of p450s and sod, the enzymes known to be involved in the production and scavenging of reactive oxygen species in different brain regions of the brain. neuroprotective effect amar jyoti et al. (2006, 2007) investigated the neuroprotective role of the beseb cdri-08 against aluminium-induced oxidative stress in the hippocampus and cere- bral cortex of rat brain and compared with l-deprenyl (seleginine). l-deprenyl is an mao-b inhibitor and neuroprotectant offering protection against the effects of neu- rotoxins and excitatory amino acids (ebadi et al., 2002). it is also used as a therapeu- tic agent for the neurodegenerative disorder parkinson’s disease involving oxidative stress. l-deprenyl prevents the apoptosis of dopaminergic neurons associated with parkinson’s disease by altering the expression of a number of genes such as sod, bcl-2, bcl-xl, nos, cjun (ebadi and sharma, 2003). l-deprenyl is also a very well-known antioxidant (xu et al., 1993) and is postulated to have antiaging effects as it has shown to properly extend life expectancy (bickford et al., 1997). the data generated clearly indicated that coadministration of beseb cdri-08 together with aluminium treatment prevented the latter’s oxidative stress effects. aluminium reduced superoxide dismutase (sod) activity significantly. cdri-08 attenuated this reduction and restored the sod activity to near normal. similarly, cdri-08 prevented the aluminium-induced increase in thio-barbituric acid-reactive substance (tba-rs) and carbonyls. this protective role is further supported by the microscopic observations, which showed that beseb cdri-08 prevented the aluminium-induced lipofuscin accumulation and ultrastructural changes in the hip- pocampal ca1 field. the hippocampal ca1 field was selected for microscopic stud- ies as its pyramidal neurons are potentially more vulnerable to aluminium-induced neurotoxicity (sreekumaran et al., 2003) and hypoxia (kawasaki et al., 1990) than ca2 and ca3 hippocampal fields. the antioxidative effect of the beseb cdri-08 was found to be similar to l-deprenyl. this is an important finding as oxidative stress (lipid peroxidation, lipo- fuscin accumulation, etc.) is postulated to be an extremely important contributory component of the ageing process. because of its antilipidperoxidative and antili- pofuscinogenitric effects, the beseb cdri-08 can thus be considered as a poten- tial antiaging substance. this postulation is further strengthened by the similarity between the effects of the beseb cdri-08 with those of l-deprenyl, which itself is considered to be a candidate antiaging drug. this is a further indication of the antiaging potential of the beseb cdri-08. the importance of this finding can be

natural medicines, nutraceuticals and neurocognition further gauged by the fact that neuroprotective effects are observed both in hip- pocampus and cortex. the severity of aluminium induced oxidative stress is more pronounced in the hippocampus and neocrotex regions than any other area of the central nervous system. such oxidative damage during aging and oxidative stress is postulated to significantly contribute to the impairment of cognitive functions like learning and memory (fukui et al., 2000). on the strength of these findings the authors have concluded that beseb cdri-08, because of its antilipidperoxidative and antilipofuscinogenistic effects, could be considered as a potential antiaging sub- stance (kaur et al., 2003). mechanism of action in order to study the mechanism of action, investigations were designed to (1) estab- lish the biochemical correlates of the memory-enhancing effects of beseb cdri-08 and (2) to elucidate its cellular mechanism of action. biochemical investigations showed that beseb cdri-08 enhanced the protein kinase activity in hippocampus. it also induced an increase in protein and sero- tonin and lowered the epinephrine levels in hippocampus. similar changes were also observed in hypothalamus and cerebral cortex (singh and dhawan, 1997). the enhancements of protein and serotonin, and the depletion of norepinephrine levels are indicative of the facilitatory effect of beseb cdri-08 on long-term and inter- mediate forms of memory (angers et al., 1998; byrne and kandel, 1996; cohen et al., 2003; crow et al., 2001; kandel, 1987; kandel et al., 1986; menaces, 1995, 2003). in brain tissue, nitric oxide causes activation of the soluble guanyl cyclase enzyme, resulting in an increase in the cellular levels of cyclic gmp (cgmp). a common stimulus for nitric oxide is the activation of a particular class of receptors for the excitatory neuro transmitter glutamate, i.e., the nmda receptors. investigations were done at the wolfson institute of biomedical research university college, london, to study (1) an effect of cdri-08 itself to indicate whether it has the ability per se to release nitric oxide and (2) an effect of cdri-08 in the presence of a submaximally effective concentration of nmda to elucidate a potentiating or inhibiting effect or whether it simulates nitric oxide formation. the results obtained showed that although cdri-08 did not possess an intrinsic effect on nitric oxide release, it potentiated nmda-mediated nitric oxide and cgmp produc- tion in the cerebellum at a concentration of 100 μg/ml. the hippocampus is a brain area associated with memory formation. at the cellu- lar level, memory is considered to be stored in the form of long-lasting changes in the strength of the synaptic connections between neurons. such changes in hippocampus are induced through tetanization, i.e., brief stimulation of synaptic connectivity at high frequency. using electrophysiological recording techniques, the effect of beseb cdri-08 on synaptic transmission in rat hippocampal slices were also studied at the wolfson institute of biomedical research, university college, london (1997). the investigations showed that beseb cdri-08 possessed clear intrinsic bio- logical effects on synaptic transmission in the hippocampus by producing a synaptic depression during application. this depression reverted to an enduring potentiation

natural medicines, nutraceuticals and neurocognition did not produce any significant diuretic or antidiuretic effect and no fall from a rota rod in a forced locomotor activity test. graded concentrations of beseb cdri-08 (10 and 50 μg/ml) produced an inhibition of serotonin-induced contraction in iso- lated guinea pig ileum preparation (singh and shanker, 1996). subacute toxicity in rodent and nonhuman primate by oral route these investigations were done in the division of toxicology, cdri. rodent beseb cdri-08 was given once daily orally for 90 days at the doses of 50, 100, and 200 times the effective dose of 40 mg/kg/p.o./day to rats of charles foster strain divided into three groups, each consisting of 15 male and 15 female animals. a fourth group of 15 male and 15 female animals were fed with corresponding volumes of vehicle and served as controls. weekly monitoring of body weights of all the animals was done. hemograms and urine analysis parameters of the animals were recorded initially and then at monthly intervals of the study. all the animals were sacrificed at the end of 90 days of the study, and terminal blood biochemistry and histopathology of all the important organs and tissues were studied. animals continued to remain active and healthy throughout the period of experi- mentation. the treated and control animals gained body weight well in comparison to one another. the laboratory investigations showed no indication of treatment- induced damage in the various hematological and biochemical, parameters, organ weights (both absolute and relative of important organs), and histopathological examinations. beseb cdri-08 was thus found to be safe in rats in the 90-day subacute toxicity by oral route at the aforementioned dose levels. nonhuman primate beseb cdri-08 suspended in 1% aqueous gum acacia was given daily by oral route at the doses of 25, 50, and 100 times the effective dose of 10 mg/kg/p.o./day body weight in a single bolus to rhesus monkeys divided into three groups, each consisting of three male and three female animals. another group of three male and three female animals were given corresponding volumes of 1% aqueous gum acacia alone in a similar manner and served as control. the treatment ­ continued for 3 months. average 24 h food consumption of the animals was recorded ini- tially and then at weekly intervals throughout the period of the study. body weights of the animals were recorded initially and then at monthly intervals. hemograms, urinalysis, and serum biochemistry were done on weeks 0, 5, 9, and 13 of the study. all the animals were sacrificed at the end of the study and bone marrow was examined. the histopathology of all the important organs and tis- sues was studied.

memory-enhancing and associated effects of beseb—cdri-08 the animals continued to remain active and healthy throughout the duration of treatment. animals of both drug-treated and control groups showed irregular trends of gain in body weight. the laboratory investigations showed no indication of drug- induced damage in urinalysis and hematological and serum biochemical parameters. elevations in sgpt (alt) levels of few animals of the treated group were noted. but there was no functional abnormality in the liver as evidenced by constantly normal levels (treated vs. controls) of serum bilirubin, serum albumin, total serum protein, and prothrombin time estimations. moreover, there was no evidence of intrahepatic biliary stasis as the levels of serum alkaline phosphatase remained within the ranges of normalcy in the treated groups of animals throughout the study. the autopsy studies (including absolute and relative weights of important organs) and gross and histopathological examinations did not reveal any sign of target organ toxicity. beseb cdri-08 was thus found to be safe in rhesus monkeys in a 3 month sub- acute toxicity study by oral route at the aforementioned dose levels (srivastava and sudhir, 1996). teratogenicity study the purpose of the study was to delineate the harmful effects of beseb cdri-08 on pregnancy and unborn offsprings with the intention to provide information on the potential hazards to the developing fetus that may arise due to administration of the compound to the pregnant rats (charles foster) and rabbits (new zealand white) by oral route during their major period of organogenesis, i.e., from day 6 to 15 and day 6 to 18 of the pregnancy period, respectively. pathogen-free male rats (175–250 g) and rabbits (1.75–2.25 kg) of proven fertil- ity and sexually mature, randomly chosen nulliparous female rats (150–225 g) and rabbits (1.75–2.00 kg) were obtained from the national laboratory animal center (nlac) of the cdri. a total of 10 female and 5 male rats and 2 male and 2 female rabbits were used for the study. each rat received a daily oral low dose of 50 mg/kg and high oral dose of 100 mg/kg and each rabbit received a daily oral low dose of 26.66 mg/kg and high oral dose of 53.32 mg/kg procedure female test animals of timed pregnancy were treated with the test substance daily throughout the appropriate treatment period, i.e., from day 6 to 15 of gestation in rats and day 6 to 18 of gestation in rabbits. signs of toxicity were recorded as and when they were observed, indicating the time of onset, the degree, and the duration. females showing signs of abortion or premature delivery were sacrificed and sub- jected to thorough macroscopic examination. the posttreatment observation period continued till 1 day prior to term. during the treatment and observation period cage side observations included changes in skin and eye and mucus membrane, as well as condition of orifices, behavior pattern, etc. food and water consumption were also observed every week if they were satisfactory or not (in the case of rabbits, only food consumption was measured). animals were also weighed.

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botanical anxiolytics, antidepressants, and hypnotics rhodiola (rhodiola rosea) darbinyan et al.123 depression: 6 week 3 arm rct (n = 89) comparing 340 mg vs. 680 mg of standardized rhodiola vs. placebo both rhodiola groups showed significant reduction of hamd symptoms and in insomnia, somatization and emotional instability subscale outcome measures b bystritsky et al.124 anxiety: 10 week open label (n = 10) using 340 mg of standardized rhodiola rhodiola significantly endpoint anxiety on hama (although no placebo comparator was employed) c saffron (crocus sativus) akhondzadeh et al.125, 126, moshiri et al.127, noorbala et al.128 depression: 4 rcts: two trials using 30–90 mg of saffron vs. placebo; two vs. synthetic antidepressants significant improvement in reducing depression compared to placebo on hamd. an equivalent therapeutic response vs. imipramine and fluoxetine a scullcap (scutellaria lateriflora) wolfson et al.129 anxiety: acute cross-over rct (n = 19) using scullcap vs. placebo scullcap dose-dependently reduced symptoms of anxiety and tension after acute administration compared with placebo b st john’s wort: sjw (hypericum perforatum) linde et al.130 depression: meta-analyses sjw vs. placebo sjw showed significant effect on hamd vs. placebo, comparable to synthetics a 9 larger rcts (n = 2044) rr 1.28 (1.10–1.49) 9 smaller rcts (n = 1020) rr 1.87 (1.22–2.87) sjw vs. ssris 12 (n = 1794) rr 1.00 (0.90–1.15) sjw vs. tri/tetracyclics (n = 1016) rr 1.02 (0.90–1.15) valerian (valeriana spp.) bent et al.131 insomnia: systematic review and meta-analysis. 16 rtcs (n = 1093). valerian vs. placebo or vs. active controls such as antihistamines meta-analysis revealed that valerian significantly improved sleep quality compared to placebo (rr of improved sleep = 1.8, 95% ci:1.2, 2.9). however, the review revealed 9/16 studies were not supportive of valerian as a soporific c level a, meta-analyses or replicated rcts with positive results; level b, one or more rcts, mainly positive results; level c, one or more clinical trials with poor methodol- ogy or mixed evidence from clinical trials; rr, relative risk. hamd = hamultion depression rating scale; hama = hamultion anxeity rating scale. a “significant” is p < 0.05. b evidence-based on lavender as an adjunctive rather than as a monotherapy.

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natural medicines, nutraceuticals and neurocognition showed no effect on muscarinic receptors. huprine x, however, a hybrid between tacrine and hupa, exhibited micromolar activity at m(l) and m(2) receptors that was probably agonistic (roman et al., 2002), and could provide therapeutic advantages in the treatment of dementia (fisher et al., 2002). brain norepinephrine (ne) and dopamine (da) levels increased significantly in a dose-dependent manner, follow- ing either systemic administration of hupa or local administration of hupa through microdialysis probe into the rat cortex (zhu and giacobini, 1995); ne and da levels were increased more than 100% after the 0.3 and 0.5 mg/kg, but 5-ht level was not affected. another trial (liang and tang, 2006) found that hupa had similar potency on increasing medial prefrontal cortex (mpfc) ach and da levels as compared to the 11- and 2-fold dosages of donepezil and rivastigmine, respectively, and had longer lasting effects after oral dosing; however, ne and 5-ht levels in the mpfc and hippocampus were not affected by any of the three treatments. these effects, if confirmed, might contribute to explain the cognitive enhancing properties of hupa, as the clinical effect of cheis has been related to the stimulation of both cholinergic and monoaminergic systems (decker and mcgaugh, 1991; alhainen et al., 1993). protective properties other interesting properties of hupa pharmacology concern an impressive span of protective actions, which could represent a way to target dementia, a multifactorial illness, from several facets, and possibly to have a role in the prevention of neuro- logical diseases. it possesses the ability to protect cells against glutamate, experi- mentally induced cytotoxicity and apoptosis, oxidative stress, β-amyloid peptide (abeta), hydrogen peroxide, ischemia. these protective effects are related to its abil- ity to reduce oxidative stress, regulate the expression of apoptotic proteins, protect mitochondria, modulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. it also has antagonizing effects on n-methyl- d-aspartate receptors and potassium currents, which may contribute to its neuropro- tection. in addition, hupa can be used as a protective (prophylactive) agent against organophosphate (op) poisoning. glutamate toxicity it has been proposed that hupa functions as a noncompetitive antagonist of n-methyl- d-aspartate (nmda) receptors, and is neuroprotective against glutamate toxicity. excitatory aminoacid (eaa)-induced over stimulation is related to many acute and chronic neurodegenerative disorders, and is caused by an excess of glutamate that activates nmda receptors and increases the flux of calcium ions in the neurons. calcium at toxic levels can kill neuronal cells. pretreatment of rat primary neuron cul- tures with hupa reduced glutamate-induced calcium mobilization and cytotoxicity (wang et al., 1999). additionally, hupa showed an age-dependent neuroprotection: more mature neuronal cells showed a greater sensitivity as well as neuroprotection to nmda-induced toxicity. by reducing glutamate-related toxicity, hupa could be used to treat dementia and as a preventive agent for ad similarly to memantine, a drug that protects the brain against the excess of glutamate observed in ad.

huperzine a oxidative stress another pathway by which hupa could be a disease-modifying agent in dementia and a preventive treatment is through protection of the brain against oxidative stress. an increase in oxidative stress, resulting from free radical damage to cellular func- tion, can lead to ad and to brain lesions called tangles and plaques, the latest caused by the deposition of abeta. in animal trials, hupa demonstrated a significant reduc- tion in blood markers of oxidative stress (including erythrocyte and plasma lipoper- oxides), thus suggesting a systemic antioxidant effect; interestingly, levels of lipid peroxidation and superoxide dismutase were lowered in the hippocampus, cerebral cortex, and serum of aged rats (shang et al., 1999). a reduction in the plasma and erythrocyte oxygen free radicals was also demonstrated in a clinical study (xu et al., 1999). huperzine b showed similar neuroprotective properties to hupa, and to other acheis (donepezil, galantamine, tacrine), attenuating the hydrogen peroxide– induced injury (zhang and tang, 2000). hupa also exerted neuroprotection in an oxygen-glucose deprivation-induced injury model in c6 rat glioma cells (zhao and li, 1999). abeta toxicity hupa protected cultivated cortical neurons against abeta toxicity, reducing the apoptosis (programmed cell death) that follows abeta injection, and reducing the level of abnormal free radicals. hupa halted the suppressive effect of abeta on long-term potentiation in rat hippocampal slices (ye and qiao, 1999). it appears that hupa treatment modifies the processing of the amyloid precursor protein by increas- ing α-secretase activity, and reducing the generation of amyloidogenic fragments (peng et al., 2006). this effect could reduce abeta toxicity and fibrillar amyloid accumulation in ad brain. hypoxic-ischemic brain injury the effect on brain metabolism, demonstrated by the protective effect of hupa on hypoxic-ischemic (hi) brain injury on neonatal rats with experimental brain dam- age, also enhances the value of hupa in the treatment of dementia, especially in the vascular type. hupa administrated daily to neonatal rats (wang et al., 2002), at the dose of 0.1 mg/kg i.p. for 5 weeks after hi injury, produced significant protec- tion from damage subsequent to hi injury on behavior (decreased escape latency in water maze) and on neuropathology (less extensive brain injury). administration of subchronical oral doses of hupa (0.1 mg/kg, twice daily for 14 days) following 5 min of global ischemia in gerbils also showed similar neuroprotection (zhou et al., 2001). nerve gas poisoning the protective actions of hupa pharmacology have proved to be effective also against soman and other poisonous nerve gases used as chemical weapons. pretreatment with hupa-protected rats and primates against soman, without the

huperzine a of the patients in the active group, and 12.5% in the placebo group. hupa treatment was also associated with significant improvement on a global measure (the cibic- plus: clinicians interview-based impression of change plus caregiver input) com- pared with placebo. the percentage of mild and transient adverse events was 3% (insomnia and bilateral ankle edema), similar to the placebo group. the authors concluded that while hupa appears to be a safe and effective treatment for ad, this needs to be confirmed in larger and longer clinical trials, using different doses (400 μg is not the maximum dose). a large clinical study reported by wang was conducted in 819 patients who met the ad criteria of national institute for communicative disorders and stroke- alzheimer’s disease and related disorders association (nincds-adrda) and diagnostic and statistic manual of mental disorders-third edition-revised (dsm- iii-r) at 39 mental hospitals in china (wang et al., 2006). after treatment with hupa at a dose of 0.03–0.4 mcg/d, patients showed improvement in their memory, cognitive skills, and ability in their daily life. no severe side effects were found. in the most recent chinese placebo-controlled trial (zhang et al., 2006), the effi- cacy of 0.5 mcg hupa was evaluated in 120 patients with ad. patients in the treat- ment group had significantly greater improvement (p < 0.01) compared with those in the control group after 18 weeks of treatment, as evaluated by the adas-cog. adverse events in the hupa group included transient gastrointestinal dysfunction and elevations of alt. the superiority of combined therapy over hupa alone was suggested (zhou et al., 2004) by significant favorable differences in mmse, activity of daily living (adl), and clinical dementia rating (cdr) scores after ad patients were treated with hupa plus nicergoline, conjugated estrogen, and nilestriol (for female ad patients). in the united states the safety and efficacy of hupa were evaluated in 26 patients meeting the dsm-ivr and the nincds–adrda criteria for uncomplicated ad and possible or probable ad (mazurek, 1999). this study (office-based) lasted 3 months and was open-label. hupa was very well tolerated at doses up to 200 μg bid, and effective in enhancing cognition as measured by the mmse. this study demonstrated that the addition of hupa 100 μg bid to prior treatment regimens (including donepezil and tacrine) resulted in improvement on mmse of 1.5, 1.75, and 2.2 points at 1, 2, and 3 months, respectively. two unpublished u.s. phase i studies of hupa have recently been completed to determine the safety and tolerability of hupa in healthy elderly volunteers (age 65–70); the first evaluated doses up to 200 μg bid, while the second escalated doses up to 400 μg bid for 1 week. another recent u.s. phase 2 clinical trial run in collaboration with the national institute on aging and the alzheimer’s disease cooperative study group (adcs) was completed in november 2007 (rafii et al., 2011). the study was a multicenter, randomized, double-blind, placebo-controlled trial in 210 patients with mild to moderate ad. the trial compared the safety, tolerability, and efficacy of either 200 or 400 μg of hupa administered orally twice a day for 16 weeks versus placebo. measures were cognitive function, activities of daily living, and behavior. of the 210 patients enrolled, nearly half received con- comitant treatment with namenda, an fda-approved drug for ad. hupa 200 μg bid did not influence change in adas-cog at 16 weeks. in secondary analyses,

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natural medicines, nutraceuticals and neurocognition age of 80 years (kelner and marx 1996). consequently, there is interest in identify- ing lifestyle factors and molecular mechanisms that can minimize the risk of these debilitating conditions, including simple dietary measures. j-shaped relationship of alcoholic beverages from prospective population-based studies, there is a clear j-shaped relationship between the consumption of alcoholic beverages such as wine, and the risk of car- diovascular diseases including myocardial infarction, which has been extended to a reduced risk of certain cancers, type 2 diabetes, and ischemic stroke (bantle et al. 2008; barstad et al. 2005; benedetti et al. 2006; booyse and parks 2001; briggs et al. 2002; gronbaek et al. 2000; mcdougall et al. 2006; park et al. 2009; pedersen et al. 2003; wannamethee et al. 2002, 2003). the moderate consumption of alcoholic beverages may reduce the risk of cardiovascular diseases, for example, by ∼35%, that of type 2 diabetes by ∼30%, and that of ischemic stroke by 20%–28%; the risk of hemorrhagic stroke is relatively unaffected by moderate alcohol consumption. over the last decade, evidence has accumulated which suggests that this j-shaped relation- ship could also be extended to a reduced risk of cognitive dysfunction, and dementias such as alzheimer’s disease, and vascular dementia (dufouil et al. 1997; huang et al. 2002; lindsay et al. 2002; luchsinger et al. 2004; rasmussen et al. 2006; simons et al. 2000; zuccala et al. 2001). mild cognitive dysfunction or impairment is a pro- drome for alzheimer’s disease. while the literature defines consistently light-to-moderate consumption as 20–40 g ethanol per day (jackson et al. 1992; klatsky 2003; nhmrc 2005; palomaki and kaste 1993), several studies have defined moderate consumption as up to 80 g ethanol per day for men (elias et al. 1999; zuccala et al. 2001), which may reflect country and cultural differences in alcohol consumption; 10 g ethanol approximates one drink or 100 ml wine. above moderate consumption, the risk of alcohol-related diseases increases dose-dependently (corrao et al. 2004). relationship of alcoholic beverages to cognitive function and dementia cognitive function is defined as the intellectual or mental processes by which knowl- edge is acquired, including perception, reasoning, acts of creativity, problem solv- ing, and possible intuition. cognitive dysfunction or impairment is associated with increased disability and an increased need for institutionalized care. dementia is a form of cognitive dysfunction whereby an individual loses the ability to think, remember, and reason due to physical changes in the brain. prior to a study by zuccala et al. (2001), there was conflicting evidence on the relationship between alcohol consumption per se and cognitive function (cervilla et al. 2000; dent et al. 1997; dufouil et al. 1997; elias et al. 1999; harwood et al. 1999; hendrie et al. 1996; leibovici et al. 1999; teri et al. 1990). zuccala et al. (2001) analyzed the association between alcohol consumption and cognitive impairment in 15,807 hospitalized older patients who were enrolled in an italian multicenter phar- macoepidemiology survey. the amount of alcohol use was recorded as daily wine

natural medicines, nutraceuticals and neurocognition are absorbed and accumulate in the brain in measurable amounts after multiple or repeated oral doses (ferruzzi et al. 2009; passamonti et al. 2005). wine-derived phenolic compounds, and particularly resveratrol, have been shown to be cerebero- or neuroprotective in various models, in vitro and in vivo, and potential mechanisms have been proposed as follows. data from similar studies using different varieties of red wines with different profiles of phenolic compounds, as well as studies compar- ing different phenolic compounds, suggest that the individual classes of phenolic compounds may exhibit differential effects in the brain (hamaguchi et al. 2009; ho et al. 2009). hemostasis and oxidative stress the beneficial effects of alcoholic beverages such as wine on the risk of cardio- vascular and cerebrovascular diseases have been partly attributed to changes in lipid and hemostatic or blood flow factors. these changes include ethanol-induced increases in the concentration of high-density lipoprotein-cholesterol, and ethanol- and phenolic-induced increases in the thrombolyic proteins tissue-type plasmino- gen activator activity and tissue-type plasminogen activator antigen, and induced reductions in fibrinogen, and clotting cofactors factor vii and von willebrand factor. these changes are also associated with atherosclerosis which is the accumulation of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large- and medium-sized arteries. as atherosclerosis has been associ- ated with both alzheimer’s disease and vascular dementia, it had been suggested that any beneficial effect of wine on atherosclerosis could be expected to benefit these dementias by preserving brain vasculature, consequently resulting in better cognitive function (wright et al. 2006), however, showed that the appearance of plaque on the carotid artery which carries blood to the brain was not associated with consumption of an alcoholic beverage and associated improvements in cog- nitive function. this suggests then that ethanol and phenolic compounds such as resveratrol may impact cognition through a separate vascular or degenerative path- way (kennedy et al. 2010). vasoactive amyloid-β (aβ), associated with alzheimer’s disease and other related neurodegenerative diseases, may also interact with cerebral blood vessels to promote free radical production and reduce local blood flow which precede other neuropathological changes in dementias, and subsequently up-regulate aβ production (thomas et al. 1996). indeed, among older persons without cerebro- vascular and neurodegenerative diseases, those who moderately consume alcoholic beverages such as wine have been shown to have fewer white-matter abnormalities and infarcts on magnetic resonance imaging than abstainers (mukamal et al. 2001), where pronounced reductions in the risk of both vascular dementia and alzheimer’s disease have been shown among persons consuming one to six standard drinks per week (mukamal et al. 2003). a lack of heme oxygenase 1, an endogenous enzyme that is induced in neurons in response to oxidative and other stress and stimulates the degradation of prooxi- dant heme into free iron, carbon monoxide, and biliverdin and/or the antioxida- tive bilirubin, may also be associated with increased neural damage from ischemic strokes (li et al. 2009), as well with alzheimer’s disease and parkinson’s disease

protective effects of wine on brain function (ma et al. 2010). heme oxygenase 1 is dose- and time-dependently induced by res- veratrol, which may provide another cerebrovascular and neuroprotective effect for phenolic compounds. indeed, parkinson’s disease has been linked to increased levels of oxidative and nitrosative stress (chung et al. 2003; dawson and dawson 2003) and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain and the appearance of lewy bodies and neurites, which comprise insoluble amyloid-like fibrils that contain the protein α-synuclein. oxidative stress apparently promotes the aggregation of α-synuclein (maguire-zeiss et al. 2005). an inverse relationship between amount of wine consumed and risk has been observed where the lowest risk was observed for wine consumers of ∼140–420 g/week (fall et al. 1999). wine-derived phenolic compounds such as catechin and epicatechin have recently been observed in vitro to inhibit the formation of α-synuclein fibrils, and to destabilize preformed fibrils (ono et al. 2008). neurotransmission cognition is also associated with acetylcholine. cognitive decline associated with dementias, huntington’s disease, and parkinson’s disease, as well as with down’s syndrome and multiple sclerosis, is characterized neurochemically by a consistent deficit in cholinergic neurotransmission, in particular in the cholinergic neurons in the basal forebrain. inhibition of acetylcholinesterase which restores cholinergic neurotransmission also appears to prevent the aggregation of aβ peptides and for- mation of amyloid fibrillar plaques (munoz et al. 1999). ethanol may stimulate the release of acetylcholine in the hippocampus leading to improved cognitive function, such that a light amount of an alcoholic beverage in normal subjects appears to improve memory for events experienced before consump- tion (fadda and rossetti 1998). in contrast, quercetin inhibits acetylcholinesterase (orhan et al. 2007). indeed, acetylcholinesterase inhibitors which reversibly bind and inactivate the enzyme that degrades acetylcholine are the primary medications prescribed associated with mild improvements in cognitive function. the impair- ment of memory performance by chronic and heavy consumption, however, parallels the reduction of acetylcholine neurotransmission. concerning alzheimer’s disease, which is associated with the presence of intra- cellular neurofibrillary tau tangles, extracellular aβ peptides, synaptic failure, mitochondrial dysfunction, and depletion of acetylcholine (anekonda and reddy 2006), it has been suggested that ethanol may directly stimulate the release of ace- tylcholine in the hippocampus; synaptic levels of acetylcholine decrease as a result of cholinergic neuron involvement. in a rat model, a moderate concentration of etha- nol (0.8 g/kg) stimulated the release of acetylcholine while a higher concentration (2.4 g/kg) inhibited its release. the formation of amyloid fibrillar plaques is also common in diseases such as parkinson’s disease, prion diseases, down’s syndrome, and type ii diabetes. another important intracellular signaling system involved in learning and mem- ory is protein kinase c (pkc), a family of 12 serine/threonine kinases. pkc modu- lates cell viability which protects certain neuronal cells against ab-induced toxicity.

natural medicines, nutraceuticals and neurocognition resveratrol has been observed to protect hippocampal cells against ab-induced ­ toxicity by activating pkc (han et al. 2004), and specific binding sites for resvera- trol have been identified in the rat brain (han et al. 2006), as have receptors for the green tea catechin gallates. amyloid-β factors and alzheimer’s disease aβ is a core component of the plaque or lesion found in the neocortex and hip- pocampus of diseased brains. it is formed after sequential proteolytic cleavage of the amyloid precursor protein (app), a transmembrane glycoprotein. app can be processed by α, β, and γ secretases. unlike α secretase which cleaves app into nontoxic amyloid-α, the toxic amyloid-β protein is generated by successive action of the β and γ secretases. the γ secretase, which produces the c-terminal end of the aβ peptide, cleaves within the transmembrane region of app and can generate a number of isoforms of 39–43 amino acid residues in length. the most common isoforms are aβ40 and aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the longer form is produced by cleav- age in the trans-golgi network. the aβ40 form is the more common of the two, but aβ42 is the more fibrillogenic or polymeric and is thus associated with disease states, promoting proinflammatory responses and activating neurotoxic pathways leading to neuronal dysfunction, and the death and loss of neurons. inhibition of the accumulation of amyloid-β peptides and the formation of aβ fibrils/plaques from amyloid-β peptides, as well as the destabilization of preformed aβ fibrils/ plaques in the brain would, therefore, be attractive therapeutic targets for the treatment of alzheimer’s disease and other related neurodegenerative diseases. as mutations in app associated with early-onset alzheimer’s disease have been noted to increase the relative production of aβ42, a potential therapy may involve modulating the activity of β and γ secretases to produce mainly aβ40. administration of a red wine to tg2576 mice equivalent to two standard drinks, which model alzheimer’s disease aβ neuropathology and corresponding cognitive deterioration, has been shown to promote the nonamyloidogenic processing of the app, which acts to prevent the generation of the aβ peptide (wang et al. 2006). for example, administration of red wine reduced amyloidogenic aβ(1–40) and aβ(1–42) peptides in the neocortex and hippocampus of tg2576 mice and correspondingly decreased the neocortical alzheimer’s disease–associated amyloid fibrils/plaque. subsequent examination of app processing and aβ peptide generation increased the concentra- tion of membrane-bound α-carboxyl terminal fragments of app in the neocortex and α secretase activity was also increased, while there was no significant change in the neocortical concentration of β and γ carboxyl terminal fragments of app or in β and γ secretases activity. the typical red wine–derived phenolic compounds catechin, quercetin, epi- catechin, myricetin, and tannic acid have, however, been shown in vitro to dose-dependently inhibit the formation of aβ fibrils from fresh aβ(1–40) and aβ(1–42), as well as their extension, and also dose-dependently destabilized preformed aβ fibrils (ono et al. 2003, 2004; roth et al. 1999). only resveratrol, however, has been shown to decrease the level of intracellular aβ produced by different cell

protective effects of wine on brain function lines expressing the wild type of swedish mutant aβ precursor protein (app695) by promoting its intracellular degradation (marambaud et al. 2005). this mechanism was proteasome-dependent, that is, resveratrol appears to activate the proteasome involved in the degradation of aβ, as the resveratrol-induced decrease of aβ could be prevented by several selective proteasome inhibitors and by sirna-directed silencing of the proteasome ­ subunit β5. resveratrol does not inhibit the production of aβ because it has no effect on β and γ secretase activity. another potential therapy may involve preventing the aggregation of aβ, as stud- ies have suggested that only when aggregated in the fibrillar form aβ is neurotoxic, although some studies alternatively suggest that the toxicity lies in soluble oligomeric intermediates rather than in the insoluble fibrils that accumulate. grape-seed phenolic compound extract, which comprises primarily catechin and epicatechin in monomeric, oligomeric, and polymeric forms, has been shown in vitro and in animal studies to inhibit aβ aggregation into high-molecular-weight oligomers (wang et al. 2008). this inhibition coincided with attenuation of alzheimer’s disease–type cognitive impair- ment. resveratrol and its glucoside, piceid, have, however, been shown in vitro to dose- dependently inhibit the formation of aβ fibrils (riviere et al. 2007, 2010); other stilbene monomers examined are less potent inhibitors. binding may be induced by hydropho- bic interactions between the phenolic rings and the hydrophobic region of aβ, thus blocking associations between aβ molecules and inhibiting fibril formation. these interactions may then be reinforced by the h-bond between the hydroxyl group of the phenolic rings and some donor/acceptor groups of aβ, as observed for other peptides. amyloid-β and apoe-epsilon 4 allele in the washington heights inwood-columbia aging project (1991−1996), however, a lower risk was confined to wine consumers without the apoe-epsilon 4 allele (luchsinger et al. 2004). this allele is implicated in atherosclerosis, alzheimer’s disease, and impaired cognitive function, possibly influencing the increased depo- sition of aβ in the brain as it is less effective compared to other alleles at facili- tating the proteolytic breakdown of this peptide, both within and between cells (selkoe 1997). indeed, the most important genetic risk factor is the apoe genotype. apoe is a protein that carries lipids in and out of cells. it occurs in three isoforms: apoe2, apoe3, and apoe4. the gene for apoe is on chromosome 19. one copy is inher- ited from each parent. the most common apoe allele is apoe3. persons who are homozygous for the apoe4 allele develop alzheimer’s disease earlier at a mean age of 70 years. the apoe4 allele is also a risk factor for hypercholesterolemia. apoe4 has been detected in neurofibrillary tangles and in aβ (luchsinger et al. 2004). this suggests that apoe lipoproteins participate in some way in the processing of app, perhaps by modulating app secretases, and may also play a role in the assembly of the neuronal cytoskeleton. high cholesterol levels during midlife increase the risk of alzheimer’s disease and lipid-lowering therapies including the consumption of wine-derived phenolic compounds can lower this risk which may accordingly lower the risk of developing alzheimer’s disease (andrade et al. 2009; broncel et al. 2007; franiak-pietryga et al. 2009).

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crc press is an imprint of the taylor & francis group, an informa business boca raton london new york edited by zoë gardner michael mcguffin expert advisory council roy upton soaring bear david winston daniel gagnon aviva jill romm tieraona low dog mary hardy lyle craker botanical safety handbook second edition american herbal products association’s reviewers david bechtel leslie beyer bill j. gurley proofreaders bill schoenbart constance a. parks

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dedication this book is dedicated to the memory of mary frances picciano, ph.d., former senior nutrition research scientist at the office of dietary supplements, national institutes of health. her interest, foresight, and willingness to have the office of dietary supplements support a partnership with the american herbal products association and the university of massachusetts made this work possible.

xiii financial support this work was made possible with financial support from the office of dietary supplements at the national institutes of health, and in-kind contributions by the medicinal plants program at the university of massachusetts, amherst. financial contributions to support this effort were also made by numerous ahpa member companies and individuals identified as follows. visionaries benefactors champions amin talati, llc crc insurance services, inc. frontier natural products co-op gnc (general nutrition centers, inc.) michael mcguffin mountain rose herbs pacific nutritional, inc. rainbow light systemic formulas vitality works sponsors alkemists laboratories animal essentials inc. arise & shine herbal products, inc. bent creek institute, inc. emerson ecologics gaia herbs golden flower chinese herbs herbalist & alchemist iovate health sciences international inc. motherlove herbal co. now foods nuherbs co. paragon laboratories jim prochnow ridgecrest herbals sabinsa corporation advocates and supporters american botanical council cindy angerhofer beehive botanicals, inc. jon benninger bi nutraceuticals bighorn botanicals ed croom steven dentali dicentra earth mama angel baby europharma usa evergreen herbs, llc james fischer dagmar goldschmidt jackie greenfield howard miller mountain meadow herbs, inc. pacific botanicals pharmline inc. st. francis herb farm inc. strategic sourcing inc. mary beth watkins

xv editors zoë gardner, m.s., ph.d.(c) research & development manager, traditional medicinals fascinated by the connection between people and plants, zoë gardner has been studying, researching, and teach- ing on the production, conservation, quality, safety, and appropriate use of medicinal plants since 1998. after completing her undergraduate degree in environmen- tal studies at the audubon expedition institute, zoë helped to establish the medicinal plant program at the university of massachusetts, earning her master’s degree there in plant & soil sciences. more recently, zoë joined the research & development department at traditional medicinals, a leading producer of botani- cal dietary supplements. a self-proclaimed “herb nerd,” zoë is currently completing her ph.d. on medicinal plant quality and safety. michael mcguffin president, american herbal products association michael mcguffin has been active in the herbal industry since 1975, having owned and managed both retail and manufacturing businesses in this field. he is the manag- ing editor of botanical safety handbook, 1st edition (1997) and of herbs of commerce, 2nd edition (2000). he serves on the boards of the american herbal pharmacopoeia and united plant savers; on the advisory board of the usc school of pharmacy regulatory science program; and as chair of the u.s. technical advisory group for iso/tc 249, the international organization for standardization’s technical committee on traditional chinese medicine (provisional title). michael maintains active involvement with regulatory agencies, and served on fda’s food advisory committee working group on good manufacturing practices for dietary supplements (1998–1999), fda’s food advisory committee’s dietary supplements subcommittee (2003–2005), and california’s office of environmental health hazard analysis food warning workgroup (2008–2010).

xvii expert advisory council roy upton, rh (ahg), dayu executive director, american herbal pharmacopoeia roy upton has been trained in traditional ayurvedic, chinese and western herbal traditions, has studied native american and caribbean ethnobotanical tradi- tions, and is a professional member of the american herbalists guild. he is the executive director and editor of the american herbal pharmacopoeia and a member of the standards committee of the american herbal products association and advisory committees for the american botanical council, aoac international, and nsf international. along with being an author and lecturer, roy was co-founder and past president of the american herbalists guild and is the herbalist and director of the california-based herbal company planetary herbals. soaring bear, ph.d. technical information specialist (ret.), national library of medicine dr. soaring bear has been collecting herbal data, with a focus on toxicology, since the early 1970s. he earned a b.s. in biochemistry with honors and a ph.d. in pharmacol- ogy from the university of arizona. his doctoral research on structure–activity relationships and chemical interac- tions provides him with a unique perspective on bioactiv- ity of herbs. he created herbmed.org and edited over ten thousand quick summaries and links into medline. his work at the national library of medicine in the medical subject headings (mesh) section included significant revisions of the herbal, alternative medicine, and chem- istry sections of mesh, which improves the quality of millions of searches done every day on the pubmed.gov database. david winston, rh (ahg) president, herbalist & alchemist david winston is an herbalist and ethnobotanist with over 40 years of training in cherokee, chinese, and western/eclectic herbal traditions. david is a founding/ professional member of the american herbalists guild and has been in clinical practice for over 33 years. he is an herbal consultant to many physicians and other health- care professionals throughout the u.s. and canada. david is also the president of herbalist & alchemist, inc. and founder and director of david winston’s center for herbal studies and the herbal therapeutics research library. he is the author of numerous texts on herbal medicine, is an internationally known lecturer, and teaches frequently at medical schools, symposia, and herb conferences. daniel gagnon, m.s., rh (ahg) president, herbs, etc. daniel gagnon, owner of herbs, etc., has been a practic- ing herbalist since 1976. daniel has studied medical herb- alism, pharmacognosy, and related subjects at the santa fe college of natural medicine, the college of santa fe, and the university of new mexico. he received his b.s. in herbal medicine from the north american college of botanical medicine and his m.s. in herbal medicine from the scottish school of herbal medicine. daniel was a fac- ulty member of the north american college of botanical medicine for over 10 years and currently serves as an herbal consultant to healthcare providers. he is the author of several books on herbal medicine. aviva jill romm, m.d. director, integrative medicine for women and children before becoming a physician, dr. aviva romm was a recognized expert in midwifery, women’s health, and women’s and pediatric botanical medicine, and she practiced as a homebirth midwife and herbalist for over 20 years. a graduate of the yale school of medicine, she completed her internship in internal medicine (yale) and her residency in family medicine (tufts). she was the president of the american herbalists guild, the founder and director of herbal medicine for women, a distance learning program, and is the medical director for the american herbal pharmacopoeia. dr. romm has been active in establishing standards for botanical medicine practice and education in the united states, and is the author of numerous texts on botanical medicine, preg- nancy, and children’s health.

expert advisory council xviii tieraona low dog, m.d. director of the fellowship, arizona center for integrative medicine, university of arizona college of medicine dr. tieraona low dog’s extensive career in natural medi- cine began more than 25 years ago. a graduate of the university of new mexico school of medicine, tieraona has served as president of the american herbalists guild and is currently the director of the fellowship at the arizona center for integrative medicine at the university of arizona school of medicine. she has been involved in national health policy and regulatory issues, serving previously on the white house commission of complementary and alternative medicine and as a member of the advisory council for the national center for complementary and alternative medicine, and is currently chair of the u.s. pharmacopeia dietary supplements and botanicals expert committee. mary hardy, m.d. medical director, ucla center for integrative oncology dr. mary hardy is an integrative medicine physician who received her doctor of medicine degree from louisiana state university school of medicine and stud- ied medical ethics at harvard divinity school and loma linda university. she has studied with herbal practi- tioners in the united states and europe and visited tra- ditional healers in peru, kenya, south africa, morocco and china. she is the complementary and alternative medicine expert for a number of research projects con- ducted by the southern california evidence-based practice center at the rand corporation, co-chairper- son of the clinical practice committee of the academic consortium of integrative medicine, and associate director of the ucla botanical research center, funded by the national institutes of health. lyle craker, ph.d. professor, medicinal plant program, university of massachusetts amherst dr. lyle craker has been a researcher in the field of medicinal plants for over 30 years. with a ph.d. in agron- omy from the university of minnesota, he is founding and past editor of the journal of herbs, spices, and medicinal plants, founding and current executive editor of the journal of medicinally active plants, past chairman of the international society for horticultural science (ishs) section on medicinal and aromatic plants, organizer of the herb, spice, & medicinal plant working group within the american society for horticultural science (ashs), and an organizing member of the international council on medicinal and aromatic plants and the american council for medicinally active plants. he is an advi- sory board member of the american botanical council and serves on the board of the ahpa foundation for education and research on botanicals.

introduction xxii botanical, and classifications should not be extrapolated to other such ingredients without additional review. classifications are generally based on data that are associated with use of the specific herb and in the quantities generally consumed for a health-promoting or therapeutic effect. any cautions may therefore be somewhat overstated for an herb that appears in the market in a smaller amount as part of a combination product, or for herbs that are used as flavorings in less than therapeutic quantities. each herb is placed in two classes based on all of the information included, along with the experience of the expert advisory council. the first is the safety class, which evaluates the safety of a particular herb. the second is the interaction class, which provides information on what is currently known about the potential for an herb to alter the effect of prescription or non-prescription drugs when the herb and drug are used concomitantly. central to the appropriate application of this document is the under- standing that classifications are based on an assumption of rational, informed use of herbs and herbal products. classes are defined below, and are followed by bullet points which list criteria and considerations for inclusion in each particular class. safety classes class 1. herbs that can be safely consumed when used appropriately. • history of safe traditional use • no case reports of significant adverse events with high probability of causality • no significant adverse events in clinical trials • no identified concerns for use during pregnancy or lactation • no innately toxic constituents • toxicity associated with excessive use is not a basis for exclusion from this class • minor or self-limiting side effects are not bases for exclusion from this class class 2.* herbs for which the following use restrictions apply, unless otherwise directed by an expert qualified in the use of the described substance: 2a: for external use only • toxicity demonstrated with crude preparation taken orally at traditional dose • adverse event data in humans with probability of causality of toxicity (e.g., hepatotoxicity, neph- rotoxicity, neurotoxicity) associated with oral use * herbs placed in any of the subparts of class 2 may also be placed in other of these subparts. 2b: not to be used during pregnancy • traditional use contraindicates • traditional use as an abortifacient or uterine stimulant • relevant adverse event data in humans exist and have probability of causality • data in animals suggesting teratogenicity or other adverse effects on the fetus or mother, with reasonable application to humans • for plants with common food uses, standard dose is in excess of typical food amounts 2c: not to be used while nursing • traditional use contraindicates • relevant adverse event data in humans exists and has probability of causality • potential hepatotoxicity or neurotoxicity • bioavailability of constituents of concern in breast milk has been demonstrated 2d: other specific use restrictions as noted • information exists that use may be unsafe for specific populations • dosage level outside of a standard range known to cause adverse effects class 3. herbs to be used only under the supervision of a qualified expert. the following labeling is recommended for class 3 herbs: “to be used only under the supervision of an expert qualified in the appropriate use of this sub- stance.” labeling must include proper use information: dosage, contraindications, potential adverse effects and drug interactions, and any other relevant information related to the safe use of the substance. • narrow therapeutic range • identified safety concerns in many populations interaction classes class a. herbs for which no clinically relevant interac- tions are expected • no case reports of suspected interactions with probability of causality • no clinically relevant interactions in human pharmacological studies, if any class b. herbs for which clinically relevant interactions are biologically plausible • human or animal pharmacological study data suggest potential for clinically relevant interaction.

introduction xxiv claviceps purpurea, chondrodendron tomento- sum, colchicum autumnale, conium maculatum, croton tiglium, datura spp., gelsemium sempervi- rens, hyoscyamus niger, nicotiana spp., rauwolfia spp., stramonium spp., strophanthus kombe, and strychnos nux-vomica. • homeopathic herbal preparations. homeopathic products are classified as over-the-counter or prescription drugs and are regulated under the homeopathic pharmacopoeia of the united states. safety concerns that arise for an herb in crude form may not apply to homeopathic preparations of the same herb, and this document does not address herbal products in homeopathic forms. • essential oils. essential oils are concentrations of specific volatile compounds. while many essen- tial oils have a well-documented history of safe use by appropriately skilled persons, they often present toxicological concerns that are absent or moderate in the crude plant materials from which the oil is derived. except for a small num- ber of essential oils that have a history of internal use, the classification of essential oils is beyond the scope of this document. • herbal products to which chemically defined active substances, including chemically defined isolated constituents of an herb, have been added. safety of such products should be determined by manufacturers and marketers prior to market introduction. • environmental factors, additives, or contami- nants. classifications do not consider potential adulteration of botanical materials, although known adulterations that present health risks may be listed in an editors’ note. safety concerns of this sort must be addressed by the manufac- turing practices of suppliers and manufactur- ers, who are responsible for assuring that herbal products are not contaminated or adulterated. literature cited bensky, d., and a. gamble. 1986. chinese herbal medicine: materia medica. seattle: eastland press. duke, j.a. 1989. crc handbook of medicinal herbs. boca raton, fl: crc press. iom. 2005. dietary supplements; a framework for evaluating safety. institute of medicine and national research council of the national academies. washington, d.c.: national academies press. kingsbury, j.m. 1979. the problem of poisonous plants. new york: columbia university press. sangalli, b., and w. chiang. 2000. toxicology of nutmeg abuse. j. toxicol. clin. toxicol. 38 (6):671-678. turner, n., and a. szczawinski. 1991. common poisonous plants and mushrooms of north america. portland, or: timber press. who. 1991. who guidelines for the assessment of herbal medicines. who/trm/91.4. geneva: world health organization.

organization of data xxvii iv. pregnancy and lactation v. toxicity studies • acute toxicity • short-term toxicity • subchronic toxicity • chronic toxicity • genotoxicity • cytotoxicity each entry closes with a listing of the literature cited for that particular entry. literature cited mcguffin, m., j. kartesz, a. leung, and a.o. tucker. 2000. herbs of commerce. 2nd ed. silver spring, md: american herbal products association.

aconitum carmichaelii 7 a and persisted after 90 min. the concentration of aconitine in organs and blood gradually decreased after repeated administration, such that on day 22 of the study, transient ventricular tachycardia and bundle branch block were rarely observed. twenty percent of mice died in the first 2 days of the study, presumably due to aconitine poisoning (wada et al. 2005). a decrease in urine taurine and trimethylamine n-oxide (tmao) and increase in urine citrate, 2-oxoglutarate, succi- nate, and hippurate were observed in rats administered an aqueous extract of prepared sichuan aconite at a dose of 18, 36, or 88 g/kg daily for 14 days (li et al. 2008). in vitro pharmacological studies a study in rat liver microsomes suggested that the com- pound aconitine may be metabolized by cyp3a and cyp1a1/2 (cao et al. 2001). iv. pregnancy and lactation traditional chinese medicine texts indicate that prepared sichuan aconite is contraindicated in pregnancy (bensky et al. 2004; chen and chen 2004). no malformations were found in fetuses of rats treated with doses up to 10.3 g/kg prepared sichuan aco- nite, although the body weight and food consumption were reduced in the pregnant rats. fetuses of rats administered 8.3 g/kg of aconitum kusnezoffii had a reduction in body length and breastbone calcification (xiao et al. 2005). the dosage form and route of administration used in this study was not specified in the english language abstract but is likely to have been a decoction administered orally (xiao et al. 2005). in rat embryos treated with the compound aconi- tine at doses of 0, 1, 2.5, 5, or 10 µg/ml, with or without s9 mix, embryonic growth and development were adversely affected at the concentration of 2.5 µg/ml aconitine with- out s9 mix. effects included reduced crown-rump length and head length, decreased number of somites, and lower morphologic score. when the concentration of aconitine was increased to 5 µg/ml, severe dysmorphogenesis effects were observed, including cardiac defects, irregular somites, and brain malformation (xiao et al. 2007). no information on the safety of prepared sichuan aco- nite during lactation was identified. v. toxicity studies acute toxicity the ld50 of prepared sichuan aconite is 161 g/kg from oral administration and 3.5 g/kg from intravenous administra- tion (chen and chen 2004). the ld50 of unprepared sichuan aconite in mice is 5.49 g/kg from oral administration and 0.49 g/kg from intravenous administration (chen and chen 2004). the ld50 of orally administered sichuan aconite root is approximately 10 g/kg in rats and over 10 g/kg in mice (minematsu et al. 1996). the lethal human dose of the compound aconitine is reported as 3 to 6 mg (frohne and pfänder 1983). short-term toxicity in mice intraperitoneally administered a decoction of sichuan aconite or aconitum kusnezoffi, at doses of 40, 200, or 400 mg/kg, no changes in liver or kidney parameters were seen at a dose of 40 mg/kg, while at doses of 200 or 400, high serum levels of lactate dehydrogenase were observed along with histological changes in the liver and kidney, but no significant changes in heart or gonads were seen (chan et al. 1995). myelo-optic neuropathy was observed in rabbits intra- peritoneally administered a tincture of aconitum spp. con- taining 0.6 mg/kg total alkaloids (suk et al. 1994). in rats orally administered prepared sichuan aconite daily for 5 weeks, the nontoxic level was estimated to be over 2.5 g/kg daily (minematsu et al. 1996). literature cited bensky, d., s. clavey, and e. stöger. 2004. chinese herbal medicine: materia medica. 3rd ed. seattle: eastland press. bisset, n.g. 1981. arrow poisons in china. part ii. aconitum— botany, chemistry, and pharmacology. j. ethnopharmacol. 4(3):247-336. but, p.p., y.t. tai, and k. young. 1994. three fatal cases of herbal aconite poisoning. vet. hum. toxicol. 36(3):212-215. cao, h., s.t. wang, l.y. wu, x.t. wang, and a.p. jiang. 2001. pharmacological study on tianxiong (tuber of aconitum car- michaeli debx.), a chinese drug for reinforcing the kidney yang retail in hong kong market. zhongguo zhong yao za zhi 26(6):369-372. chan, t.y., j.c. chan, b. tomlinson, and j.a. critchley. 1994a. poisoning by chinese herbal medicines in hong kong: a hos- pital-based study. vet. hum. toxicol. 36(6):546-547. chan, t.y., b. tomlinson, and j.a. critchley. 1993. aconitine poison- ing following the ingestion of chinese herbal medicines: a report of eight cases. aust. n. z. j. med. 23(3):268-271. chan, t.y., b. tomlinson, j.a. critchley, and c.s. cockram. 1994b. herb-induced aconitine poisoning presenting as tetraplegia. vet. hum. toxicol. 36(2):133-134. chan, t.y., b. tomlinson, l.k. tse, et al. 1994c. aconitine poi- soning due to chinese herbal medicines: a review. vet. hum. toxicol. 36(5):452-455. chan, t.y.k. 2002. incidence of herb-induced aconitine poison- ing in hong kong: impact of publicity measures to promote awareness among the herbalists and the public. drug safety 25(11):823-828. chan, t.y.k. 2009. aconite poisoning. clin. toxicol. 47(4):279-285.

acorus calamus 10 a chronic toxicity in rats fed diets containing 0, 500, 1000, 2500, or 5000 ppm (0, 0.05, 0.1, 0.25, and 0.5%) jammu calamus essential oil (~75% β-asarone) daily for 2 years, all of the 5000 ppm group died within 45 weeks, all of the 2500 ppm group died within 68 weeks, and all of the 1000 ppm group died within 104 weeks. gross abnormalities were observed, including liver damage, fluid in the pleural and or peritoneal cavity, and tumorous masses in the intestines. cardiac atrophy was observed in both test and control animals but was more severe in test animals (taylor 1967, 1981). in rats fed diets containing 0.1, 0.5, 1.0, or 2.0% european calamus essential oil (~5% β-asarone) daily for 2 years, leio- myosarcomas, hepatocellular adenomas, and hepatocellu- lar adenocarcinomas were observed at the 1 and 2% dose levels. other dose-dependent adverse effects on the livers were observed, with effects at the 0.1% dose being similar to those in the controls, or slightly increased. dose-dependent changes observed in the heart included myocardial atrophy, fibrosis, fatty degeneration, and fatty infiltration (taylor 1981). in rats fed diets containing 0, 400, 800, or 2000 ppm (0, 0.04, 0.08, or 0.2%) β-asarone for 2 years, none of the ani- mals receiving 2000 ppm β-asarone survived more than 84 weeks, and mortality was increased at the 800 ppm dose. gross pathological changes were observed and included serous fluid in the abdominal and pleural cavities, liver and kidney changes, and tumorous masses in the intestinal tract. occurrence of tumors was dose-related. changes in the heart included myocardial atrophy, fibrosis, thrombosis, fatty degeneration, and fatty infiltration (taylor 1981). genotoxicity no mutagenic activity of a calamus extract was observed in salmonella typhimurium strains ta97a, ta100, ta102, and ta104. dose-dependent antimutagenic activity was observed at concentrations of 25 to 100 µg/plate (aqil et al. 2008). the compound cis-asarone has shown mutagenic activity in vitro (goggelmann and schimmer 1983), although this activ- ity has been characterized as weak in comparison with other mutagenic/carcinogenic natural substances (wichtl 2004). no mutagenic activity of β-asarone was observed in salmonella typhimurium strains ta98, ta100, ta1535, ta1537, or ta1538 at concentrations of 2 to 200 µg/plate with meta- bolic activation. tests without metabolic activation were not completed (hsia et al. 1979). no mutagenic activity of α-asarone was observed in the ames test with salmonella typhimurium at concentrations of up to 5000 ppm with or without activation. in a related study, β-asarone was not mutagenic at 50 ppm, but did show mutagenic activity at a concentration of 5000 ppm with acti- vation (yabiku et al. 1979). cytotoxicity an ethanol extract of calamus demonstrated cytotoxic activ- ity in a brine shrimp lethality test (padmaja et al. 2002). literature cited abel, g. 1987. chromosome-damaging effect of beta-asarone on human lymphocytes. planta med. 53(3):251-253. agarwal, s.l., p. dandiya, k. singh, and r. arora. 1956. a note on the preliminary studies of certain pharmacological actions of acorus calamus. j. am. pharm. assn. 45:655-6. aqil, f., m. zahin, and i. ahmad. 2008. antimutagenic activity of methanolic extracts of four ayurvedic medicinal plants. indian j. exp. biol. 46(9):668-672. balachandran, b., s.n. sivaswamy, and v.m. sivaramakrishnan. 1991. genotoxic effects of some foods and food components in swiss mice. indian j. med. res. 94:378-383. bensky, d., s. clavey, and e. stöger. 2004. chinese herbal medicine: materia medica. 3rd ed. seattle: eastland press. cfr. 2011. code of federal regulations, title 21 part 189.110, 2011 ed. substances prohibited from use in human food. calamus and its derivatives. washington, dc: u.s. government printing office. chadha, y. 1988. the wealth of india: a dictionary of indian raw mate- rials and industrial products. delhi: council of scientific and industrial research. dandiya, p.c., r. baxter, and h. cullumbine. 1958. studies on acorus calamus. i. phytochemical investigation. can. pharm. j. 91:607. dandiya, p.c., and h. cullumbine. 1959. studies on acorus cala- mus. iii. some pharmacological actions of the volatile oil. j. pharmacol. exp. ther. 125:353-359. dandiya, p.c., h. cullumbine, and e.a. sellers. 1959. studies on acorus calamus. iv. investigations on mechanism of action in mice. j. pharmacol. exp. ther. 126:334-337. dasgupta, s.r., b. patra, and s. sikdar. 1977. preliminary studies of the effect of a chloroform extracted factor from acorus cala- mus on the behavior of conscious rhesus monkeys. sci. culture 43:218. de smet, p.a. 1985. a multidisciplinary overview of intoxicat- ing snuff rituals in the western hemisphere. j. ethnopharmacol. 13(1):3-49. fao/who. 1981. β-asarone. fao/who expert committee on food additives. toxicological evaluation of certain food addi- tives. who food additives series 16. geneva. goggelmann, w., and o. schimmer. 1983. mutagenicity testing of beta-asarone and commercial calamus drugs with salmonella typhimurium. mutat. res. 121(3-4):191-194. habermann, r.t. 1971. carcinogenicity of beta-asarone in rats in a two-year feeding study. cited in fao/who. 1981. β-asarone. fao/who expert committee on food additives. toxicological evaluation of certain food additives. who food additives series 16. geneva. hanson, k., m. gayton-ely, l. holland, p. zehr, and b. söderberg. 2005. rapid assessment of beta-asarone content of acorus calamus by micellar electrokinetic capillary chromatography. electrophoresis 26(4-5):943-946.

acorus gramineus 14 a review details i. drug and supplement interactions clinical trials of drug or supplement interactions no clinical trials of drug or supplement interactions were identified. case reports of suspected drug or supplement interactions no case reports of suspected drug or supplement interac- tions were identified. animal trials of drug or supplement interactions a dose-dependent increase in pentobarbital-induced sleep- ing time was observed in mice orally administered an aque- ous extract of 0.5 to 5.0 g/kg of grass-leaf sweetflag (liao et al. 1998). inhalation of the aroma of grass-leaf sweetflag also prolonged the pentobarbital-induced sleeping time in mice (koo et al. 2003). ii. adverse events case reports of adverse events no case reports of adverse events were identified. iii. pharmacology and pharmacokinetics human pharmacological studies no relevant human pharmacological studies were identified. animal pharmacological studies a dose-dependent decrease in locomotor activity was observed in mice orally administered an aqueous extract of 0.5 to 5.0 g/kg of grass-leaf sweetflag (liao et al. 1998). in vitro pharmacological studies no relevant in vitro pharmacological studies were identified. iv. pregnancy and lactation no teratogenic effects were observed in chicken eggs injected with α-asarone at doses up to 4 mg/egg. in eggs injected with β-asarone, 43% of embryos survived a dose of 0.04 mg/egg, while none survived a dose of 4 mg/egg (yabiku 1980). no information on the safety of grass-leaf sweetflag in lactation was identified. v. toxicity studies also see entry for acorus calamus rhizome of the asarone-con- taining triploid or tetraploid varieties for more information on the toxicity of β-asarone. acute toxicity the ld50 of intraperitoneally administered aqueous extract of grass-leaf sweetflag in mice was 53 g/kg (chen and chen 2004). the ld50 of intraperitoneally administered α-asarone in mice was 339 mg/kg. toxic effects included seizures, con- vulsions, and slowed respiration (chen and chen 2004). literature cited bensky, d., s. clavey, and e. stöger. 2004. chinese herbal medicine: materia medica. 3rd ed. seattle: eastland press. chang, h.-m., and p.p.h. but. 1986. pharmacology and applications of chinese materia medica. english ed. singapore, philadelphia: world scientific. chen, j.k., and t.t. chen. 2004. chinese medical herbology and phar- macology. city of industry, ca: art of medicine press. cho, j., y.h. kim, j.y. kong, c.h. yang, and c.g. park. 2002. protection of cultured rat cortical neurons from excitotoxicity by asarone, a major essential oil component in the rhizomes of acorus gramineus. life sci. 71(5):591-599. koo, b.s., k.s. park, j.h. ha, et al. 2003. inhibitory effects of the fragrance inhalation of essential oil from acorus gramineus on central nervous system. biol. pharm. bull. 26(7):978-982. liao, j.f., s.y. huang, y.m. jan, l.l. yu, and c.f. chen. 1998. central inhibitory effects of water extract of acori graminei rhizoma in mice. j. ethnopharmacol. 61(3):185-193. sugimoto, n., m. mikage, h. ohtsubo, f. kiuchi, and y. tsuda. 1997a. pharmacognostical investigations of acori rhizomes: i. histological and chemical studies of rhizomes of a. calamus and a. gramineus distributed in japan. nat. med. 51(3):259-264. sugimoto, n., h. ohtsubo, m. mikiage, et al. 1997b. pharmacognostical investigation of acori rhizomes: ii. histological and chemical studies of acori rhizomes in asian markets. nat. med. 51(4):316-324. yabiku, h.k. 1980. calamus oil—toxicological aspects and their control in alcoholic beverages. cited in who. 1981. β-asarone. toxicological evaluation of certain food additives. who food additives series 16. joint fao/who expert committee on food additives. yabiku, h.y., s. oga, and f.m. lajolo. 1979. toxic effects of acorus calamus oil. preliminary study with rats and chicken embryos. an. farm. quim. sao paulo 19(2):252-258.

actaea racemosa 20 a review details v. toxicity studies acute toxicity the ld50 of the compound acteina was greater than 500 mg/ kg in mice after intraperitoneal administration, was 1000 mg/kg in rats after oral administration, and was 70 mg/ kg in rabbits after intravenous administration. toxic doses of acteina could not be determined in rabbits administered the compound orally or subcutaneously (genazzani and sorrentino 1962). short-term toxicity in a study of an ethanolic extract of black cohosh adminis- tered by gavage to rats in daily doses from 1 to 1000 mg/kg for 21 days, some dose-dependent changes in liver cell mito- chondria were observed beginning at the 10 mg/kg dose. at 10 mg/kg, a slight amount of mitochondrial swelling and an enlargement of bile canaliculi was observed. at the 100 or 300 mg/kg dose, more distinct mitochondrial swelling and alterations in mitochondrial morphology such as vacuoles in the matrix was observed. at 1000 mg/kg, effects included microvesicular steatosis of the hepatocytes, and glycogen depletion (lüde et al. 2007). no changes in liver morphology or hepatic function indi- ces were observed in rats orally administered 300 mg/kg of black cohosh extract daily for 30 days (mazzanti et al. 2008). chronic toxicity in rats administered black cohosh extract up to 5000 mg/kg/ day, slight and reversible increases in some organ weights were noted in animals administered the highest doses, but no toxic effects were noted at any of the dose levels (korn 1991). genotoxicity no evidence of mutagenicity was demonstrated in the ames test (beuscher 1996; boblitz et al. 2000; schaper and brümmer 1990). literature cited al-akoum, m., s. dodin, and a. akoum. 2007. synergistic cyto- toxic effects of tamoxifen and black cohosh on mcf-7 and mda-mb-231 human breast cancer cells: an in vitro study. can. j. physiol. pharmacol. 85(11):1153-1159. bai, w., h.-h. henneicke-von zepelin, s. wang, et al. 2007. efficacy and tolerability of a medicinal product contain- ing an isopropanolic black cohosh extract in chinese women with menopausal symptoms: a randomized, double blind, parallel-controlled study versus tibolone. maturitas 58(1):31-41. beuscher, n. 1996. european phytotherapy: cimicifuga rac- emosa l.—black cohosh. q. rev. nat. med. (spring):19-27. boblitz, n., e. liske, and p. wüstenberg. 2000. black cohosh: efficacy, effect and safety of cimicifuga racemosa in gyne- cology. dtsch. apoth. ztg. 140(24):107-114. bodinet, c., and j. freudenstien. 2002. influence of cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. breast cancer res. treat. 76(1):1-10. bolle, p., s. mastrangelo, f. perrone, and m.g. evandri. 2007. estrogen-like effect of a cimicifuga racemosa extract subfraction as assessed by in vivo, ex vivo and in vitro assays. j. steroid biochem. mol. biol. 107(3-5):262-269. bradley, p.r. 1992. british herbal compendium: a handbook of scien- tific information on widely used plant drugs. bournemouth, dorset: british herbal medicine association. brinker, f. 2001. herb contraindications and drug interactions. 3rd ed. sandy, or: eclectic medical publications. chow, e.c., m. teo, j.a. ring, and j.w. chen. 2008. liver fail- ure associated with the use of black cohosh for meno- pausal symptoms. med. j. aust. 188 (7):420. cohen, s.m., a.m. o’connor, j. hart, n.h. merel, and h.s. te. 2004. autoimmune hepatitis associated with the use of black cohosh: a case study. menopause 11(5):575-577. davis, v.l., m.j. jayo, a. ho, et al. 2008. black cohosh increases metastatic mammary cancer in transgenic mice express- ing c-erbb2. cancer res. 68(20):8377-8383. dixon shanies, d., and n. shaikh. 1999. growth inhibition of human breast cancer cells by herbs and phytoestrogens. oncol. rep. 6:1383-1387. dugoua, j.j., d. seely, d. perri, g. koren, and e. mills. 2006. safety and efficacy of black cohosh (cimicifuga racemosa) during pregnancy and lactation. can. j. clin. pharmacol. 13(3):e257-e261. düker, e.m., l. kopanski, h. jarry, and w. wuttke. 1991. effects of extracts from cimicifuga racemosa on gonadotropin release in menopausal women and ovariectomized rats. planta med. 57:424-427. dunbar, k., and s.f. solga. 2007. black cohosh, safety, and pub- lic awareness. liver int. 27(7):1017. eagon, c.l., m.s. elm, and p.k. eagon. 1996. estrogenicity of traditional chinese and western herbal remedies. proc. am. assoc. cancer res. 37:284. eagon, p.k., n.b. tress, h.a. ayer, et al. 1999. medicinal botanicals with hormonal activity. proc. am. assoc. cancer res. 40:161-162. einbond, l.s., t. su, h.a. wu, et al. 2007. gene expression analy- sis of the mechanisms whereby black cohosh inhibits human breast cancer cell growth. anticancer res. 27(2):697-712. einbond, l.s., y. wen-cai, k. he, et al. 2008. growth inhibitory activity of extracts and compounds from cimicifuga species on human breast cancer cells. phytomedicine 15(6-7):504-511. einer-jensen, n., j. zhao, k.p. andersen, and k. kristoffersen. 1996. cimicifuga and melbrosia lack oestrogenic effects in mice and rats. maturitas 25(2):149-153.

actaea racemosa 21 a ellingwood, f. 1919. american materia medica therapeutics and phar- macognosy. 11th ed. chicago: ellingwood’s therapeutist. emea. 2006. assessment of case reports connected to herbal medicinal products containing cimicifugae racemosae rhizoma (black cohosh, root). emea/hmpc/269258/2006. european medicines agency. london. felter, h.w. 1891. eclectic medicines—i. macrotys. med. gleaner 3(5):109-111. felter, h.w., and j.u. lloyd. 1898. king’s american dispensatory. 18th ed., 3rd rev. 2 vols. cincinnati: ohio valley co. foldes, j. 1959. the actions of an extract of cimicifuga racemosa. arzneimittelforschung 13:623-624. freudenstein, j., and c. bodinet. 1999. influence of an isopropa- nolic aqueous extract of cimicifuga racemosa rhizoma on the proliferation of mcf-7 cells (abstract). paper read at 23rd int. lof-symposium on phyto-oestrogens, at university of gent, belgium. freudenstein, j., c. dasenbrock, and t. nisslein. 2002. lack of pro- motion of estrogen-dependent mammary gland tumors in vivo by an isopropanolic cimicifuga racemosa extract. cancer res. 62(12):3448-3852. gaube, f., s. wolfl, l. pusch, t.c. kroll, and m. hamburger. 2007. gene expression profiling reveals effects of cimicifuga racemosa (l.) nutt. (black cohosh) on the estrogen receptor positive human breast cancer cell line mcf-7. bmc pharmacol. 7(1):11. genazzani, e., and l. sorrentino. 1962. vascular action of acteina: active constituent of actaea racemosa l. nature 194:544-555. gizicky, h.u. 1944. arzneipflanzen in ihren beziehungen zum weiblichen genitalsystem. versuche anweissen ratten und mausen mit cimicifuga racemosa. z. ges. exp. med. 113:635-644. gurley, b.j., g.w. barone, d.k. williams, et al. 2006. effect of milk thistle (silybum marianum) and black cohosh (cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. drug metab. dispos. 34(1):69-74. gurley, b.j., s.f. gardner, m.a. hubbard, et al. 2005. in vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome p450 1a2, 2d6, 2e1, and 3a4/5 phenotypes. clin. pharmacol. ther. 77(5):415-426. guzman, g., e.r. kallwitz, c. wojewoda, et al. 2009. liver injury with features mimicking autoimmune hepatitis following the use of black cohosh. case rep. med. 2009:1-8. harnischfeger, g., and n. cillien. 1996. influence of cimicifuga rac- emosa extract fractions on the proliferation of human carcinoma cells in vitro with regard to their estrogen receptor sensitivity. paper presented at 44th annual congress of georg august universitat, at gottingen, germany. hirschberg, a.l., m. edlund, g. svane, et al. 2007. an isopropa- nolic extract of black cohosh does not increase mammographic breast density or breast cell proliferation in postmenopausal women. menopause 14(1):89-96. hostanska, k., t. nisslein, j. freudenstein, j. reichling, and r. saller. 2004. cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast car- cinoma cell lines by induction of apoptosis. breast cancer res. treat. 84(2):151-160. huntley, a. 2004. the safety of black cohosh (actaea racemosa, cimicifuga racemosa). expert opin. drug safety 3(6):615-623. huntley, a., and e. ernst. 2003. a systematic review of the safety of black cohosh. menopause 10(1):58-64. ingraffea, a., k. donohue, c. wilkel, and v. falanga. 2007. cutaneous vasculitis in two patients taking an herbal supple- ment containing black cohosh. j. am. acad. dermatol. 56(5 suppl):s124-s126. jarry, h., and g. harnischfeger. 1985. endocrine effects of constitu- ents of cimicifuga racemosa. 1. the effect on serum levels of pitu- itary hormones in ovariectomized rats. planta med. 51(1):46-49. jarry, h., g. harnischfeger, and e. duker. 1985. the endocrine effects of constituents of cimicifuga racemosa. 2. in vitro binding of constituents to estrogen receptors. planta med. 51(4):316-319. jarry, h., s. leonhardt, c. duls, et al. 1999. organ-specific effects of cimicifuga racemosa in brain and uterus (abstract). paper read at 23rd international lof-symposium on phyto-oestrogens, at university of gent, belgium. jarry, h., m. metten, b. spengler, v. christoffel, and w. wuttke. 2003. in vitro effects of the cimicifuga racemosa extract bno 1055. maturitas 44(suppl 1):s31-s38. jiang, b., f. kronenberg, p. nuntanakorn, m.h. qiu, and e.j. kennelly. 2006. evaluation of the botanical authenticity and phytochemical profile of black cohosh products by high per- formance liquid chromatography with selected ion monitor- ing liquid-chromatography mass spectrometry. j. agric. food. chem. 54:3242-3253. joy, d., j. joy, and p. duane. 2008. black cohosh: a cause of abnor- mal postmenopausal liver function tests. climacteric 11(1):84-88. korn, w.d. 1991. six month oral toxicity study with remifemin- granulate in rats followed by an 8-week recovery period. hannover, germany. international bioresearch. kretzschmar, g., t. nisslein, o. zierau, and g. vollmer. 2005. no estrogen-like effects of an isopropanolic extract of rhizoma cimicifugae racemosae on uterus and vena cava of rats after 17 day treatment. j. steroid biochem. mol. biol. 97(3):271-277. levitsky, j., t.a. alli, j. wisecarver, and m.f. sorrell. 2005a. fulminant liver failure associated with the use of black cohosh. dig. dis. sci. 50(3):538-539. levitsky, j., t.a. alli, j. wisecarver, and m.f. sorrell. 2005b. fulminant liver failure associated with the use of black cohosh. dig. dis. sci. 53 (3):869. light, t.d., and j.a. light. 2003. acute renal transplant rejec- tion possibly related to herbal medications. am. j. transplant. 3(12):1608-1609. liske, e., w. hanggi, h.h. henneicke-von zepelin, et al. 2002. physiological investigation of a unique extract of black cohosh (cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect. j. women’s health gend. based med. 11(2):163-174. liu, z., z. yang, m. zhu, and j. huo. 2001a. estrogenicity of black cohosh (cimicifuga racemosa) and its effects on estrogen recep- tor level in human breast cancer mcf-7 cells. wei sheng yan jiu 30(2):77-80. liu, z., b. yu, j.s. huo, c.q. lu, and j.s. chen. 2001b. estrogenic effects of cimicifuga racemosa (black cohosh) in mice and on estrogen receptors in mcf-7 cells. j. med. food 4:171-178. lohning, a., e.j. verspohl, and h. winterhoff. 2000. cimicifuga rac- emosa: in vitro findings using mcf-7 cells (abstract). paper read at phytopharmakaforschung, at bonn, germany. low dog, t.l., k.l. powell, and s.m. weisman. 2003. critical evaluation of the safety of cimicifuga racemosa in menopause symptom relief. menopause 10(4):299-313.

aesculus hippocastanum 26 a average of 4 days. the cases were primarily seen in children ages 2 to 10 and were observed after 3 to 4 days of normal renal function. the overall mortality rate was 10.7% (grasso and corvaglia 1976; hellberg et al. 1975; klose and pistor 1976; voigt and junger 1978). commenting on these cases, a text on the use of drugs in patients with renal insufficiency notes that the cases involved patients administered either the standard dose or overdose, and that some were also taking other drugs. also, most of the patients were polytraumatic after accidents or had undergone severe surgery, conditions that alone may lead to acute renal failure (seyffart 1991). aescin may cause hemolysis after injection, and the liber- ated hemoglobin can deposit in the kidneys, leading to renal failure. such effects are not expected with oral use of horse chestnut (mills and bone 2005). hepatic injury was reported in a 37-year-old man who had received a single intramuscular injection of 65 mg of a standardized horse chestnut extract prior to surgery. liver tests performed 17 days after injection revealed moderate elevation of total bilirubin, alp, ggtp and mild eosino- philia. the lymphocyte stimulation test was positive, and the liver biopsy demonstrated marked cholestasis with zonal necrosis in the centrilobular areas but showed little or no changes in the portal tracts (takegoshi et al. 1986). allergic reactions, including anaphylactic reactions, to horse chestnut have been reported (jaspersen-schib et al. 1996; sirtori 2001). iii. pharmacology and pharmacokinetics human pharmacological studies in trials assessing the renal effects of intravenously admin- istered aescin (a mixture of saponins from horse chestnut; 10 to 25 mg daily for 3 to 10 days), no impairment of renal func- tion was observed in patients with healthy kidneys, and no worsening of function was observed in patients with renal impairment (ascher 1977; bastian and valilensieck 1976; sirtori 2001; wilhelm and feldmeier 1975). animal pharmacological studies no relevant animal pharmacological studies were identified. in vitro pharmacological studies inhibition of the drug-metabolizing isoenzyme cyp3a4 and the p-gp drug efflux transporters was observed in cdna baculovirus-expressed cyp3a4 and caco-2 cells treated with horse chestnut extract. the effects were less than that of st. john’s wort (hellum and nilsen 2008). some inhibition of cyp2d6 was observed in cdna baculovirus-expressed cyp2d6, although the activity was not considered to be clin- ically relevant (hellum and nilsen 2007). general inhibitory potential of the drug-metabolizing isoenzymes cyp1a2, cyp2d6, and cyp3a4 were observed in primary human hepatocytes treated with an extract of horse chestnut. the activity was less than that of other botanicals considered to have clinically relevant cyp inter- actions (hellum et al. 2007). a twofold induction of the drug-metabolizing isoen- zyme cyp1a2 was observed in human colon cancer cells (ls180) treated with horse chestnut extract. no effects on cyp3a4 or the transporter protein mdr1 were observed (brandin et al. 2007). no significant effects of horse chestnut extract were observed in the drug-metabolizing isoenzymes cyp2c19 and cyp2e1 in cultured human hepatocytes (hellum et al. 2009). iv. pregnancy and lactation several clinical studies on the use of horse chestnut extract in pregnant women have been completed. dosages were 480 to 600 mg daily (standardized to 100 mg aescin) for 2 to 4 weeks. in these studies, no adverse effects on fetal develop- ment were reported (alter 1973; steiner 1990; steiner and hillemanns 1986; steiner and hillemanns 1990). no teratogenic effects were observed in the offspring of rats orally administered 100 or 300 mg/kg or rabbits orally administered 100 mg/kg horse chestnut extract during pregnancy. in rabbits administered 300 mg/kg, a signifi- cant reduction in the weight of fetuses was observed (liehn et al. 1972). no teratogenic or embryotoxic effects of horse chestnut extract were observed in rats intravenously admin- istered 9 or 30 mg/kg on days 6 to 15 of pregnancy, or rabbits administered the same doses on days 6 to 18 of pregnancy (liehn et al. 1972). no information on the safety of horse chestnut during lactation was identified. v. toxicity studies acute toxicity the ld50 of orally administered horse chestnut extract is 990 mg/kg in mice, 2150 mg/kg in rats, 1120 mg/kg in guinea pigs, 1530 mg/kg in rabbits, 10,700 mg/kg in hamsters, and 10,600 mg/kg in chicks (liehn et al. 1972; williams and olsen 1984). in dogs, no oral ld50 could be determined, as dogs vomited the test substance at doses over 130 mg/kg (liehn et al. 1972). the ld50 of intrave- nously administered horse chestnut extract is 138 mg/kg in mice, 165 mg/kg in rats, 465 mg/kg in guinea pigs, and 180 mg/kg in rabbits. the ld50 of intraperitoneally admin- istered horse chestnut in mice was 342 mg/kg (liehn et al. 1972). subchronic toxicity in rats intravenously administered 9, 30, or 90 mg/kg horse chestnut extract daily for 8 weeks, no adverse effects were reported at the 9 mg/kg dose. at the 90 mg/kg dose, 8 of the 30 test animals died during the first several days, although the rest of the animals in that treatment group developed normal body weights (liehn et al. 1972).

aesculus hippocastanum 27 a no toxic effects or organ damage were observed in dogs orally administered 20, 40, or 80 mg/kg (8 times the human dose) or rats orally administered 100, 200, or 400 mg/kg (40 times the human dose) of horse chestnut extract 5 days per week for 34 weeks (liehn et al. 1972). genotoxicity in the ames test for mutagenicity, horse chestnut extract was weakly mutagenic with metabolic activation by s9 but showed no mutagenicity without activation. fluid extracts of horse chestnut showed no mutagenic activity without activation, and weak mutagenic activity with activation (schimmer et al. 1994). the authors of this study indicated that the mutagenic effects were likely due to the compound quercetin, and quercetin is not considered to have clini- cally relevant mutagenic activity in humans (harwood et al. 2007). literature cited alter, h. 1973. zur medikamentösen therapie der varikosis. z. allg. med. 49:1301-1304. ascher, p. 1977. renale funktionsgroessen unter na-aescinat bei nierengesunden und nierenkranken patienten. therapiewoche 52:3-10. bastian, h.p., and w. valilensieck. 1976. nierenfunktion unter par- enteraler aescin-behandlung. med. klin. 71:1295-1299. brandin, h., e. viitanen, o. myrberg, and a.k. arvidsson. 2007. effects of herbal medicinal products and food supplements on induction of cyp1a2, cyp3a4 and mdr1 in the human colon carcinoma cell line ls180. phytother. res. 21(3):239-244. grasso, a., and e. corvaglia. 1976. due casi di sospetta tubulone- frosi tossica da escina. gazz. med. ital. 135:581-584. harwood, m., b. danielewska-nikiel, j.f. borzelleca, et al. 2007. a critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/ carcinogenic properties. food chem. toxicol. 45(11):2179-2205. hellberg, k., w. ruschewski, and r. de vivie. 1975. medikamentoes bedingtes post-operatives nierenversagen nach herzchirur- gischen eingriffen. thoraxchirurgie 23:396-399. hellum, b.h., z. hu, and o.g. nilsen. 2007. the induction of cyp1a2, cyp2d6 and cyp3a4 by six trade herbal products in cultured primary human hepatocytes. basic clin. pharmacol. toxicol. 100(1):23-30. hellum, b.h., z. hu, and o.g. nilsen. 2009. trade herbal products and induction of cyp2c19 and cyp2e1 in cultured human hepatocytes. basic clin. pharmacol. toxicol. 105(1):58-63. hellum, b.h., and o.g. nilsen. 2007. the in vitro inhibitory poten- tial of trade herbal products on human cyp2d6-mediated metabolism and the influence of ethanol. basic clin. pharmacol. toxicol. 101(5):350-358. hellum, b.h., and o.g. nilsen. 2008. in vitro inhibition of cyp3a4 metabolism and p-glycoprotein-mediated transport by trade herbal products. basic clin. pharmacol. toxicol. 102(5):466-475. jaspersen-schib, r., l. theus, m. guirguis-oeschger, b. gossweiler, and p.j. meier-abt. 1996. acute poisonings with toxic plants in switzerland between 1966 and 1994. schweiz. med. wochenschr. 126(25):1085-1098. klose, p., and k. pistor. 1976. posttraumatisches nierenversagen bei 2 kindern nach beta-aescin-therapie. munch. med. wschr. 719-720. liehn, h.d., p.a. franco, h. hampel, and g. hofrichter. 1972. a toxicological study of extractum hippocastani semen. panminerva med. 14(3):84. mills, s., and k. bone. 2005. the essential guide to herbal safety. st. louis: elsevier. pittler, m.h., and e. ernst. 2006. horse chestnut seed extract for chronic venous insufficiency. cochrane database syst. rev. (1):cd003230. schimmer, o., a. krüger, h. paulini, and f. haefele. 1994. an eval- uation of 55 commercial plant extracts in the ames mutagenic- ity test. pharmazie 49:448-451. seyffart, g. 1991. drug dosage in renal insufficiency. boston: kluwer. siebert, u., m. brach, g. sroczynski, and k. berla. 2002. efficacy, routine effectiveness, and safety of horsechestnut seed extract in the treatment of chronic venous insufficiency. a meta-anal- ysis of randomized controlled trials and large observational studies. int. angiol. 21(4):305-315. sirtori, c.r. 2001. aescin: pharmacology, pharmacokinetics and therapeutic profile. pharmacol. res. 44(3):183-193. steiner, m. 1990. untersuchungen zur ödemvermindernden und ödemprotektiven wirkung von roßkastaniensamenextrakt. phlebol. proktol. 19:239-242. steiner, m., and h. hillemanns. 1986. untersuchungen zur ödem- protektiven wirkung eines venentherapeutikums. munch. med. wschr. 128:551-555. steiner, m., and h. hillemanns. 1990. venostasin retard in the management of venous problems during pregnancy. phlebology 5:41-44. takegoshi, k., t. tohyama, and k. okuda. 1986. a case of venoplant-induced hepatic injury. gastroenterol. jap. 21(1):62-65. voigt, e., and h. junger. 1978. acute posttraumatic renal failure following therapy with antibiotics and beta-aescin. anaesthesist 27(2):81. wilhelm, r., and c. feldmeier. 1975. postoperative und post- traumatische oedemprophylaxe und therapie. med. klin. 70:2079-2083. williams, m.c., and j.d. olsen. 1984. toxicity of seeds of three aesculus spp. to chicks and hamsters. am. j. vet. res. 45(3):539-542.

alisma plantago-aquatica 38 a nausea, vomiting, abdominal pain, diarrhea, and dis- turbance of liver function have been reported in association with asian water plantain use (bensky et al. 2004). allergic skin rash after exposure to asian water plan- tain has been reported (bensky et al. 2004). pharmacological considerations one in vitro study has indicated that asian water plantain may inhibit the drug-transporting protein p-glycoprotein (fong et al. 2007). pregnancy and lactation no information on the safety of asian water plantain in pregnancy or lactation was identified in the scientific or tra- ditional literature. although this review did not identify any concerns for use while pregnant or nursing, safety has not been conclusively established. review details i. drug and supplement interactions clinical trials of drug or supplement interactions no clinical trials of drug or supplement interactions were identified. case reports of suspected drug or supplement interactions no case reports of suspected drug or supplement interac- tions were identified. animal trials of drug or supplement interactions no animal trials of drug or supplement interactions were identified. ii. adverse events case reports of adverse events long-term use or overdose of asian water plantain can dis- turb the electrolyte balance and may cause hematuria and, in severe cases, acidosis (bensky et al. 2004). nausea, vomiting, abdominal pain, diarrhea, and dis- turbance of liver function were reported in association with asian water plantain use (bensky et al. 2004). allergic skin rash after exposure to asian water plan- tain was reported (bensky et al. 2004). iii. pharmacology and pharmacokinetics human pharmacological studies no relevant human pharmacological studies were identified. animal pharmacological studies no relevant animal pharmacological studies were identified. in vitro pharmacological studies in multidrug-resistant cancer cells, extracts of asian water plantain showed a synergistic growth inhibitory effect with cancer drugs that are p-glycoprotein (p-gp) substrates including actinomycin d, puromycin, paclitaxel, vinblas- tine, and doxorubicin. the authors of the study concluded that asian water plantain may contain components that are effective inhibitors of p-gp (fong et al. 2007). iv. pregnancy and lactation no information on the safety of alisma in pregnancy or lac- tation was identified. v. toxicity studies acute toxicity the ld50 of an intravenously injected alcohol extract of asian water plantain in rats was 0.98 g/kg and 1.27 g/kg after intraperitoneal injection (chen and chen 2004). subchronic toxicity no adverse effects on internal organs were observed in rats orally administered an extract of asian water plantain at doses of 1 or 2 g/kg daily for 3 months (chen and chen 2004). literature cited bensky, d., s. clavey, and e. stöger. 2004. chinese herbal medicine: materia medica. 3rd ed. seattle: eastland press. chen, j.k., and t.t. chen. 2004. chinese medical herbology and phar- macology. city of industry, ca: art of medicine press. fong, w.f., c. wang, g.y. zhu, et al. 2007. reversal of multi- drug resistance in cancer cells by rhizoma alismatis extract. phytomedicine 14(2-3):160-165. zhu, y.p. 1998. chinese materia medica chemistry, pharmacology and applications. boca raton, fl: crc press.

aloe vera 49 a iii. pharmacology and pharmacokinetics human pharmacological studies several clinical trials have studied the effects of topical appli- cations of aloe on healing of various types of wounds and skin conditions. a speeded healing time was observed in patients treated with aloe after dermabrasion (a surgical scraping of the skin) therapy for acne (fulton 1990) and for healing in pso- riasis patients (syed et al. 1996). a slowed healing time was observed in postsurgical complicated wounds treated topi- cally with aloe (schmidt and greenspoon 1991). in allergic patch testing of 700 patients, no reactions to a concentrated (10×) aloe vera leaf gel were observed (reider et al. 2005). animal pharmacological studies animal pharmacological studies were identified but omit- ted due to availability of human data. in vitro pharmacological studies in vitro pharmacological studies were identified but omitted due to availability of human data. iv. pregnancy and lactation a review of published and unpublished indian research on plants for fertility regulation indicated that, in one study, aloe vera leaf extracts (100 to 500 mg/kg daily) administered to female rats on postcoital days 1 through 7 had some activ- ity in preventing pregnancy. contrarily, four similar studies indicated no effect on pregnancy (kamboj and dhawan 1982). no information on the safety of aloe vera leaf gel during lactation was identified. v. toxicity studies short-term toxicity no clinical signs of toxicity, mortality, or other adverse events were observed in rats orally administered 2 ml aloe vera leaf in water daily for 14 days (mds 2000). subchronic toxicity no significant adverse effects were noted when technical grade acemannan (a polysaccharide fraction of aloe gel) was administered orally to rats for 14 days as 5% of the diet and for 6 months at up to 2000 mg/kg daily and to beagle dogs for 90 days at up to 1500 mg/kg daily (fogelman et al. 1992). no changes in organ weights or body weight were reported in male mice fed 100 mg/kg daily aloe vera extract for 90 days. degeneration of sex organs was reported in 20% of mice (shah et al. 1989). chronic toxicity no harmful effects were reported in rats that ingested aloe vera leaf powder as 1% of their diet from 42 days old until natural death (ikeno et al. 2002). genotoxicity some genotoxicity but no cytotoxicity was noted for aloe vera leaf pulp in a bacterial transformation assay with the pulp added to e. coli and exposed to uv light (paes-leme et al. 2005). literature cited brinker, f. 1997. interactions of pharmaceutical and botanical medicines. j. naturopathic med. 7(2):14-20. cao, d., c.h. yoon, b.s. shin, et al. 2005. effects of aloe, aloe- sin, or propolis on the pharmacokinetics of benzo[a]pyrene and 3-oh-benzo[a]pyrene in rats. j. toxicol. env. health a 68(23-24):2227-2238. cholongitas e., katsoudas, s., and dourakis, s. 2005. henoch– schonlein purpura associated with aloe vera administration. eur. j. intern. med. 16(1):59-60. ferreira, m., m. teixeira, e. silva, and m. selores. 2007. allergic contact dermatitis to aloe vera. contact dermat. 57(4):278-279. fogelman, r.w., t.e. shellenberger, m.f. balmer, r.h. carpenter, and b.h. mcanalley. 1992. subchronic oral administration of acemannan in the rat and dog. vet. hum. toxicol. 34(2):144-147. fulton, j.e. 1990. the stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dress- ing. j. dermatol. surg. oncol. 16(5):460-467. hogan, d.j. 1988. widespread dermatitis after topical treatment of chronic leg ulcers and stasis dermatitis. can. med. assoc. j. 138(4):336-338. hunter, d., and a. frumkin. 1991. adverse reactions to vitamin e and aloe vera preparations after dermabrasion and chemical peel. cutis 47(3):193-196. ikeno, y., g.b. hubbard, s. lee, b.p. yu, and j.t. herlihy. 2002. the influence of long-term aloe vera ingestion on age-related dis- ease in male fischer 344 rats. phytother. res. 16(8):712-718. kamboj, v.p., and b.n. dhawan. 1982. research on plants for fer- tility regulation in india. j. ethnopharmacol. 6(2):191-226. lee, a., p.t. chui, c.s. aun, t. gin, and a.s. lau. 2004. possible interaction between sevoflurane and aloe vera. ann. pharmacother. 38(10):1651-1654. leung, a.y., and s. foster. 1996. encyclopedia of common natural ingre- dients used in food, drugs, and cosmetics. 2nd ed. new york: wiley. mds. 2000. mds pharma services. single dose toxicity study by the oral route in the rat. unpublished data. in bergfeld et al. 2004. safety assessment of aloe. cosmetic ingredient review. morrow, d.m., m.j. rapaport, and r.a. strick. 1980. hypersensitivity to aloe. arch. dermatol. 116(9):1064-1065. paes-leme, a.a., e.s. motta, j.c. de mattos, et al. 2005. assessment of aloe vera (l.) genotoxic potential on escherichia coli and plas- mid dna. j. ethnopharmacol. 102(2):197-201. pigatto, p.d., and g. guzzi. 2005. aloe linked to thyroid dysfunc- tion. arch. med. res. 36(5):608. reider, n., a. issa, t. hawranek, et al. 2005. absence of contact sen- sitization to aloe vera (l.) burm. f. contact dermat. 53(6):332-334. roboz, e., and a.j. haagen-smit. 1948. a mucilage from aloe vera. j. am. chem. soc. 70(10):3248-3249.

andrographis paniculata 57 a case reports of adverse events as of june 2003, no adverse events in persons taking androg- raphis had been reported to any national drug safety moni- toring agencies including those in the united kingdom, germany, and austria (coon and ernst 2004). one case of anaphylactic shock and two cases of anaphylactic reac- tions had been reported to the world health organization. all cases were from sweden, and no details on the case reports were available in the published literature (coon and ernst 2004). data obtained from manufacturers of androg- raphis products indicated that one company had received five reports of allergic reactions to products that contained andrographis (coon and ernst 2004). iii. pharmacology and pharmacokinetics human pharmacological studies no relevant human pharmacological studies were identified. animal pharmacological studies no testicular toxicity was observed in male rats orally administered a standardized extract of andrographis at doses up to 1000 mg/kg daily for 60 days (burgos et al. 1997). a decrease in sperm counts and lack of motil- ity in spermatozoa were observed in 3-month-old male rats orally administered 25 or 50 mg/kg of the com- pound andrographolide daily for 48 days (akbarsha and murugaian 2000). conversely, no significant changes in sperm morphology and motility were observed in male mice orally administered 50 mg/kg of the compound andrographolide daily for up to eight weeks. after four weeks of treatment, an increase in serum testosterone lev- els was observed as compared to control. male mice receiv- ing andrographis mounted females more quickly and with greater frequency than untreated males (sattayasai et al. 2010). reductions in alkaline phosphatase activity and total protein were observed in the reproductive organs of male rats orally administered an andrographis powder suspension at a dose of 10 or 20 mg per animal daily for 24 or 48 days (akbarsha and manivannan 1993). reduced libido was observed in male mice fed a diet supplemented with 0.75% andrographis stem powder for up to 4 weeks (shamsuzzoha et al. 1979). inhibition of fasting serum glucose levels and glucose tolerance test levels was observed in diabetic rats orally administered an ethanolic extract of andrographis at doses of 100, 200, or 400 mg/kg (zhang and tan 2000). prevention of hyperglycemia but no effects on adrenaline-induced hyper- glycemia were observed in rabbits orally administered 10 mg/kg of an aqueous extract of andrographis (borhanuddin et al. 1994). similarly, a significant reduction in blood glucose levels was observed in hyperglycemic rats orally adminis- tered an aqueous extract of andrographis. the hyperglyce- mic effect was enhanced when the freeze-dried extract was used (husen et al. 2004). no significant changes in cyp450 enzymes were observed in rats administered 1 g/kg andrographis extract or 10 mg/kg of the compound andrographolide, each in sin- gle doses (choudhury et al. 1987). dose-dependent choleretic action of the compound andrographolide was observed in rats and guinea pigs administered doses of 1.5 to 12 mg/kg (shukla et al. 1992). in vitro pharmacological studies in human platelets, the compound andrographolide inhib- ited platelet-activating-factor-induced aggregation in a dose-dependent manner (amroyan et al. 1999). in mouse platelets, a standardized aqueous extract of andrographis, and the compounds andrographolide and 14-deoxy-11,12-di- dehydroandrographolide inhibited thrombin-induced platelet aggregation in a dose-dependent manner (thisoda et al. 2006). methanolic and ethanolic extracts of andrographis inhibited cyp3a4 and cyp2d6 in vitro (subehan et al. 2006; usia et al. 2006). the compound andrographolide induced cyp1a1 and cyp1a2 but had no effect on cyp1b1 in vitro (jaruchotikamol et al. 2007). the compound bisandrographolide a has been shown to activate transient receptor potential v4 (trpv4) with an ec50 (half maximal effective concentration) of 790 to 950 nm (smith et al. 2006). iv. pregnancy and lactation after administration of 2 g/kg daily as part of the diet for 6 weeks, no pregnancies occurred in fertile female mice when the females were mated with male mice (not administered andrographis) known to be fertile (zoha et al. 1989). no antifertility effects were observed in mice admin- istered powdered andrographis leaf or root as 1% of the diet (~2 g/kg daily) for 14 days prior to mating, and 21 days during mating (shamsuzzoha et al. 1978). similarly, no anti- fertility effects were observed in female mice administered andrographis stem powder for 28 days prior to mating (shamsuzzoha et al. 1979). intraperitoneal administration of an aqueous extract of whole andrographis plants (dose not specified in english language abstract) prevented implantation in mice and caused abortion in mice during the first, sec- ond, and third trimesters of pregnancy (but 1988; chen and chen 2004). in rats orally administered 200, 600, or 2000 mg/kg (30 to 300 times higher than the standard human dose) of an andrographis extract for days 0–19 of pregnancy, no change in progesterone levels and no progesterone-mediated preg- nancy termination were observed (panossian et al. 1999). no teratogenicity or toxicity was observed in preg- nant mice orally administered 200 or 400 mg/kg androgra- phis leaf powder suspension on alternate days for 4 weeks (dhammaupakorn and chaichantipyuth 1989).

andrographis paniculata 58 a no information on the safety of andrographis during lactation was identified. v. toxicity studies acute toxicity the ld50 of an orally or subcutaneously administered alco- holic extract of andrographis in mice could not be deter- mined at doses up to 15 g/kg (sithisomwongse et al. 1989). the ld50 of an intraperitoneally administered alcoholic extract was 14.98 g/kg (sithisomwongse et al. 1989). the ld50 of an aqueous-methanolic andrographis whole plant extract intraperitoneally administered in mice could not be determined at doses up to 1 g/kg (nakannishi et al. 1965). the ld50 of the compound andrographolide orally administered in mice could not be determined at doses up to 40 g/kg (chang and but 1986). literature cited akbarsha, m.a., and b. manivannan. 1993. biochemical changes in the testis and male accessory organs of albino rats on treat- ment with andrographis paniculata (nees). indian j. comp. an. physiol. 11(2):103-108. akbarsha, m.a., and p. murugaian. 2000. aspects of the male reproductive toxicity/male antifertility property of androgra- pholide in albino rats: effect on the testis and the cauda epi- didymidal spermatozoa. phytother. res. 14(6):432-435. amroyan, e., e. gabrielian, a. panossian, g. wikman, and h. wagner. 1999. inhibitory effect of andrographolide from andrographis paniculata on paf-induced platelet aggregation. phytomedicine 6(1):27-31. borhanuddin, m., m. shamsuzzoha, and a.h. hussain. 1994. hypoglycaemic effects of andrographis paniculata nees on non- diabetic rabbits. bangladesh med. res. counc. bull. 20(1):24-26. burgos, r.a., e.e. caballero, n.s. sanchez, et al. 1997. testicular toxicity assessment of andrographis paniculata dried extract in rats. j. ethnopharmacol. 58(3):219-224. but, p. 1988. chinese medicine for birth control. abstr. chin. med. 2(2):247-269. calabrese, c., s.h. berman, j.g. babish, et al. 2000. a phase i trial of andrographolide in hiv positive patients and normal volun- teers. phytother. res. 14(5):333-338. chang, h.-m., and p.p.h. but. 1986. pharmacology and applications of chinese materia medica. english ed. singapore, philadelphia: world scientific. chen, j.k., and t.t. chen. 2004. chinese medical herbology and phar- macology. city of industry, ca: art of medicine press. choudhury, b.r., s.j. haque, and m.k. poddar. 1987. in vivo and in vitro effects of kalmegh (andrographis paniculata) extract and andrographolide on hepatic microsomal drug metabolizing enzymes. planta med. 53(2):135-140. coon, j.t., and e. ernst. 2004. andrographis paniculata in the treat- ment of upper respiratory tract infections: a systematic review of safety and efficacy. planta med. 70(4):293-298. dhammaupakorn, p., and c. chaichantipyuth. 1989. cited in mills, s., and k. bone. 2005. the essential guide to herbal safety. st. louis: elsevier. husen, r., a.h. pihie, and m. nallappan. 2004. screening for anti- hyperglycaemic activity in several local herbs of malaysia. j. ethnopharmacol. 95(2-3):205-208. jaruchotikamol, a., k. jarukamjorn, w. sirisangtrakul, et al. 2007. strong synergistic induction of cyp1a1 expression by andrographolide plus typical cyp1a inducers in mouse hepa- tocytes. toxicol. appl. pharmacol. 224(2):156-162. mandal, s.c., a.k. dhara, and b.c. maiti. 2001. studies on psy- chopharmacological activity of andrographis paniculata extract. phytother. res. 15(3):253-256. melchoir, j., s. palm, and g. wikman. 1996. controlled clinical study of standardised andrographis paniculata extract in com- mon cold—a pilot trial. phytomedicine 3:315-318. nakannishi, k., s. sasaki, a. kiang, et al. 1965. phytochemical and pharmacological screening. chem. pharm. bull. 13:822. panossian, a., a. kochikian, e. gabrielian, et al. 1999. effect of andrographis paniculata extract on progesterone in blood plasma of pregnant rats. phytomedicine 6(3):157-161. sattayasai, j., s. srisuwan, t. arkaravichien, and c. aromdee. 2010. effects of andrographolide on sexual functions, vascular reactivity and serum testosterone level in rodents. food. chem. toxicol. 48 (7):1934-1938. shamsuzzoha, m., m.s. rahman, and m.m. ahmed. 1979. antifertility activity of a medicinal plant of the genus andrografis (sic) wall (family acanthaceae). part ii. bangladesh med. res. counc. bull. 5(1):14-18. shamsuzzoha, m., m.s. rahman, m.m. ahmed, and a.k. islam. 1978. antifertility effect in mice of medicinal plant of family acanthaceae. lancet 312(8095):900. shukla, b., p.k. visen, g.k. patnaik, and b.n. dhawan. 1992. choleretic effect of andrographolide in rats and guinea pigs. planta med. 58(2):146-149. sithisomwongse, n., j. phengchata, and s. cheewapatana. 1989. acute and chronic toxicity of andrographis paniculata nees. thai j. pharm. sci. 14(2):109-117. smith, p.l., k.n. maloney, r.g. pothen, j. clardy, and d.e. clapham. 2006. bisandrographolide from andrographis panicu- lata activates trpv4 channels. j. biol. chem. 281(40):29897. subehan, t. usia, h. iwata, s. kadota, and y. tezuka. 2006. mechanism-based inhibition of cyp3a4 and cyp2d6 by indonesian medicinal plants. j. ethnopharmacol. 105(3):449-455. thisoda, p., n. rangkadilok, n. pholphana, et al. 2006. inhibitory effect of andrographis paniculata extract and its active diterpe- noids on platelet aggregation. eur. j. pharmacol. 553(1-3):39-45. usia, t., h. iwata, a. hiratsuka, et al. 2006. cyp3a4 and cyp2d6 inhibitory activities of indonesian medicinal plants. phytomedicine 13(1-2):67-73. zhang, c.y., and b.k. tan. 1997. mechanisms of cardiovascular activity of andrographis paniculata in the anaesthetized rat. j. ethnopharmacol. 56(2):97-101. zhang, x.f., and b.k. tan. 2000. anti-diabetic property of ethano- lic extract of andrographis paniculata in streptozotocin-diabetic rats. acta pharmacol. sin. 21(12):1157-1164. zoha, m.s., a.h. hussain, and s.a. choudhury. 1989. antifertility effect of andrographis paniculata in mice. bangladesh med. res. counc. bull. 15(1):34-37.

angelica dahurica 63 a editors’ note other species of angelica are commonly traded as bai zhi (bensky et al. 2004; chang and but 1986). adverse events and side effects topical allergic reactions and dermatitis caused by contact with the fresh herb have been reported (bensky et al. 2004). although furanocoumarin compounds, such as those pres- ent in fragrant angelica, have photosensitizing effects (a heightened response of the skin to sunlight or other ultra- violet light) after contact with skin, no cases of photosensi- tivity due to oral ingestion of fragrant angelica are known (bensky et al. 2004); such a reaction is theoretically possible. pharmacological considerations an animal study indicated that fragrant angelica inhib- ited the drug-metabolizing isoenzymes cyp2c, cyp3a, cyp2d1, and cyp2c9 (ishihara et al. 2000). the relevance of this information to human use is not known. pregnancy and lactation no information on the safety of fragrant angelica in preg- nancy or lactation was identified in the scientific or tradi- tional literature. although this review did not identify any concerns for use while pregnant or nursing, safety has not been conclusively established. review details i. drug and supplement interactions clinical trials of drug or supplement interactions no clinical trials of drug or supplement interactions were identified. case reports of suspected drug or supplement interactions no case reports of suspected drug or supplement interac- tions were identified. animal trials of drug or supplement interactions coumarins isolated from fragrant angelica administered orally to rats in single doses of 25, 50, or 100 mg/kg increased the duration of hypnosis induced by pentobarbital sodium. the 100 mg/kg dose also prolonged the latent period and shortened the duration of hypnosis induced by barbital sodium (liu et al. 2006). ii. adverse events case reports of adverse events large doses (30–60 g) of fragrant angelica may cause slowed heart rate, increased blood pressure, increased depth of res- piration, nausea, vomiting, dizziness, difficulty breathing, sweating, or numbness of the limbs (bensky et al. 2004; chen and chen 2004). cases of gross overdose have been associ- ated with seizures and convulsions (chen and chen 2004). although several sources indicate that persons ingest- ing fragrant angelica should limit exposure to the sun, due to the furanocoumarin content of the herb, no cases of photosensitivity associated with oral ingestion are known (bensky et al. 2004). topical allergic reactions and dermatitis caused by contact with the fresh herb have been reported (bensky et al. 2004). two cases of phytophotodermatitis associated with accidental skin contact with a multi-herb decoction including fragrant angelica have been reported (zhang and zhu 2011). iii. pharmacology and pharmacokinetics human pharmacological studies no relevant human pharmacological studies were identified. animal pharmacological studies inhibition of the drug-metabolizing isoenzymes cyp2c, cyp3a, and cyp2d1 was observed in rats orally admin- istered a single dose of 1 g/kg of fragrant angelica. at the same dose level, fragrant angelica prolonged the half-life and reduced the clearance of intravenously administered tolbutamide (a cyp2c9 substrate) (ishihara et al. 2000). the furanocoumarin compound phellopterin was shown to be a partial agonist of the central benzodiazepine receptors. two other naturally occurring furanocoumarins, byakangelicol and imperatorin, exhibited significantly less potent binding activity to the benzodiazepine site of the rat brain gaba-a receptor (dekermendjian et al. 1996). in vitro pharmacological studies infusions of fragrant angelica inhibited the drug-metaboliz- ing isoenzyme cyp3a4. activity varied according to horti- cultural variety, and the infusions were significantly more active than the 40% ethanol extract of the different products (guo et al. 2001). of 11 furanocoumarin compounds isolated from fra- grant angelica, 2 showed strong abilities to induce alkaline phosphatase with ec50 values of 1.1 and 0.8 µg/ml, respec- tively, whereas the other 9 furanocoumarins were weakly or only slightly active (piao et al. 2006). fragrant angelica inhibited melanogenesis in b16 mela- noma cells (cho et al. 2006). of eight furanocoumarin compounds isolated from fra- grant angelica, one strongly inhibited (ic50 of 0.36 µm) bind- ing of diazepam to central nervous system benzodiazepine receptors, while other structurally similar compounds had minimal effect on receptor binding (bergendorff et al. 1997).

angelica sinensis 67 a and bronchoprovocation tests showed an early asthmatic response to dong quai extract (lee et al. 2001). iii. pharmacology and pharmacokinetics human pharmacological studies in patients with ulcerative colitis, intravenous administra- tion of 40 ml daily of dong quai extract inhibited platelet activation (dong et al. 2004). intravenous administration of 200 ml daily of a 25% solution of dong quai for 20 days to patients with acute ischemic stroke resulted in decreases in a number of hematological parameters including plate- let adhesion rate, platelet electrophoresis time, and whole blood adhesion, and an increase in prothrombin time (tu and huang 1984). a reduction in whole blood viscosity was observed for approximately 3 hours in people orally admin- istered a dong quai extract (terasawa et al. 1985). in a human study of dong quai in menopausal women, involving administration of 4.5 g daily of dong quai for 24 weeks, no changes in serum hormone levels, vaginal cytol- ogy, or endometrial thickness were observed, indicating a lack of estrogenic effects (hirata et al. 1997). animal pharmacological studies in rats administered 3 g/kg dong quai aqueous or ethanolic extracts, both extracts significantly induced the drug-metab- olizing isoenzymes cyp2d6 and cyp3a (tang et al. 2006). injection of 1 g/ml dong quai prevented platelet aggregation and erythrocyte stasis in alveolar capillaries induced by the injection of measles vaccine (yan et al. 1987). administration of two doses of 6 or 8 ml each (1.5 hours between doses) of an aqueous extract of dong quai to fasting rats resulted in a decrease in time to thrombus formation and an increase in prothrombin time (li and yang 1982). no increase in uterine weight was observed in ovariec- tomized mice orally administered 500 µl daily of an etha- nolic extract of dong quai for 4 days (amato et al. 2002). in ovariectomized rats administered 100 or 300 mg/kg daily of a dried ethanolic extract of dong quai or 1 µg/rat estradiol, a significant increase in uterine weight was observed in rats administered dong quai, but the increase was significantly less than that observed in rats administered estradiol. mean luteinizing hormone levels were reduced in rats treated with dong quai, and no changes were observed in follicle-stimu- lating hormone levels. these results suggest an estrogenic effect of dong quai (circosta et al. 2006). in vitro pharmacological studies in a study of a dong quai ethanolic extract on mcf-7 (er positive) human breast cancer cells, dong quai induced the growth of mcf-7 cells by 16-fold over that of untreated con- trol cells. in a transient gene expression assay system, dong quai failed to show transactivation of either estrogen recep- tor erα or erβ cdna (amato et al. 2002). an aqueous extract of dong quai dose-dependently stimulated the proliferation of mcf-7 and bt-20 (er negative) breast cancer cells (lau et al. 2005). an extract of dong quai inhibited growth of t-47d (er positive) and mcf-7 human breast cancer cells (dixon- shanies and shaikh 1999). iv. pregnancy and lactation a survey of 593 pregnant women in hong kong indicated that 12% had used “chinese angelica” during their preg- nancy. this was the second most popular herb for use dur- ing pregnancy in the survey. no data on maternal or infant health was collected in the survey (ong et al. 2005). subcutaneous administration of 0.1 to 0.4 ml daily of an aqueous dong quai extract to mice for 5 days did not affect fertility or show any teratogenic effects (matsui et al. 1967). dong quai essential oil applied to isolated uteri pro- duced a relaxant effect while the nonvolatile fractions pro- duced a stimulant effect, potentiating uterine contraction (zhu 1998). three unpublished cases of rashes have been reported in breast-feeding newborn infants whose mothers were tak- ing dong quai (dose, duration, and preparation unreported) (upton 2003). a breast-feeding woman and her 3-week-old infant developed high blood pressure after the woman consumed an unspecified amount of dong quai prepared in a soup. blood pressure of both the woman and her infant returned to normal 48 hours after cessation of dong quai (nambiar et al. 1999). v. toxicity studies acute toxicity the ld50 of orally administered dong quai concentrated extract (8:1 to 16:1) in rats is 100 g/kg (zschocke et al. 1998); of intravenously administered aqueous extract in mice is 100 g/kg (wei 1987); and of orally administered 50% ethanol extract in mice is over 40 g/kg (yang and chen 1992). the ld50 of 4:1 concentrated extract of dong quai in rats is 100 g/ kg (route of administration unspecified) (zhu 1987). no toxic effects of dong quai extract were observed in rats or mice after single doses of 6 g/kg (tanaka et al. 1983). the ld50 of intravenously administered ferulic acid in mice is reported to be 856.6 mg/kg (ozaki and ma 1990); of intraperitoneally administered ligustilide in mice is approx- imately 410 mg/kg (xie and tao 1985), and of orally admin- istered 3-n-butylidene phthalide in rats is 2.45 g/kg (opdyke 1979). in a review of the toxicology literature on dong quai, intravenous injection of the volatile fraction of dong quai was reported to cause kidney degeneration (mei et al. 1991). short-term toxicity after 21 days of oral administration of 1.5 or 3 g/kg dong quai extract daily to rats, increases in serum free cholesterol levels and kidney cyp450 enzymes were observed (tanaka et al. 1983).