Infl ammatory Bowel Disease

A sampling of targeted integrative therapies

Infl ammatory Bowel Diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, relapsing-remitting infl ammatory diseases with several hallmarks of dysfunction, including a breakdown in intestinal barrier function and intestinal permeability, unchecked chronic infl ammation, and an exaggerated immune response characterized by imbalanced anti-infl ammatory and proinfl ammatory cytokines. Proinfl ammatory cytokines such as IL-1, IL-6, IL-12, IFN-gamma and TNF-alpha are increased with lowered anti-infl ammatory and regulatory cytokines like IL-10 and TGF-beta. When diagnosed with IBD later in life, aside from regular check-ups with gastroenterologists between procedures and to monitor effi cacy of pharmaceutical interventions, many adults have questions about their specifi c needs and are looking for additional support. However, many patients are reluctant to seek out integrative healthcare as they are concerned they will be encouraged not to take their medications which are helping to reduce their symptoms and provide quality of life. Naturopathic doctors have a unique opportunity to support patients with IBD by using the most appropriate treatments during diff erent stages of the disease process.

Supporting Intestinal Barrier Function and Intestinal Permeability

1.Prebiotic and Probiotic support Prebiotic supports (i.e. oligofructosaccharides and/or inulin found in chicory, wheat, onions, bananas) encourage growth of benefi cial bacteria and have the capability of skewing directional growth of probiotic strains which confer specifi c host benefi ts (Bouhnik 2004, Langlands 2004, Looijer-van Langen 2009). Some of these host benefi ts include providing energy sources for intestinal bacteria to ferment into short chain fatty acids (SCFA) (Looijer-van Langen 2009). Short chain fatty acids (SCFA’s) such as butyrate are a source of energy for colonocytes and can regenerate mucosa, as well as having the capacity to reduce infl ammation through enhancement of anti-infl ammatory cytokines such as IFN-gamma and NF-kB which are down-regulated in both Crohn’s disease and ulcerative colitis (Looijer-van Langen 2009). In a group of 19 patients with active UC (mild-moderate disease severity) administered inulin for 2 weeks in addition to the 3g/daily of mesalamine, a signifi cant reduction in calprotectin (a fecal infl ammatory marker increased in IBD) compared with the placebo control group was observed (Casellas 2007, Konikoff 2006). UC in general shows more signifi cant benefi t from prebiotic support compared with CD.

Probiotic support is widely considered a gold-standard intervention in both conventional and integrative medicine for both active and remission phases of IBD, with benefi ts of the most popular investigated strains summarized in Table 1. Current research has explored specifi c strains and their ability to infl uence active vs. remission phases of IBD, as summarized in Table 2. Of research produced to date, administering the proper probiotic strain(s) is crucial to seeing rapid improvements in bowel mucosa, stool quality and frequency, as well as reducing systemic infl ammation (Looijer-van Langen 2009). e probiotic VSL#3, which provides a high- dose milieu of bacteria, is more appropriate in IBD disease remission than is S. boulardii, which shows fantastic response for diarrhea-control and initiating remission (Ewaschuk 2010).

A recent meta-analysis comparing multiple studies and strains contrasted these conclusions for CD specifically, finding significance for E.coli and S. boulardii but not for lactobacillus strains (Rahimi 2008). Hence, screening for the proper strains by looking at disease activity and subjective symptomatology is the most useful strategy in selection appropriate probiotic blends for IBD management.

2. Amino Acid Supplementation Increased intestinal permeability can be predictive of how soon an individual relapses to active disease. IFN-gamma and TNF-a, central mediators of intestinal inflammatory diseases, induce intestinal epithelial barrier dysfunction (MacDonald 1990, Wyatt 2004). L-glutamine, the major feeding source for enterocytes, has been suggested to have antioxidant potential by reducing nitrous oxide (NO) as well as restoring loose connections between tight junctions of colonocytes (Coeffier 2010, Grozswitz 2009). Animal-models of IBD induced via dextran sulfate sodium or acetic acid show promise with reduction of proinflammatory cytokines (TNF-alpha and IL-8) and intestinal damage in the presence of L-glutamine consumption (Coeffier 2010). However, when used in human studies, glutamine supplementation does not show the same benefits in symptomatic reduction of disease activity through subjective scoring of the disease activity indices (CDAI) (Akobeng 2007, Den Hond 1999, Ockenga 2005). Study designs could use some improvements both in consistency of dosages administered as well as methodology of testing. Biopsies of inflamed gastrointestinal mucosa and measurements of cytokine levels are for the most part lacking in human trials post-glutamine consumption; perhaps it is in the microscopic changes of the intestinal barrier where the impact of L- glutamine supplementation will be observed (Coeffier 2005, Coeffier 2010)

Reducing Chronic Inflammation

A. N-3 Fish oil The inflammation-reducing capacity of high-potency n-3 fish oils via the arachidonic acid pathways are well- publicized, acting as do current pharmaceutical supports for IBD including 5-ASA (Belluzzi 2000). While patients with IBD have steatorrhea and fat-soluble vitamin malabsorption, fish oil supplementation should be a top priority in integrative support of IBD (Hartman 2009). A selection of research groups in comparison of N-3, N-6 and N-9 oil usage for IBD across 10 years has been quickly summarized in Table 3 to further confirm the absolute necessity of n-3 fish oil for IBD support.

B. Curcuma longa or Curcumin Curcumin shows incredible promise from both preclinical models and recent human trials in IBD. It has demonstrated the ability to influence the arachidonic acid pathway and downregulate chemokine production (Arafa 2009, Goel 2007, Jagetia 2007). Neutrophil motility in IBD is correlated with disease severity with higher rates of neutrophil migration leading to reduced epithelial barrier function (Larmonier 2011); curcumin administration in murine models of IBD has demonstrated reduced neutrophil motility as well as reduced NF-kappaB as has led to further exploration in human IBD (Salh 2003).

Ex vivo¸biopsies from colonic mucosa and myofibroblasts from children and adults with active IBD exposed to curcumin in culture has demonstrated IL-10 production, reduction of IL-1B activity, and further reduction of cell signaling molecules in inflammatory pathways (Epstein 2009).

An RCT involving 89 patients with UC in remission were exposed to either 2 g/day of curcumin with sulfasalazine or placebo with sulfasalazine, with significant findings for delay of relapse in patients given curcumin (4.65%) as treatment compared with placebo (20.51%; p=0.040) (Hanai 2006). Further studies need to be completed, in addition to answering questions surrounding curcumins oral bioavailability (Marczylo 2007).

Oxidative stress

Reactive oxygen species and radical nitrogen metabolites accumulate rapidly during intestinal inflammation in patients with IBD, of which antioxidant support can be invaluable (Aghdassi 2003, Najafzadeh 2009). In addition to vitamin C, quercetin shows promise in animal models of IBD and has been used in combination with fish oil to restore glutathione concentration and to reduce COX-2 more significantly than with just fish oil alone (Camuesco 2006).

Dietary Support

As integrative healthcare providers, we concern ourselves with elimination of irritating proinflammatory foods such as dairy products (primarily cow’s milk), wheat gluten, peanuts, citrus fruits, fish and shellfish, synthetic and excessive sugar, and soy products. The “Western diet” high in animal meats, dairy, and sugars has been implicated in the increase in prevalence of both UC and CD in a comparison between 1990 and 2007 of reduced microbes in the intestines and food consumption (Asakura 2008).

Along the same vein, lactose intolerance and lactose malabsorption have a strong amount of research support with correlations to worsening IBD, especially CD compared with controls (Szilagyi 1998). Lactulose breath tests are often used to confirm this, however as most patients with IBD have imbalanced or higher than normal quantities of bowel flora, results prove to be inconsistent across many studies (Szilagyi 1998). Milk allergy and/or IgE antibodies to cow’s milk proteins are not often positive, which adds to the confusion where patients feel well avoiding dairy products but blood titres do not confirm the subjective improvements (Knoflach 1987, Mishkin 1997). Even if and when allergy results are positive and patients avoid offending foods for a period of time through elimination, intestinal permeability may still be increased as was demonstrated in a group of patients with IBD who avoided allergen exposure for six months yet still had high lactulose/mannitol ratios (Wyatt 1993). Intestinal permability can be an independent issue that is not easily solved with food avoidance.

In addition, replacement or substitution for these caloric losses in food avoidance is an issue as there is a need to nourish patients with IBD. Prednisone as an anti-inflammatory support in some patients with active IBD leaches calcium from the bones, and vitamin D is not only essential in directing calcium to the bones but to support proinflammatory cytokines such as IL-1 and TNF-alpha suppression in IBD and in colorectal cancer prevention (Raman 2011). Among patients in remission from CD, 50% were shown to have low plasma concentrations of vitamin C (84%), copper (84%), niacin (77%), and zinc (65%) in addition to malabsorption of fat and fat-soluble vitamins (Filippi 2006). Exploring all options including screening for celiac disease, lactose intolerance, and multiple food allergies would be prudent rather than strictly eliminating foods without testing for such intolerances, thus taking each patient’s care as a unique situation despite general IBD trends.

Conclusion

Integrative healthcare providers play a unique supportive role in IBD. Recognizing the current disease state (active vs remission), the extent of inflammation, bowel flora status, and supporting processes of oxidative stress can improve quality of life for patients. Patients need the reassurance that they will not be in a competition or battle between their integrative healthcare provider and conventional supports (GI specialist, MD) but that we can provide improved quality of life by working as part of an integrative health care team.

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HPA Axis Dysregulation and Human Health

What is the evidence?

Regulation of hypothalamus-pituitary-adrenal (HPA) axis activity has far reaching implications for many areas of human health. Abnormalities in HPA axis reactivity and secretion of its primary effector, cortisol, have been observed in various autoimmune diseases, chronic fatigue syndrome (CFS) and fibromyalgia (FM), as well as in patients with major depression and cancer (Brivio 2010, Chrousos 1995, Nussey 2001, Romer 2009). Cortisol exerts widespread anti-inflammatory, immunosuppressive, catabolic, hyperglycemic, and anti-reproductive effects that may modulate these disease processes; strategies that modulate cortisol activity either through direct hormone replacement, or herbal/ nutritional/ lifestyle strategies, may be useful as therapy for such conditions (Chrousos 1995). This article reviews determinants of the HPA stress response, the concept of hypoadrenalism/ adrenal fatigue, and existing human trials of low-dose hydrocortisone replacement. HPA axis function in specific conditions, adrenal function testing, and nutritional/ herbal interventions strategies are to be discussed in future articles.

HPA Axis Physiology

Activation of the HPA axis in response to a perceived stressor begins with the secretion of corticotropin releasing hormone (CRH) and arginine-vasopressin (AVP) from the paraventricular nucleus (PVN) of the hypothalamus (Smith 2006, Tsigos 2002). This triggers release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which in turn stimulates the secretion of glucocorticoids, notably cortisol, by the adrenal cortex. Cortisol acts through the ubiquitous distribution of glucocorticoid receptor (GR) throughout the body, altering cellular gene expression through activation of glucocorticoid response elements (Chrousos 1995). Inhibition of the HPA axis is by negative feedback of cortisol on hypothalamic and pituitary centers, thus limiting the duration of tissue exposure to the deleterious effects of chronic elevated cortisol (Nussey 2001).

Stressors

Stressors that drive CRH/ cortisol secretion can be categorized as physical stressors such as exertion, trauma, and lack of sleep; psychological stressors; and biochemical stressors such as hypoglycemia and inflammation (Balbo 2010). Sleep deprivation or irregularity is an often overlooked contributor to a patient’s overall stress load. Sleep onset modestly inhibits cortisol secretion, while awakenings are accompanied by increased secretion, an effect that is likely mediated in part by melatonin, the diurnal counterpart to cortisol (Balbo 2010). Chapotot demonstrated that plasma cortisol level, secretory rate, and pulse amplitude were all significantly increased in healthy young men after a night of sleep deprivation compared to regular nocturnal sleep (p<0.05) (2001). Sleep phase shift like that which occurs during travel across time zones or with irregular hours of sleep also induces dramatic increases in cortisol (Balbo 2010).

Inflammatory mediators such as TNF-α, IL-1, and IL-6 have also been shown to activate the HPA axis (Tsigos 2002). These cytokines, particularly IL-6, signal the HPA axis at multiple levels (hypothalamus, pituitary, and adrenal glands) to secrete more glucocorticoids in order to control inflammation (Chrousos 1995, Mastorakos 1995). Tsigos showed that administration of IL-6, a key mediator of inflammation, resulted in acutely elevated plasma ACTH and elevation in cortisol lasting for over four hours in healthy subjects (1997). Mastorakos found that IL-6 administration increased ACTH and cortisol levels in cancer patients (1993). Interestingly, Vgontzas showed that sleep deprivation in otherwise healthy subjects induced significantly increased daytime secretion of IL-6, which may represent an indirect mechanism by which sleep loss induces cortisol (1999).

Rapidly fluctuating blood glucose levels represent another unsuspected source of biochemical stress. Hypoglycemia requires adrenal compensation, triggering cortisol mediated liver gluconeogenesis in order to restore normal glucose levels (Chen 2010). It is interesting to note that a feeding response is also commonly observed, such that cortisol tends to rise modestly after meals, particularly at noon (Lemmens 2011, Vicennati 2002). Although there is conflicting evidence, it seems that intake of carbohydrates and simple sugar results in a higher post meal cortisol response compared to water, fats, and protein (Martens 2010), while animal studies suggest that high protein and high fat foods may reduce post meal cortisol (Lacroix 2004). This makes sense in light of the fact that consumption of fats and protein results in a smoother, more even post-prandial blood glucose profile, requiring less compensation by the adrenal glands. A corollary of this is that functional hypoglycemia may therefore also be an indication of hypoadrenalism (Gaby 2010).

Obesity has been associated with greater 24 hour cortisol secretion (Vicennati 2002), which may be due in part to the inflammatory milieu created by abdominal adiposity, with elevated CRP etc, however obesity is also characterized by HPA axis hyperresponsiveness to neuroendocrine stimuli (Vicennati 2000, 2004). Vincennati conducted a study of HPA stimulation and suppression through the administration of arginine-vasopressin (AVP, an HPA stimulant produced by the hypothalamus) and alprazolam (a short acting benzodiazepine and centrally acting HPA inhibitor used to treat anxiety) in women (2004). Overweight/ obese women showed higher ACTH and cortisol responses to the AVP stimulation test, and significantly greater inhibition after alprazolam compared to non-overweight controls (Vicennati 2004). Alprazolam also decreased 24h-urinary free cortisol excretion by approximately 50% in the overweight/obese subjects, but not in controls.

Other endocrine axes also interact with cortisol and the HPA-axis. In women, an age-related decrease in estradiol is thought to decrease the responsiveness of the HPA axis to stimulatory cytokines, based on evidence in animal models of ovarian failure (Straub 2000, Xia-Zhang 1995), and estrogen replacement therapy in menopausal women has been shown to suppresses the HPA axis response to emotional stress (Carrasco 2003, Lindheim 1992). Tsigos reports that activation of the HPA axis is associated with decreased production of TSH and decreased peripheral conversion of T4 to the more biologically active T3 (as seen in ‘‘euthyroid sick’’ syndrome), which may serve to conserve energy during stress (2002). In animal models, induction of the stress response (ACTH secretion) has been shown to decrease circulating levels of T4 and T3 (Helmreich 2005).

Cortisol synthesis

The adrenal cortex is responsible for three major pathways/ products: the mineralocorticoid pathway leading to production of aldosterone; the androgen/ estrogen pathway producing DHEA, testosterone, and estradiol; and the glucocorticoid pathway leading to production of cortisol. These are depicted in Figure 1. Two key enzymes convert intermediaries to cortisol: 21ß-hydroxylase converts 17-hydroxy-progesterone to 11- ßdeoxycortisol, which is then converted to cortisol by 11ß-hydroxylase. Measurement of serum 17-hydroxy-progesterone (17-OH-P) level is often used to assess the activity of these enzymes; in the event of an enzyme deficiency, as in non-classical congenitial adrenal hyperplasia (NCAH) for example, 17-OH-P will accumulate in the pathway (Kelestimur 2006). Negative (eg. catabolic) effects of cortisol are countered in part by the adrenal androgen DHEA (Straub 2000).

Cortisol rhythm

Cortisol secretion is pulsatile, diurnal, and stress-responsive (Balbo 2010). ACTH and cortisol levels peak in the morning (acrophase) just prior to waking, with gradual decline throughout the rest of the day, and an extended period of low levels around midnight (nadir), followed by a rapid rise during the second half of the night (Balbo 2010). Control of diurnal cortisol secretion is thought to be under direct neural control via a multisynaptic pathway from the pineal gland (site of melatonin synthesis), as well as through an intrinsic circadian oscillator in the adrenal gland itself that can be directly modulated by melatonin (Balbo 2010).

The Evolution of HPA and Disease

Seyle’s now-famous General Adaptation Syndrome (GAS) describes three phases of HPA activity in response to stress; the Alarm Reaction, Resistance, and Exhaustion. His 1950 paper describes the biology of each phase in surprising detail. In brief, during the first stage the adrenal glands release epinephrine and glucocorticoids to help restore homeostasis; when homeostasis is restored, adaptation is maintained through sustained secretion of glucocorticoids; when resistance to the stressor can no longer be maintained, exhaustion ensues, accompanied by the onset of disease. This has usually been thought of as the downregulation over time of adrenal gland responsiveness to ACTH/ stressors, or decreased adrenal reserve, resulting in inadequate cortisol secretion to meet physiological requirements and consequent loss of anti-inflammatory control (Gaby 2011, Jefferies 2004). Seyle wrote about “diseases of adaptation” (1950), providing a detailed list of chronic inflammatory diseases, including allergies, asthma, eczema, psoriasis, lupus, rheumatoid arthritis, ulcerative colitis, and chronic urticaria, which may be one of the earliest medical descriptions of what is now considered by naturopathic doctors as “adrenal fatigue” or mild hypoadrenalism.

Although glucocorticoid therapy has since evolved such that standard use involves large pharmacological doses for limited periods of time, William Jefferies pioneered the use of physiologic doses of cortisol as long term therapy of many conditions (2004). Jefferies distinguishes between 1) replacement dosage (~35-40 mg/d) such as that used in adrenalectomized patients or in Addison’s disease; 2) supra-replacement dosage (>40mg/d) or pharmacological doses; and 3) sub-replacement dosage, the dose he utilizes as physiologic cortisol therapy in patients with intact adrenals: hydrocortisone 20mg/d in four divided doses, with food to avoid gastrointestinal side effects such as hyperacidity (2004). In his book, Safe Uses of Cortisol, Jefferies reports cases of many patients with diverse clinical presentations from his own practice who have benefited from physiologic doses of cortisol: rheumatoid arthritis and autoimmune disease, allergies, infertility and recurrent miscarriage, viral infections, functional hypoglycemia, thyroid conditions, and chronic fatigue syndrome (Jefferies 2004).

Jefferies explains that although it is low dose, the physiologic use of cortisol has not historically been considered as a therapeutic option because of the assumption that it carries the same safety concerns as pharmacological doses (eg. diabetes, osteoporosis, etc). He emphasizes the importance of four divided doses (roughly q6h) rather than twice daily “because of evidence that normal blood levels and some metabolic effects … do not last longer than eight hours” (2004). This maintains a smoother cortisol curve without sharp peaks and troughs throughout the day, which more closely mimics physiological secretion. A retrospective chart analysis by Howlett lends support to this dosing schedule: using data from 130 patients and 174 3-point serum cortisol curves, Howlett found that TID dosing achieved “optimal replacement” more frequently than BID dosing, 60% versus 15% of cases (p<0.001) (1997). Optimal replacement was defined as the dose that achieved a urinary free cortisol and 0900h serum cortisol within the normal range to avoid over-replacement, while maintaining 1230h and 1730h cortisol above 50nmol/L, and ideally above 100 nmol/L to avoid under-replacement (1997).

In his text, Nutritional Medicine, Alan Gaby discusses mild hypoadrenalism or adrenocortical insufficiency, differentiating it from the severe, autoimmune hypoadrenalism of Addison’s disease (2011). He lists characteristic symptoms as including fatigue, weakness, anorexia, nausea, vomiting, weight loss, salt craving, hypotension or orthostatic hypotension, hypoglycemia, hyperpigmentation of the skin, decreased body hair in women, and poor tolerance to stress or exertion. Gaby notes that the inability of a clinically hypothyroid patient to tolerate even low doses of thyroid hormone may indicate hypoadrenalism. Gaby also describes low dose hydrocortisone therapy as a treatment option for hypoadrenalism and chronic fatigue syndrome, corroborating Jefferies’ experience (2011). He relates that he uses the lowest effective dose of hydrocortisone, sometimes lower than 5mg QID, and has noted improvement at doses as low as 1mg TID.

Hydrocortisone is the glucocorticoid of choice for treatment of hypoadrenalism because it is the biochemical equivalent to endogenous cortisol. Other corticosteroids are often more potent in their activity, and as discussed above are dosed very differently. A comparison of glucocorticoids adapted from the Compendium of Pharmaceuticals and Specialties (CPS 2011) is provided in Table 1. According to this table, Prednisone is approximately four times as potent as hydrocortisone.

Human Trials of Hydrocortisone Therapy: CFS and PTSD Chronic Fatigue Syndrome

It has been noted by many authors that CFS resembles Addison’s in its symptomotology (Cleare 2001, Gaby 2011). HPA abnormalities have been documented at many levels of the axis in CFS, but not all with equal consistency (Chrousos 1995, Cleare 2001, Gaab 2002, Jerjes 2007, Papadopoulos 2009, Scott 2000). Cleare reviews HPA axis activity in CFS, stating that “tests of negative feedback using dexamethasone support [the] hypersuppression of cortisol and negative feedback…with over half the studies [also] suggesting lowered basal cortisol and/ or blunted HPA axis responses” (2004). A detailed analysis is beyond the scope of this paper, however three controlled human trials of low dose hydrocortisone therapy conducted in patients with CFS are discussed below.

Cleare found benefit from hydrocortisone in a randomized placebo controlled crossover trial of 32 CFS patients without comorbid psychiatric disorder (1999, 2001). Two dosages investigated: either 5mg or 10mg, taken as a single daily dose with breakfast for 28 days. Both dosages had comparable effects on fatigue scores (p=0.90). In the collective treatment group fatigue score dropped 7.2 points, compared to 3.3 points in the placebo group, a mean difference of 4.5 points (p<0.009). Mean disability score also decreased with treatment but not placebo. Fatigue scores normalized in nine (28%) of the hydrocortisone group compared to two (9%) of the placebo group (p=0.05). Importantly, insulin stress testing showed that these doses of hydrocortisone did not induce adrenal suppression. Reported side effects in three patients on hydrocortisone included: worsening of acne, nervousness, and improvement of eczema.

In contrast, RCTs by McKenzie and Blockmans found no clinically significant benefits, albeit at doses and schedules that were shown to induce adrenal suppression: 25-35mg hydrocortisone BID and a combination of 5mg hydrocortisone + 20mg fludrocortisone daily (Blockmans 2003, McKenzie 1998). McKenzie did find that a greater percentage (53% vs 29%; P=.04) recorded an improvement of five or more points in Wellness score, and a higher average improvement in Wellness score on more days compared to placebo recipients (P<.001) (1998). A lack of correlation between the magnitude of impaired basal/ stimulated serum cortisol levels and disease severity in this study, yet small improvements with hydrocortisone therapy suggests the possibility of peripheral glucocorticoid resistance (Chrousos 1995, McKenzie 1998). Blockmans notes that CFS is a heterogeneous disorder, and treatment with low-dose steroids may only be effective for a certain subset of patients (2003).

Although hydrocortisone for treatment of fibromyalgia has not been investigated, patients with this condition also display HPA axis dysfunction, with lowered salivary cortisol, urinary cortisol excretion and more pronounced suppression of cortisol compared with controls on low dose dexamethasone testing (Izquierdo- Alvarez 2008, Riva 2010, Wingenfeld 2007).

Post Traumatic Stress Disorder (PTSD)

Aerni conducted a small randomized, double blind, placebo controlled cross over trial of three patients with PTSD (2004). Low dose hydrocortisone 10mg doses either as a single daily dose in one patient and as two divided doses in the other two patients or placebo was given for one month. Results showed that there was a significant treatment effect in all the patients, with “cortisolrelated reductions of at least 38% in one of the daily rated symptoms of traumatic memories, as assessed by self-administered rating scales” (Aerni 2004). Additionally, the clinician-Administered PTSD Scale ratings assessed after each month showed cortisolrelated improvements for reexperiencing symptoms, and in one patient, for avoidance symptoms also, but there was no impact on hyperarousal symptoms.

Conclusion

The HPA axis is activated in response to physical, psychological, and biochemical stresses. Mild hypoadrenalism is thought to contribute to the onset of a spectrum of chronic inflammatory conditions. Drs Jefferies and Gaby have pioneered the use of physiological doses of hydrocortisone as therapy for autoimmune disease and other conditions such as chronic fatigue syndrome. Although limited, human trials of low dose hydrocortisone suggest that this therapy may be of benefit to some patients with this condition, with one trial suggesting benefit in approximately 1/3 of patients. There is a need for better understanding of testing methods and natural strategies that can be used to treat conditions characterized by mild hypoadrenalism.

References:

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Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004 Mar;15(2):55-9.

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Cleare AJ, Heap E, Malhi GS, Wessely S, O’Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999 Feb 6;353(9151):455-8.

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Martens MJ, Rutters F, Lemmens SG, Born JM, Westerterp-Plantenga MS. Effects of single macronutrients on serum cortisol concentrations in normal weight men. Physiol Behav. 2010 Dec 2;101(5):563-7.

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Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab. 1993 Dec;77(6):1690-4.

McKenzie R, O’Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, Garcia- Borreguero D, Blackwelder W, Straus SE. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998 Sep 23- 30;280(12):1061-6.

Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Chapter 4: The Adrenal Gland. Feedback control of glucocorticoids. BIOS Scientific Publishers Limited, 2001. Available at NCBI: http://www.ncbi.nlm.nih.gov/books/NBK26/ Accessed 27 May 2011.

Riva R, Mork PJ, Westgaard RH, Rø M, Lundberg U. Fibromyalgia syndrome is associated with hypocortisolism. Int J Behav Med. 2010 Sep;17(3):223-33.

Römer B, Lewicka S, Kopf D, Lederbogen F, Hamann B, Gilles M, Schilling C, Onken V, Frankhauser P, Deuschle M. Cortisol metabolism in depressed patients and healthy controls. Neuroendocrinology. 2009;90(3):301-6.

Scott LV, Svec F, Dinan T. A preliminary study of dehydroepiandrosterone response to low-dose ACTH in chronic fatigue syndrome and in healthy subjects. Psychiatry Res. 2000 Dec 4;97(1):21-8.

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Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8(4):383-95.

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Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002 Oct;53(4):865-71.

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Vicennati V, Ceroni L, Gagliardi L, Gambineri A, Pasquali R. Comment: response of the hypothalamic-pituitary-adrenocortical axis to high-protein/fat and highcarbohydrate meals in women with different obesity phenotypes. J Clin Endocrinol Metab. 2002 Aug;87(8):3984-8.

Vicennati V, Ceroni L, Gagliardi L, Pagotto U, Gambineri A, Genghini S, Pasquali R. Response of the hypothalamic-pituitary-adrenal axis to small dose arginine-vasopressin and daily urinary free cortisol before and after alprazolam pre-treatment differs in obesity. J Endocrinol Invest. 2004 Jun;27(6):541-7.

Vgontzas AN, Mastorakos G, Bixler EO, Kales A, Gold PW, Chrousos GP. Sleep deprivation effects on the activity of the hypothalamic-pituitary-adrenal and growth axes: potential clinical implications. Clin Endocrinol (Oxf). 1999 Aug;51(2):205-15.

Wingenfeld K, Wagner D, Schmidt I, Meinlschmidt G, Hellhammer DH, Heim C. The low-dose dexamethasone suppression test in fibromyalgia. J Psychosom Res. 2007 Jan;62(1):85-91.

Xia-Zhang L, Xiao E, Ferin M. A 5-day estradiol therapy, in amounts reproducing concentrations of the early-mid follicular phase, prevents the activation of the hypothalamo-pituitary-adrenal axis by interleukin-1 alpha in the ovariectomized rhesus monkey. J Neuroendocrinol. 1995 May;7(5):387-92.

Homeopathy

An introduction to application in pediatrics

The use of complementary and alternative medicine (CAM) in pediatric primary care is common, with homeopathy being one of the most widely used CAM modalities in the world. In a recent survey done in the UK, the rate of homeopathic use in children amongst GPs is 22%, with most prescribing taking place for infants less than one year old with minor self-limiting conditions at a relatively low rate of approximately one per month. A smaller number of GPs report prescribing much more frequently (Ekins-Daukes 2005). In Germany, homeopathy is the most frequently used CAM treatment for childhood ailments, where nearly 50% of the homeopathic medicines are prescribed by medical doctors and Heilpraktiker, and used to treat a wide range of conditions with a greater rate of use for self limiting conditions (Du 2009). The publications on the use of CAM in pediatric primary care and oncology indicate that homeopathy plays a complimentary but largely unofficial role in pediatric oncology in Israel (Ben Arush 2006), Canada (Fernandez 1998), Italy (Steinsbekk 2006), and Netherlands (Grootenhuis 1998). In the US, it is estimated that over 900 000 children are administered homeopathic medicines on a yearly basis (Barnes 2008). In India, homeopathy is widely used in pediatric care, as it is incorporated as a system of primary care within the established medical system (Ghosh 2010).

Homeopathic remedies are potentized substances at a dilution level often greatly surpassing the Avogadro number. This naturaly gives rise to questions about the mechanism of action of homeopathic remedies. Despite much experimentation, the exact mechanism through which homeopathic remedies effect change remains elusive. Recent work has focused on the memory of water hypothesis in which properties of water are held to be influenced by the history of substances water has been in contact with (Chaplin 2007). Other work on the subject has focused on quantum interactions and entanglement of the remedies with the substances from which they are made, as well as quantum entanglement between the patient and practitioner (Molski 2010, Neuhouser 2001). Although no firm consensus has yet emerged, research into the question is gaining solid ground (Enserink 2010).

Most homeopathic remedies are made from natural ingredients (plants, minerals, or animals), yet numerous recent remedies have been created from a wider range of substances, such as colored light (Griffith 2008) and physiological tissues from the birth process (Assilem 2009). In addition, more recent work by Jan Scholten and the members of the Mumbai school in India have introduced classification of remedies into thematically oriented groups, and have offered deeper exploration into the unconscious levels of remedy pictures (Sankaran 2008). Their work has re-energized the field of homeopathy, widening the number of remedies that can be matched to childhood ailments.

Homeopathic remedies are symptom specific. Prescribing in pediatric patients requires keen observational skills as well as a strong knowledge of materia medica. The choice of remedy must take into consideration general temperament of the child, the emotional responses to challenges that they are facing, as well as the unique details of the physical symptoms they are exhibiting or experiencing. This requires careful observation on the part of the parent and the physician since children are often unable to report the subtleties of their symptoms. In addition, observation of the parents and the social environment of the child may offer great clues to remedy selection (Master 2006).

Homeopathic remedies can be prescribed to children on an acute or constitutional basis. Constitutional prescribing is mostly indicated in chronic or recurrent conditions and is based on the child’s overall physical, emotional, and mental symptom picture. A constitutional remedy strengthens and stimulates the child’s vitality, improves physical and mental development and helps maintain their overall health over time. For acute presentations, symptom-specific prescribing based on the totality of the presentation at the time of intake is most commonly employed. A matching acute remedy will promptly releave the child’s symptoms and significantly increase rate of recovery.

Dosing strategies in children are similar to adult protocols. Although most books on pediatric dosing recommend low dose prescribing, for healthy children with strong vitality, dosing higher potencies of 200c, 1M, and 10M often show great results, as long as the remedy is a close similimum. It is generally prudent, however, to begin with lower potencies (such as 6c, 30c) and gradually move up to 200c, 1M and 10M if vitality of the child is vague, or if the remedy match is not entirely revealed. For children with chronic illneses and disabilities, higher potency remedies may provoke aggravations or worsening of the presenting symptoms. In such sensitive cases, liquid dosing and LM dosing are recommended.

The following protocol is designed to minimize aggravations in sensitive children, yet speed up progress of their condition considerably: Begin with 6c potency of the selected remedy diluted and succussed in alcohol and water. Administer 1-10 drops to the child and observe for a week. If no response, redose. If positive response results, redose only when you see child ceasing to improve. If progress comes to a plateau, dose more often until daily dosing. The typical progression of potencies in this protocol is 6c, 30c, LM-1, LM-2, and upwards (De Schepper 2004).

References:

Assilem, M. Matridonal Remedies of The Human Family: Gifts of the Mother. 2009. Idolatry. ink . USA. Pp. 60- 69.

Barnes P, Bloom B. Complementary and Alternative Medicine Use Among Adults and Chilren: United States 2007. National Health Statistics Reports. Number 12. Dec. 2008

Ben Arush MW, Geva H, Ofir R, Mashiach T, Uziel R, Dashkovsky Z. Prevalence and characteristics of complementary medicine used by pediatric cancer patients in a mixed western and middle-eastern population. Journal of Pediatric Hematology/Oncology. 2006;28(3):141–146.

Boon, HS et al. Practice patterns of naturopathic physicians: results from a random survey of licensed practitioners in two US States. “javascript:AL_get(this,%20’jour’,%20’BMC%20 Complement%20Altern%20Med.’);”BMC Complement Altern Med. 2004 Oct 20; 4:14.

Fernandez CV, Stutzer CA, MacWilliam L, Fryer C. Alternative and complementary therapy use in pediatric oncology patients in British Columbia: prevalence and reasons for use and nonuse. Journal of Clinical Oncology. 1998;16(4):1279–1286

“http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chaplin%20 MF%22%5BAuthor%5D”Chaplin MF. The Memory of Water: an overview. “javascript:AL_ get(this,%20’jour’,%20’Homeopathy.’);”Homeopathy. 2007 Jul;96(3):143-50.

De Schepper, L. Achieving and maintaining the simillimum : strategic case management for successful homeopathic prescribing. 2004. Full of Life Publishing. Santa Fe, NM.

Du Y, Knopf H. Paediatric homoeopathy in Germany: results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Pharmacoepidemiol Drug Saf 2009 May;18(5):370-9

Ekins-Daukes S, Helms PJ, Taylor MW, Simpson CR, McLay JS. Paediatric homoeopathy in general practice: where, when and why? British Journal of Clinical Pharmacology. 2005;59(6):743–749.

Enserink M, Newsmaker Interview: Luc Montagnier, French Nobelist Escapes “Intellectual Terror” to Pursue Radical Ideas in China. Science 24 December 2010: Vol. 330 no. 6012 p. 1732.

Fernandez CV, Stutzer CA, MacWilliam L, Fryer C. Alternative and complementary therapy use in pediatric oncology patients in British Columbia: prevalence and reasons for use and nonuse. Journal of Clinical Oncology. 1998;16(4):1279–1286 “http://www.ncbi.

nlm.nih.gov/pubmed?term=%22Ghosh%20AK%22%5BAuthor%5D”Ghosh AK. A short history of the development of homeopathy in India. “javascript:AL_get(this,%20’jour’,%20 ’Homeopathy.’);”Homeopathy. 2010 Apr;99(2):130-6.

Griffith, C. The New Materia Medica: Key Remedies for the Future of Homeopathy. 2008. Sterling. New York.

Grootenhuis MA, Last BF, de Graaf-Nijkerk JH, van der Wel M. Use of alternative treatment in pediatric oncology. Cancer Nursing. 1998;21(4):282–288.

Le Roux, P. Butterflies. 2009. Narayana. Kandern, Germany. Pp. 42-43, 95-99.

Master F. Clinical Observations of Children’s Remedies. 2006. 3rd edition. Lutra Services BV. Eidhoven, Netherlands

Milgrom, L.R. Patient-practitioner-remedy (PPR) entanglement. Part 5. Can homeopathic remedy reactions be outcomes of PPR entanglement? Homeopathy 93, 94-98 (2004). “http:// www.ncbi.nlm.nih.gov/pubmed?term=%22Molski%20M%22%5BAuthor%5D”Molski M. Quasi-quantum phenomena: the key to understanding homeopathy. “javascript:AL_ get(this,%20’jour’,%20’Homeopathy.’);”Homeopathy. 2010 Apr;99(2):104-12.

Neuhouser ML, Patterson RE, Schwartz SM, Hedderson MM, Bowen DJ, Standish LJ. Use of alternative medicine by children with cancer in Washington State. Preventive Medicine. 2001;33(5):347–354.

Sankaran, R. Structure, Experiences with the Mineral Kingdom: Vol 1. 2008. Mumbai, India : Homeopathic Medical Publishers.

Scholten, J. Homeopathy and the Elements. 1996. Stichting Alonnissos. Utrecht, Netherlands. Simpson N, Roman K. Complementary medicine use in children: extent and reasons. A population-based study. Br J Gen Pract. 2001;51(472):914–16.

Steinsbekk A, Bentzen N, Brien S. Why do parents take their children to homeopaths? An exploratory qualitative study. Forschende Komplementärmedizin. 2006;13(2):88–93.

Vermuelen F. Concordant Materia Medica. 2000. 3rd Edition. Emryss bv Publishers. Haarlem, Netherlands

Zand J, Rountree R, Walton R. Smart Medicine for Healthier Child. 2003. 2nd Edition. Penguin Group. NY.

L-theanine

Neuropsychiatric applications

The amino acid L-theanine is considered to be unique because it is found almost exclusively in Camellia sinensis, a popular tea plant (Monograph 2005). Theanine is the dominant amino acid found in teas leaves and is primarily responsible for the flavor of teas (Juneja 1999). Teas are one of the most common beverages globally consumed. The popularization of tea is said to be due to its ‘relaxation’ type effects (Juneja 1999). Interest in theanine was sparked due to its abundance in traditional diets (particularly in the Japanese diet) and its positive effects such as the ‘relaxed but alert’ state associated with consuming tea. Current literature, including human and non-human studies, suggests that L-theanine is a psychoactive compound that improves cognitive function and reduces anxiety (Gomez-Remirez 2007, Kimura 2007, Kobayashi 1998, Lu 2004, Nobre 2008, Yokogoshi 1998). Studies indicate L-theanine is also neuroprotective, possesses anti-cancer and immune supporting properties, and may help control hypertension (Bryan 2008, Juneja 1999, Monograph 2005, Nathan 2006). Each one of these areas warrants consideration. However, this article will focus on evidence that links L-theanine with cognitive and mood related effects.

Physiology

L-theanine (N-ethyl-L-glutamine) is a derivative of glutamic acid which is also a neurotransmitter in humans (Yokogoshi 1998). It is a water-soluble compound and is absorbed in the small intestine by a Na+ -coupled transporter found in the brush boarder membrane (Monograph 2005, Unno 1999). In the central nervous system (CNS), L-theanine crosses the blood-brain barrier through a leucinepreferring transport system in a concentration-dependant manner (Nathan 2006, Terashima 1999, Yokogoshi 1998). L-theanine is eliminated through hydrolysis to glutamic acid and thylamine in the kidneys (Unno 1999). Peak serum and hepatic concentrations of L-theanine occur 1 hr after administration, while brain levels peak after 5 hrs (Terashima 1999). Concentrations then decline gradually over 24 hrs following administration (Terashima 1999).

Toxicology

Borzelleca (2006) conducted a study to evaluate the safety of L-theanine. Rats were administered L-theanine via the diet at various concentrations (adjusted weekly) to sustain target doses of 1500, 3000, and 4000 mg/kg bw/day for 13 weeks. The monitored parameters of adverse effects included; behavior, morbidity, mortality, body weight, food consumption, clinical chemistry, hematology, and unrinalysis. The results were as follows:

• No treatment-related deaths

• Lower body weights in both female and male animals were observed at 3000 and 4000mg/kg bw/day doses (p< 0.05) but was determined to be due to significantly lower food consumption (unpalatability of diet) • No significant behavioural changes

• Reduced locomotor activity in males at weeks 3 and 14 but deemed unrelated to treatment (biological significance is unknown)

• No treatment related adverse effects related to clinical pathology were reported.

It was concluded that L-theanine is well tolerated and the LD50 is greater than 5000 mg/kg in rats, exponentially higher than the dose used for therapeutic administration in humans (Borzelleca 2006, Monograph 2005). Mutagenic or carcinogenic risks were not found in animals or bacteria (Borzelleca 2006, Monograph 2005).

Non-Human Studies

Although animal studies are not directly clinically applicable, the early in vivo evidence provides an understanding of the basic mechanism by which L-theanine exerts it neuropsychiatric effects, and the basis upon which further human investigations were conducted. A brief discussion of these findings is provided here.

Yokogoshi (1998) investigated (i) the transport system of theanine through the blood-brain barrier and (ii) the effects of theanine on brain monoamine (eg. dopamine) concentrations and the activity of dopaminergic neurons. It was determined that theanine competitively used the leucine- preferred transport system (LTS) to cross the blood brain barrier, since high concentrations of theanine appeared to affect levels of other amino acids that used the LTS. Non-LTS amino acid concentrations were unaffected. Catecholamines and 5-hydroxyindole levels were increased after theanine administration. This was especially noticed in the striatum where dopaminergic neurons are highly concentrated. Dopamine concentrations increased following theanine injection, but further investigation was suggested in order to more directly correlate theanine administration with dopaminergic effects. Collectively, these findings suggest that L-theanine may alter brain monoamine concentrations, thereby affecting cognitive function and mood. In this study serotonin concentration in the stratum and hippocampus were elevated, however, a subsequent study indicated a general decrease of serotonin release (Bryan 2008). It was suggested that theanine decreases serotonin levels only when caffeine is present (Bryan 2008, Nathan 2006, Yokogoshi 1998).

Lending support to such a caffeine-theanine interaction, another study demonstrated that theanine has antagonistic effects on caffeine’s stimulatory action. Kakuda (2000) monitored brain waves, using electroencephalography (EEG), after I.V. administration of caffeine and theanine in rats. The minimum dose of five micromol/kg body weight was determined to be the level at which caffeine was stimulating according to brain wave monitoring. Injection of theanine at a similar concentration inhibited caffeine’s stimulatory action; however, injection of theanine alone at levels of 1 -2 micromol/kg caused excitatory effects. These results suggest that theanine has inhibitory effects on caffeine’s stimulatory actions, but dose- dependant excitatory effects when administered alone. At the human level, this interaction has been confirmed by some studies while not in others, such as Rogers (2008) wherein theanine had no antagonistic effect on caffeine with respect to jitteriness, alertness or mood (please see Table 1 for summary).

Human Studies

Thirteen human studies were identified of L- theanine for impact on neuropsychiatric outcomes (see Table 1 and Table 2).

A novel trial administered 400mg/day of L- theanine as addon to antipsychotic treatment in randomized, double- blind, placebo controlled fashion to 60 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder (Ritsner 2011). Outcome measures included the Positive and Negative Syndrome Scale (PANSS), the Hamilton Anxiety Rating Scale (HARS), The Cambridge Neuropsychological Test Automated Battery (CANTAB), side effects and quality of life. Forty patients completed the eight week trial. Last observation carried forward (LOCF) was applied to the statistical analysis, and therefore 12 patients who dropped out of the trial between weeks four and six were included in the analysis.

L- theanine administration achieved significant benefit to the positive scores of the PANSS (p=0.009) compared to placebo, but failed to impact the PANSS negative subscales (p>0.05). On the five-Factor PANSS model the following was observed:

• Significant decrease of positive scores from week six onward

• Reduced activation (from week 2 onward)

• Reduced dysphoric mood (from week 2 onward)

•Reduced autistic preoccupations (from week 8 onward) On the HARS scores, improvement was seen on the second week compared to placebo. The results were as follows:

• Reduced anxious mood

• Reduced tension

No treatment- related adverse effects were observed. The authors conclude that co-treatment with antipsychotic therapy and Ltheanine improves anxiety and general psychopathology symptoms. Since the dopamine system has been implicated in schizophrenia, these findings would seem to support the preclinical indications that L-theanine acts upon this neurotransmitter pathway.

Lu and colleagues (2004) compared the anxiolytic effects of L-theanine to the benzodiazepine alprazolam. Sixteen patients were randomized to 200mg L- theanine, 1mg alprazolam, or placebo in double blind fashion. Participants were subjected to an experimentally induced anxiety related condition and also assessed under a relaxed condition. Acute effects of alprazolam and L-theanine were assessed by subjective self-reports of anxiety (Beck Anxiety Inventory (BAI), Visual Analogue Mood Scale (VAMS), and The State-Trait Anxiety Inventory (STAI)). The study determined that both L-theanine and alprazolam had no effect on subjective anxiety levels under the induced anxiety condition. On the VAMS tranquil-trouble subscale during resting conditions, L-theanine significantly reduced subjective anxiety when compared to alprazolam (p<0.05) and placebo (p<0.05). Therefore, L- theanine was able to produce a subjective anxiolytic outcome superior to alprazolam and placebo in a resting state.

Several human trials have investigated the impact of L- theanine on brain wave activity through application of EEG analysis. Reproducibly, L- theanine administration has been demonstrated to increase alpha wave activity (Gomez-Ramirez 2007, Kobayashi 1998, Nobre 2008) (see Table 1). Increased alpha wave activity is thought to indicate a state of wakeful relaxation. It has been associated with a general state of mental alertness or arousal; creativity; enhanced performance under stress; and improved cognitive function (learning and concentration), as well as decreased perceived anxiety (Bryan 2008, Gomez-Ramirez 2007, Mason 2001, Yokogoshi 1998).

Conclusion

L-theanine appears to be a safe, natural option for improving cognitive functioning such as attention, learning, and concentration. Evidence also suggests mood modulating effects (e.g. ‘relaxation’, sedation) which could be beneficial for improving anxiety related symptoms. Therapeutic dosage ranges from 50mg to 200mg and appears to complement conventional therapies well. Although the evidence to date is promising, the human level studies are minimal at present. Further human clinical trials are needed. In the mean time, dietary sources of L-theanine (green tea, black tea, white tea) appear to be beneficial to health and can be considered as a simple way to enhance or improve cognitive function and relaxation; administration of L-theanine can be considered as a complementary treatment for anxiety.

References

Bryan J. Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev. 2008; 66(2): 82-90.

Borzelleca JF, Peters D, Hall W. A 13-week dietary toxicity and toxicokinetic study with l-theanine in rats. Food Chem Toxicol. 2006 Jul;44(7):1158-66.

Dimpfel W, Kler A, Kriesl E, Lehnfeld R, Keplinger-Dimpfel IK. Source density of the human EEG after ingestion of a drink containing decaffeinated extract of green tea enriched with L-theanine and theogallin. Nutr Neurosci. 2007; 10(3-4): 169-180.

Einöther SJL, Martens VEG,Rycroft JA, De Bruin EA. L-Theanine and caffeine improve task switching but not intersensory attention or subjective alertness. Appetite. 2010; 54: 406-409.

Giesbrecht T, Rycroft JA, Rowson MJ, De Bruin EA. The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness. 2010: 13(6): 283-290.

Gomez-Ramirez M, Higgins BA, Rycroft JA, Owen GN, Mahoney J, Shpaner M, Foxe JJ. The deployment of intersensory selective attention: a high-density electrical mapping study of the effects of theanine. Clin Neuropharmacol. 2007; 30(1): 25-38.

Haskell CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008; 77: 113-122.

Juneja LR, Chu DC, Okubo T, Nagato Y, Yokogoshi H. L-theanine – a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Tech. 1999; 10: 199-204.

Kakuda T, Nozawa A, Unno T, Okamura N, Okai O. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem. 2000; 64(2): 287-293.

Kelly SP, Gomez-Ramirez M, Montesi JL, Foxe JJ. L-theanine and caffeine in combination affect human cognition as evidenced by oscillatory alpha-band activity and attention task performance. J Nutr. 2008; 138: 1572S-1577S.

Kimura K, Ozeki M, Juneja LR, Ohira H. L-theanine reduces psychological and physiological stress responses. Biol Psychol. 2007; 74: 39-45.

Kobayashi K, Nagato Y, Aoi N, Juneja LR, Kim M, Yamamoto T, Sugimoto S. Effects of L-theanine on the release of α-brain waves in human volunteers. Nippon Nōgei Kagakukaishi. 1998; 72:153-157. (Abstract). Accessed on Google Scholar, March 2011.

Lu K, Gray MA, Oliver C, Liley DT, Harrison BJ, Bartholomeusz CF, Phan KL, Nathan PJ. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol Clin. 2004; 19: 457-465.

Mason R. 200 mg of zen: L-theanine boosts alpha waves, promotes alert relaxation. Alternative & Complimentary Therapies. 2001; 91-95.

Monograph. L-theanine. Altern Med Rev. 2005; 10(2): 136-138.

Nathan PJ, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine (N-Ethyl-L-Glutamine): a possible neuroprotective and cognitive enhancing agent. Journal of Herbal Pharmacology. 2006; 6(2): 21-30.

Nobre AC, Rao A, Owen GN. Ltheanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr. 2008; 17(S1): 167-168.

Owen GN, Parnell H, De Bruin EA, Rycroft JA. The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci. 2008; 11(4): 193- 198.

Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study. J Clin Psychiat. 2011; 72(1): 34-42.

Rogers PJ, Smith JE, Heatherly SV, Pleydell-Pearce CW. Time for tea: mood, blood pressure and cognitive performance effects of caffeine and theanine administered alone and together. Psychopharmacology. 2008; 195: 569-577.

Terashima T, Takido J, Yokogoshi H. Time-dependent changes of amino acids in the serum, liver, brain, and urine of rats administered with theanine. Biosci. Biotechnol. Biochem: 1999: 63:615-618

Unno T, Suzuki Y, Kakuda T, Hayakawa T, Tsuge H. Metabolism of theanine, γ-glutamylethylamide, in rats. J Agric Food Chem; 1999: 1593-1596.

Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T. Effect of theanine, γ-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res. 1998; 23(5): 667-673.

Polycystic ovary syndrome

Clinical considerations and therapeutic options

Polycystic ovary syndrome (PCOS) is a complex condition of metabolic and endocrine dysfunction. Estimates of its prevalence in women range from 6-18% worldwide (Azziz 2009, Kumarapeli 2008, March 2010), making it one of the most common human disorders (Goodarzi 2011).

The central features of PCOS include clinical hyperandrogenism or biochemical hyperandrogenemia, oligoanovulation and polycystic ovaries (Goodarzi 2011). Three diagnostic schemes appearing in the current literature identify a wide range of PCOS phenotypes involving diverse combinations of hyperandrogenism, hyperandrogenemia and ovarian dysfunction (March 2010). Diagnostic methods and criteria have evolved considerably since PCOS was first described in 1935 by Stein and Leventhal (Azziz 2009), but agreement has yet to be reached as to which symptoms truly define this syndrome.

Clinical presentation

Hyperandrogenism can appear clinically as hirsutism, acne, and androgenic alopecia. Of these three symptoms, hirsutism appears to be most predictive of PCOS, with 75-80% of hirsute women fitting diagnostic criteria for this syndrome (Azziz 2009). Ethnic variation does exist, and fewer East Asians with PCOS present with unwanted hair growth than white or black women (Goodarzi 2011). Clinical symptoms of hyperandrogenism may be supported by laboratory findings (hyperandrogenemia) which may include elevated testosterone and dehydroepiandrosterone sulfate (DHEAS). However, up to 40% of women with PCOS are estimated to have androgen levels within the normal range (Azziz 2009).

Menstrual dysfunction in the form of oligomenorrhea or amenorrhea occurs in 70-80% of women with PCOS (Teede 2010). Dysfunction may not be easily appreciated in women with regularly-occurring but anovulatory periods, and may only be revealed through comprehensive hormonal assessment.

Although polycystic ovaries are present in an estimated 80% of women with PCOS, their identification is not required for diagnosis (March 2010). As asymptomatic polycystic ovaries may be found in up to 30% of the population (Azziz 2009), changes in ovarian morphology, while common, are not an essential feature of PCOS, despite its name.

Diagnosis of exclusion

Alternative pathologies must be excluded before a diagnosis of PCOS may be made. Disturbances in thyroid function can cause changes to the menstrual cycle (Krassas 2000) while hyperprolactinemia is associated with infertility and amenorrhea (Patel 2007). Non-classic congenital adrenal hyperplasia may not appear until the reproductive years, and is associated with hyperandrogenism (Young 2010), while hirsutism may be a sign of Cushing’s syndrome (Shibli-Rahhal 2006). Clinicians must also be attuned to the possibility that these conditions may exist concomitantly.

Associated conditions

Other signs are often associated with PCOS and exacerbate the impact of this syndrome, although they are not required for diagnosis. The most important of these is insulin resistance, and associated hyperinsulinemia. Excess insulin drives endocrine derangement by stimulating androgen production (Bergh 1993), and decreasing hepatic production of sex hormone binding globulin (SHBG) (Goodarzi 2011). Insulin resistance is less commonly observed in lean women with PCOS (Stovall 2011) and is worsened by smoking (Cupisti 2010).

Obesity exacerbates the clinical features of PCOS by promoting insulin resistance (Teede 2010) and unopposed estrogen production (Azziz 2009). The link between PCOS and obesity is amplified further, as insulin-driven hyperandrogenemia, in turn, contributes to abdominal adiposity (Tolino 2005). While increased BMI only marginally increases the risk of developing PCOS (Yildiz 2008), and while as many as 50% of women with PCOS are not obese (Goodarzi 2011), obesity has a significant, negative impact on quality of life in this population (Jones 2008).

Fertility challenges are natural sequelae to any condition affecting ovarian function. PCOS is responsible for up to 70% of cases of anovulatory infertility (Brassard 2008), although as many as 60% of women with PCOS may be able to conceive (Teede 2010). Obesity independently contributes to decreased fertility in women with PCOS (Marquard 2010), and weight loss may improve the chances of conceiving (Crosignani 2003). During pregnancy, women with PCOS are at increased risk for pre-eclampsia, hypertension and gestational diabetes (Goodarzi 2011).

Associated risks

The long-term health effects of PCOS must also be of concern to the clinician:

• PCOS-associated insulin resistance increases the risk of developing Type 2 diabetes, especially in women who are also obese.

• Dyslipidemia, a common finding in US women with PCOS, increases the risk of cardiovascular disease.

• The metabolic syndrome, which incorporates abnormalities in both insulin and cholesterol metabolism, occurs more frequently in US women with PCOS than those without (Goodarzi 2011).

• Increased cardiovascular risk is a concern, even in lean women with PCOS (Costa 2010).

The significance of these risk factors is highlighted by reports of increased incidence of cardiovascular events and decreased event-free survival in this population (Shaw 2008).

Preliminary data show that rates of endometrial cancer may be slightly higher in women with PCOS (Chittenden 2009), and were significantly associated with high BMI, hirsutism and very irregular periods in an Australian case control study (Fearnley 2010). Investigations continue into associations between PCOS and other gynaecological cancers.

Treatment of PCOS – Lifestyle interventions

A recent systematic review (Moran 2011) found that exercise, either alone or in combination with caloric restriction, addressed the exacerbating conditions associated with PCOS. Participants in the trials reviewed lost weight, decreased abdominal obesity, and saw improvements in insulin resistance. A meta-analysis was not performed, but the results appeared to be consistent throughout the trials. None of the included studies reported on reproductive outcomes, but observed improvements in both clinical and biochemical signs of hyperandrogenism suggest an additional impact upon endocrine parameters.

BMI, insulin resistance and serum hormone levels

Other studies confirm these results. Karimzadeh (2010) compared lifestyle changes (caloric deficit of 500kcal/day, combined strength/aerobic training for 20-60 minutes, 3-5 times per week) to pharmacological therapy (metformin and clomiphene citrate (CC)), and reported significant improvements in waist circumference, insulin, LDL and SHBG with the lifestyle intervention. Another small study (n=20) comparing regular aerobic exercise (30 minutes of exercise at 60-70% of the maximal oxygen consumption (VO2max), 3 times per week) to a high protein (35%), hypocaloric diet (deficit of 800kcal/day) reported improvement in both groups in BMI, insulin resistance and waist-hip ratio (WHR) (Palomba 2008).

Weight loss alone, achieved through strict caloric restriction, has been shown to improve insulin (Stamets 2004), SHBG and testosterone levels (Tolino 2005) in women with PCOS. Additionally, nutritional counselling and exercise therapy (90 minutes of combined aerobic/resistance training, 3 times per week) in the absence of weight loss was shown to benefit waist circumference and fasting insulin levels (Bruner 2006) through improved body composition. A combination of these therapies can reasonably be expected to have an additive and positive effect in PCOS patients.

Reproductive outcomes

Improvements in rates of ovulation and pregnancy may also be anticipated with lifestyle changes. A small, prospective trial of 33 overweight women with PCOS, treated with caloric restriction and exercise recommendations, saw improvements in ovulatory function and morphology, and 30% of participants (10/33) achieved pregnancy (Crosignani 2003). Karimzadeh (2010), found parallel rates of ovulation (55-66%) and pregnancy (12-20%) in all treatment arms (described above). Otta (2010) reports statistically significant amelioration of menstrual cycling with caloric restriction and exercise, both in combination with metformin and with placebo (between-group differences were not reported).

Treatment of PCOS – Inositol

Inositol phosphoglycan (IPG) is an insulin mediator influencing the uptake of glucose in the body (Baillargeon 2010). D-chiro inositol (DCI) is an important component of IPG, and defects in the DCI-IPG system have been linked with insulin resistance (Galazis 2011). In women with PCOS, DCI-IPG is less responsive to insulin challenge than in normal controls, and it is speculated that the uncoupling of DCI-IPG with insulin levels may contribute to insulin resistance in this population (Galazis 2011). Given the potential for hyperinsulinemia to exacerbate PCOS, improving insulin sensitivity is an important therapeutic goal.

Studies have investigated the impact of supplementation with inositol, both as DCI or its precursor, myo-inositol (MYO) (Papaleo 2009), in women with PCOS. Daily dosing in published research ranges from 200mg-1200mg of DCI and 2g-4g of MYO.

Although studies are small and heterogeneous, recent reviews (Fritz 2009, Galazis 2011) have described benefit from inositol therapy. The proposed effects of inositol supplementation are reviewed below.

Inositol and insulin resistance

Inositol does appear to benefit glucose metabolism in women with PCOS, likely through its interaction with IPG. Evidence of increased insulin sensitivity (Costantino 2009), decreased insulin resistance (Genazzani 2008) or improved glucose tolerance (Nestler 1999) has been seen in trials using either form of inositol. One researcher also attributed improvements in BMI to inositol, providing a second mechanism through which insulin resistance may be addressed (Gerli 2003, Gerli 2007).

Benefit to clinical features of PCOS

Clinical hyperandrogenism, evidenced by hirsutism and/or acne, improved with 4g MYO supplementation over a 6 month period (Zacche 2009). Hyperandrogenemia, assessed through serum testosterone and DHEAS, was significantly improved by the administration of both MYO (Costantino 2009, Genazzani 2008, Zacche 2009) and DCI (Iuorno 2002, Nestler 1999).

A series of small randomized, controlled trials (RCT) have found significant benefit of both forms of inositol in restoring ovulatory cycles in comparison to placebo, or to metformin (Costantino 2009, Gerli 2007, Nestler 1999 Raffone 2010). These improved rates of ovulation appear to translate into fewer oocytes of poor quality (Ciotta 2010, Papaleo 2009) and a trend towards increased frequency of pregnancies (Morgante 2011), although this latter outcome has yet to reach statistical significance in recent RCTs (Papaleo 2009, Raffone 2010).

Treatment of PCOS – N-acetylcysteine (NAC)

NAC has been shown to affect glucose metabolism (Ammon 1992) and may function as an insulin-sensitizing agent in women with PCOS, possibly through its influence upon intracellular levels of glutathione (GSH) (Fulghesu 2002). Two small trials of NAC as a monotherapy demonstrated improvement in insulin sensitivity following 4-6 weeks of treatment at a dose of 1.8g per day (Fulghesu 2002, Kilic-Okman 2004), although a third trial did not support these findings (Elnashar 2007). Further studies are needed to identify factors impacting the effect of this therapy.

NAC and ovulation induction

The benefit of NAC as an insulin-sensitizing agent may be most apparent in its use as an adjunct to clomiphene citrate (CC). Insulin-sensitizing agents are used to amplify response in resistant patients (Nestler 2000, Rizk 2005), and NAC has shown some promise in this application. Two recent trials found a significant increase in ovulation rates compared to controls (49.3% vs. 1.3% (Rizk 2005) and 52.1% vs. 17.9% (Badawy 2007) when 1.2g of NAC was administered with 100mg of CC.

Other insulin-sensitizing agents such as metformin have been shown to confer greater benefit in terms of ovulation, pregnancy and miscarriage incidence (Abu Hashim 2010), but NAC may still be a valuable option when these agents cannot be used. NAC may also exert its influence through insulin-independent pathways, having the potential for positive effects on vasculature, immune parameters and cervical mucous (Badawy 2007).

The hormonal effects of NAC may be significant in a PCOS-affected population as this agent has been shown to significantly decrease testosterone levels (Elnashar 2007) and increase SHBG (Fulghesu 2002, Kilic-Okman 2004). Fulghesu reported the greatest benefit to insulin levels and hormonal parameters in subjects that were hyperinsulinemic at baseline, indicating that effect of NAC on hormonal levels may be insulin-mediated.

Conclusion

PCOS, a complex, multifaceted condition, presents with varying degrees of endocrine and metabolic dysfunction and poses significant risk of short- and long-term morbidity. Caloric restriction and increases in aerobic and resistance exercise can powerfully impact BMI, WHR, insulin resistance and reproductive outcomes. Dietand lifestyle-based therapies are considered first-line, especially in overweight and obese patients (Franks 2011).

Pharmacological therapies may be used to prompt ovulation and menstruation, antagonize androgens, improve insulin sensitivity, and/or address cardiovascular risk factors. Recent research supports the use of inositol and NAC, both as monotherapies and as adjunctive agents to pharmacotherapy, with demonstrated benefits to insulin sensitivity and hormonal parameters. The wide range of clinical presentations and patient concerns in PCOS provide the clinician with numerous therapeutic targets requiring a truly comprehensive approach to care.

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Bacopa monnieri

Application for cognitive enhancement

Our population demographics are changing – Statistics Canada has projected that by 2056 between 25 – 30 % of the Canadian population will be over the age of 65 (up from 13.7% in 2006) (Statistics Canada 2010). This has both social and economic implications – from the stand point of cognitive health and performance; it is plausible that cognitive enhancing agents may become increasingly sought after by the otherwise healthy aging adult (Calabrese 2008). A recent (2004) community survey of 2551 adults between 60-64 years of age conducted in Australia showed that 2.8% of the sample reported using a non-prescription drug for memory aid or cognitive enhancement. Bacopa monnieri (B. monnieri) was amongst the top three agents used (Jorm 2004).

Bacopa monnieri, also commonly known as Water Hyssop or Brahmi in India is a member of the Scrophulariaceae plant family (Calabrese 2008). It has ancient historical use as a brain tonic for anxiety, memory, poor cognition and concentration in traditional Ayurvedic medicine; chronicles of its use date back to as early as 100 A.D. (Calabrese 2008, Chowdhuri 2002, Usha 2008). B. monnieri has many other purported actions including analgesic, anti-inflammatory, antipyretic, sedative and anti-epileptic properties, however its use as a memory enhancing agent has predominated (Nathan 2001, Stough 2001).

The following review examines available clinical evidence for the use of B. monnieri for cognitive enhancement, specifically for its use in memory augmentation.

Mechanism of action:

The exact mechanism of B. monnieri on psychoneurological parameters remains unknown (Stough 2001). In vitro as well as in vivo animal studies indicate that the effect of B. monnieri on memory appears to be multifocal and suggests that it includes modulation of the cholinergic system, altered antioxidant status as well as anti stress activity by modulation of HSP70, P450 and superoxide dismutase within the brain (Bhattacharya 2000, Roodnenrys 2002, Stough 2001). Most recently B. monnieri has demonstrated neuroprotective effects and cognitive enhancement in preclinical Alzheimer’s disease models (Limpeanchob 2008, Uabundit 2010).

The cognitive enhancing effects of B. monnieri extracts are attributed to the saponins within the plant, specifically bacosides A and B (Joshua- Allan 2008). Research suggests that the bacosides are the component of the plant that are involved in the reversal of amnesic effects of neurotoxins, scopolamine, phenytoin, electroschock, immobilization stress and diazepam as seen in animal studies (Calabrese 2008, Prabhakar 2008).

A rat study showed that B monnieri extract produced a dose-dependent effect on antioxidants superoxide dismutase, catalase and glutathione peroxidase activity in the frontal cortex, striatum and hippocampus of the brain (Bhattacharya 2000). It has been hypothesized that this effect may in part result in enhancement of the cognitive functions associated with those parts of the brain: memory, executive decision making and information processing (Bhattacharya 2000). It should be noted that the standardization of bacosides in this rat study was to bacoside A at 82% +/- 0.5 % which is significantly higher than that used in human trials (bacoside standardization of 40-55%).

Clinical Evidence:

Bacopa monnieri has been the subject of eight double blind randomized placebo controlled trials (n=498) with the primary objective including assessing the effect of B. monnieri on memory. All but two of the trials were conducted on healthy adults ranging from 18 – 65 years of age and lasting up to 16 weeks in duration. Several of the trials also assessed for safety, tolerability as well as anxiety and depression.

In all of the trials, assessments of cognitive enhancement was conducted through a battery of neuropsychological testing including the Rey Auditory Verbal Learning Test (AVLT), which objectively measures audioverbal and visual memory, and the Wechsler Adult Intelligence Scale, but the types and number of assessments employed varied significantly between studies (Morgan 2010).

Raghav (2006) (n=40) and Morgan (2010) (n=98) specifically examined the effect of B. monnieri on adults (> 55 yoa) with age related memory impairment in the absence of diagnosed dementia. Both trials showed statistically significant improvements in the trial groups. Morgan (2010) assessed for audio-verbal and visual memory performance using the AVLT, Rey-Osterrith Complex Figure Test (CFT) and Reitan Trail Making Test (TMT). Subjective memory performance was also assessed. The team found that B. monnieri was able to produce statistically significant improvements in memory acquisition and retention as per AVLT assessment. Raghav and colleagues used the Wechsler memory scale and its subsets and reported improvements in logical memory, mental control and paired associated learning (Raghav 2006).

All but one RCT concluded that B. monnieri produced cognitive enhancement in adults with or without adult age related memory impairment. The trials by Calabrese 2008, Stough 2001, Morgan 2010 and Roodenrys 2002 all used similar dosing of B. monnieri; 300 mg qd for a 12 week duration. All four trials concluded that B. monnieri enhanced cognition in adults; however the specific effects reported on cognition differed between trials (See Table 1).

The study by Stough and colleagues showed improved information processing, learning rate and memory consolidation (2001). Roodenrys 2002 which employed a slight variation in dosing depending on the subject weight (300 mg qd for subjects < 90kg and 405 mg qd for subjects >90 kg) reported improvements in retention of new information; however no improvements were noted in attention, verbal and visual short term memory, or retrieval of pre-existing knowledge or anxiety, which had previously been reported to be improved in the studies conducted by Calabrese 2008 and Stough 2002 (Roodenrys 2002). Morgan 2010 also reported significant improvements in memory acquisition whereas Roodenrys 2002 suggests it is the rate of forgetting that was decreased by B. monnieri (Morgan 2010).

From this is becomes apparent that there is a need for further clinical trials which use the same neuropsychological assessments in order to ascertain the specific effect B. monnieri has on memory – whether it increases fact retention or decreases the rate of forgetting.

The trial that did not show any statistically significant effect of B. monnieri on neuropsychological parameters was investigating the acute (2 hours) effects of the herb on cognitive parameters (Nathan 2001).

Supplementation with B. monnieri may have cognitive enhancing effects even after its intake is discontinued (Rhagav 2006). In one double blind RCT the trial groups were randomized to either B. monnieri or placebo for 12 weeks, after this period the B. monnieri group was also given placebo for a subsequent four weeks; where as the placebo group consumed placebo for the entire 16 week trial (Raghav 2006). Neuropsychological assessments were significantly improved in the B. monnieri group at the end of the trial and no decrease in memory performance scores were noted between week 12 and week 16 time points (Raghav 2006). This study demonstrates that outcomes delivered through B monnieri supplementation persist for at least four weeks following discontinuation of the intervention.

Safety & Dosing:

Dosing varied between the trials (from 250 mg qd to 750 mg qd), with the majority prescribing 300 mg qd of standardized B. monnieri extract either in one single dose or in divided doses. The extracts were standardized to bacoside content, which varied between 40 – 55% (Calabrese 2008, Morgan 2010, Nathan 2001, Raghav 2006, Stough 2001). Two studies used 750 mg qd of which 100 mg was a whole plant extract and the remaining 650 mg was powdered plant (Mandal, Nangelil). In Roodenrys (2002) dosing was done by weight in which persons under 90kg where given 300 mg and those over 90kg were given 450 mg of B. monnieri, which was equated to 6 and 9g of dried B. monnieri rhizome, respectively.

A 2007 toxicological in vivo study in Sprague-Dawley rats reported a median oral lethal dose of 2400mg/kg of B. monnieri extract (Joshua- Allan 2007). Repeated daily oral dosing for 14 days was well tolerated in rats at up to 500mg/kg; furthermore, a sub-chronic study for 90 days with doses up to 500 mg/kg did not result in toxicities in these animals (Joshua- Allan2007).

A phase I safety study on a B. monniere extract has been conducted in 23 healthy human subjects who were given 300 mg of the extract with a dose escalation up to 450 mg qd for a total of 30 days (Morgan 2010, Pravina 2007). Three of the 23 subjects reported gastrointestinal adverse events; the trial concluded that B. monnieri was safe and did not produce either clinical nor laboratory evidence indicating that it was unsafe at 300 mg qd (Pravina 2007).

B. monnieri has a long historical use which speaks to its safety profile; that being said, a small number of adverse events were noted in four of the studies, they included gastrointestinal effects (increased stool frequency, abdominal cramping and nausea) (Calabrese 2008, Morgan, 2010, Pravina 2007, Roodnenrys 2002) fatigue and dry mouth (Stough 2001). It has been hypothesized that the gastrointestinal adverse events may be due to the cholinergic effects of B. monnieri (Morgan 2010).

Conclusion:

At present, clinical as well as laboratory research has shown that B. monnieri appears to have cognitive enhancing effects; however the specific mechanisms of action are not well understood and from the clinical trials completed there appears to be a discrepancy as to how it may impact memory specifically.

There is a large number of limitations to the current research including: small trial sample size, large variation in assessment methods between trials, lack of long term data, inconsistency in dosing and standardization of B. monnieri extract. Thus far the research is encouraging and combined with the historical use of B. monnieri as a cognitive enhancement agent in Ayurvedic medicine, this should provide a basis for further research for this promising agent.

References:

Bhattacharya S.K., Bhattacharya A., Kumar A., Ghosal S. Antioxidant activity of Bacopa monniera in rat frontal cortex striatum and hippocampus. Phytother Res. 2000; 14(3): 174 – 179.

Calabrese C., Gregory W., Leo M., Kraemer D., Bone K., Oken B. Effect of standardized Bacopa monnieri extract on cognitive performance, anxiety, depression in the elderly: randomized, double-blind, placebo-controlled trial. The Journal of Alternative and Complementary Medicine. 2008; 14(6): 707-713.

Chowdhuri DK., Parmar D., Kakkar P., Shukla R., Seth P.K., Srimal R.C. Antistress effecs of Bacosides of Bacopa monnieri: Modulation of Hsp70 expression, superoxide dismutase and cytochrome p450 activity in rat brain. Phytother. Res. 2002; 16: 639-645.

Jorm AF, Rodgers B, Christensen H. Use of medications to enhance memory in a large community sample of 60-64 year olds. Int Psychogeriatr. 2004;16:209–217.

Joshua- Allan J., Damodaran A., Deshmukh N.S., Goudar K.S., Amit A., Safety evaluation of a standardized phytochemical composition extract from Bacopa monnieri in Sprague-Dawley rats. Food and Chemical Toxicology. 2007; 45: 1928-1937.

Limpeanchob N., Jaipan S., Rattanakaruna S., Phrompittayarat W., Inkaninan K., Neuroprotective effect of Bacopa monnieri on beta-amyloid-induced cell death cortical culture. Journal of Ethnopharmacology. 2008; 120: 112 – 117

Mandal A. A clinical study to evaluate the efficacy and safety of Bacopa caplets in memory and learning ability: A double blind placebo controlled study. The Himalayan Drug Company. [Received via e-mail on 29 January 2010]. Unpublished.

Morgan A., Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo controlled, double blind trial. The Journal of Alternative and Complementary Medicine. 2010; 16 (7): 753-759

Nangelil V. Effect of Bacopa caplet on human memory: a double blind placebo controlled study. The Hialayan Drug Company. [ Received via e-mail on 29 January 2010]. Unpublished.

Nathan P.J., Clarke J., Lloyde J., Hutchison C.W., Downey L., Stough C. The acute effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy normal subjects. Hum Psychopharmacol. 2001; 16: 345 – 351.

Prabhakar S., Saraf M.K., Pandhi P., Anand A., Bacopa monniera exerts antiamnesic effec on diazepam induced anterograde amnesia in mice. Psychopharmacology. 2008; 200: 27-37.

Pravina K., Ravindra K.R., Goudar D.R., Vind A.J., Joshua P., Wasim K., Venkatehwarlu V.S., Saxena A.A. Safety evaluation of BacoMind in healthy volunteers: A phase I study. Phytomedicine. 2007; 14:301-308.

Raghav S., Singh H., Dalai P.K., Srivastava J.S., Asthana O.P. Randomized controlled trial of standardized Bacopa monniera extract in age- associated memory impairment. Indian J Psychiatry. 2006; 48(4): 238-242

Roodenrys S., Booth D., Bulzomi S., Phipps A., Micallef C., Smoker J. Chronic effects of Brahmi (Bacopa monnieri) on human memory. Neuropsychopharmacology. 2002; 27: 279 – 281.

Statistics Canada – Demographic Change, 2010 [ Accessed online 20 December 2010 at [http://www.statscan.gc.ca/pub/82-229-x/2009001/demo/int1-eng.htm]

Stough C., Lloyd J., Clarke J., Downey L.A., Hutchison C.W., Rodgers T., Nathan P.J. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology. 2001; 156:481-484.

Uabundit N., Wattanathorn J., Supaporn M., Kornkanok I. Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. Journal of Ethnopharmacology. 2010; 127: 26-31.

Usha P.D., Wasim P., Joshua J.A., Geetharani P., Murali B., Mayachari A.S., Venkateshwarlu K., Saxena V.S., Deepak M., Amit A. BacoMind: A cognitive enhancer in children requiring individual education programme. Journal of Pharmacology and Toxicology. 2008; 3(4): 302-310.