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- SUPPLEMENT FACTS
|Supplement FactsServing Size 1 capsule Servings Per Container 30|
|Amount Per Serving||% Daily Value|
|Vitamin A (as beta-carotene)||1,500 mcg||167%|
|Vitamin C (as ascorbic acid)||90 mg||100%|
|Vitamin D3 (as cholecalciferol)||25 mcg(1,000 IU)||125%|
|Vitamin E (as d-alpha tocopheryl succinate)||20 mg||134%|
|Vitamin K2 (as menaquinone-7)||45 mcg||56%|
|Vitamin B1 (as thiamin mononitrate)||15 mg||1250%|
|Vitamin B2 (as riboflavin, riboflavin-5’-phosphate)||15 mg||1150%|
|Niacin (as niacinamide)||50 mg NE||313%|
|Vitamin B6 (as pyridoxine HCl, pyridoxal-5’-phosphate)||10 mg||588%|
|Folate (as L-5 methyltetrahydrofolate calcium)||667 mcg DFE (400 mcg folic acid)||167%|
|Vitamin B12 (as methylcobalamin)||100 mcg||4167%|
|Pantothenic acid (as d-calcium pantothenate, pantethine)||23 mcg||460%|
|Calcium (as calcium carbonate and d-calcium pantothenate)||25 mg||2%|
|Iron (as Ferrochel® iron bisglycinate)||18 mg||100%|
|Iodine (as potassium iodide)||150 mcg||100%|
|Magnesium (as magnesium oxide)||12.5 mg||3%|
|Zinc (as amino acid chelate)||11 mg||100%|
|Selenium (as selenomethionine)||55 mcg||100%|
|Copper (as copper gluconate)||0.9 mg||100%|
|Manganese (as manganese aspartate)||2.3 mg||100%|
|Chromium (as chromium polynicotinate)||35 mcg||100%|
|Molybdenum (as amino acid chelate)||45 mcg||100%|
|Choline (as choline bitartrate)||10 mg||†|
|Inositol (as myo-inositol)||10 mg||†|
|Echinacea purpurea extract 1:4 (root)||233 mg||†|
|† Daily value not established.|
Take 1 capsule daily with breakfast or lunch.
|Health/wellness & general claims|
|May significantly improve adequate intake of key vitamins and minerals more than diet alone.*||Multivitamin study 1|
|Contains over 25 vitamins, minerals and nutraceuticals to support health and wellness.*||The 25+ vitamins, minerals and nutraceuticals are listed in supplement facts box. The other citations in this document show the relationship to supporting health and wellness, as do Multivitamin study 2-7.|
|Contains B-vitamin coenzymes, the biologically active forms of these nutrients.*||Listed in supplement facts box.Riboflavin study 1Vitamin B6 study 1Vitamin B12 study 1|
|Heart health claims|
|Supports healthy heart function.*||Multivitamin study 7|
|Vitamin K2 supports a healthy heart*, orVitamin K2 provides support for cardiovascular health.*||Vitamin K2 study 1|
|Folic acid has been clinically tested to help maintain healthy homocysteine levels already within normal ranges.*||Folic acid/homocysteine study 1-7|
|Provides key B vitamins which support healthy cognitive function.*||B vitamins study 1|
|Provides key B vitamins which support some measures of healthy memory performance.*||B vitamins study 1|
|Promotes mood and cognitive performance including working memory and attentional processing.*||Berocca study 4|
|Stress & Energy claims|
|Provides B-vitamins, which are intimately involved in function of nervous system*||B vitamins study 3-4|
|Provides B-vitamins, which may help counter some negative effects of stress.*||B vitamins study 5Stress study 1-2|
|Provides a generous supply of B-vitamins, some of which can be depleted during stress.*||B vitamins study 6-7|
|Provides B-vitamins and other nutrients that may help people handle their stress better.*||B vitamins study 8|
|Provides B-vitamins to support energy production.*||B vitamins study 2|
|Improved measures of stress, mental health and vigor as well as improved cognitive performance during intense mental processing.*||Berocca study 1|
|Significantly improved measures of stress in adults with high stress.*||Berocca study 2|
|Significantly reduced perceived stress and tiredness, and improved ability to concentrate.*||Berocca study 3|
|Improved perceived stress, and aspects of everyday mood including fatigue.*||Berocca study 5|
|Immune health-specific claims|
|Supports overall immune health||Vitamin C study 2-3Zinc study 1-4Selenium study 1-3|
|Supports a healthy immune system|
|Contains vitamin C, an effective antioxidant which helps support a healthy immune system, including the function of immune cells.||Vitamin C study 2-3|
|Contains zinc, an essential mineral that supports immune function. Alternative: Zinc is essential for the integrity of the immune system. Alternative: Zinc affects multiple aspects of the immune system, from the barrier of the skin to cellular function.||Zinc study 1-4|
|Contains selenium, an antioxidant mineral that supports a healthy immune system. Alternative: Selenium helps provide antioxidant protection against free radicals and other damaging reactive oxygen species.||Selenium study 1-3|
|Supports aggressive immune system response.*Alt: Supports powerful immune response.*Alt: Supports exceptional immune response.*||Echinacea study 1-4|
|Helps your body mobilize your immune system.*||Echinacea study 1-3|
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
- SUBSTANTIATION STUDIES
Multivitamin study 1
Use of multivitamin-multimineral supplements is widespread and can contribute substantially to total nutrient intakes. In the Hawaii-Los Angeles Multiethnic Cohort (MEC), 48% of men and 56% of women without chronic diseases reported use of multivitamin supplements at least weekly over the past year. We calculated the prevalence of nutrient adequacy for 17 nutrients based on responses to a self-administered quantitative food-frequency questionnaire administered to MEC participants at baseline in 1993-1996. Prevalence of nutrient adequacy from food only was higher for multivitamin supplement users (n = 21,056) than for nonusers (n = 69,715) (P < 0.0001).. For multivitamin users, the prevalence of adequacy improved by an average of 8 percentage points for both men and women when intake from supplements was included. Users were also more likely to have potentially excessive intakes, particularly for iron, zinc, vitamin A, and niacin. The 26,735 MEC participants in Hawaii who answered an open-ended question about multivitamin use in 1999-2001 reported using 1246 different products. The nutrient profile of these products varied widely, and the composition of products at the 90th percentile was 10-fold greater than the composition at the median for some nutrients. We conclude that analyses of nutrient adequacy and excess for supplement users should be extended to national samples and that composition data on actual supplements used are preferable to assuming a default nutrient profile for multivitamin supplements. Multivitamin products could be better formulated to reduce the prevalence of inadequacy and also to reduce the risk of excessive intakes.
Multivitamin study 2
To determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men, a large-scale, randomized, double-blind, placebo controlled trial was conducted (Physicians” Health Study II) with 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011. The intervention was a daily multivitamin or placebo. The main outcome measures were total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points. Results showed that during a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1000 person-years; hazard ratio [HR], 0.92; 95% CI, 0.86-0.998; P=.04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1000 person-years; HR, 0.98; 95% CI, 0.88-1.09; P=.76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1000 person-years; HR, 0.89; 95% CI, 0.68-1.17; P=.39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1000 person-years; HR, 0.88; 95% CI, 0.77-1.01; P=.07). Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56-0.96; P=.02), but this did not differ significantly from that among 13 329 men initially without cancer (HR, 0.94; 95% CI, 0.87-1.02; P=.15; P for interaction=.07). In conclusion, this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.
Multivitamin study 3
To evaluate the associations between intakes of vitamins A, C, and E and risk of colon cancer, primary data from 13 cohort studies was used, estimating study- and sex-specific relative risks (RR) with Cox proportional hazards models and subsequently pooled RRs using a random effects model. Results showed that among 676,141 men and women, 5,454 colon cancer cases were identified (7-20 years of follow-up across studies). Vitamin A, C, and E intakes from food only were not associated with colon cancer risk. For intakes from food and supplements (total), the pooled multivariate RRs (95% CI) were 0.88 (0.76-1.02, >4,000 vs. ≤ 1,000 μg/day) for vitamin A, 0.81 (0.71-0.92, >600 vs. ≤ 100 mg/day) for vitamin C, and 0.78 (0.66-0.92, > 200 vs. ≤ 6 mg/day) for vitamin E. Adjustment for total folate intake attenuated these associations, but the inverse associations with vitamins C and E remained significant. Multivitamin use was significantly inversely associated with colon cancer risk (RR = 0.88, 95% CI: 0.81-0.96). In conclusion, modest inverse associations with vitamin C and E intakes may be due to high correlations with folate intake, which had a similar inverse association with colon cancer. An inverse association with multivitamin use, a major source of folate and other vitamins, deserves further study.
Multivitamin study 4
Epidemiologic data relating multivitamin supplement use to the risk of cardiovascular disease are sparse and inconsistent. We examined the association between self-selected use of low dose multivitamin supplements and the risk of myocardial infarction (MI). Our results are based on data from a large population-based, case-control study of subjects aged 45-70 y residing in Sweden, a country in which consumption of fruits and vegetables is relatively low and foods are not fortified with folic acid. The study included 1296 cases (910 men, 386 women) with a first nonfatal MI and 1685 controls (1143 men, 542 women) frequency-matched to the cases by sex, age and hospital catchment area. Odds ratios (OR) and 95% CI were calculated from unconditional logistic regression models. Among controls, 57% of the women and 35% of the men used dietary supplements; corresponding figures for the cases were 42 and 27%, respectively. Of those taking supplements, 80% used multivitamin preparations. After adjustment for major cardiovascular risk factors, the OR of MI comparing regular users of supplements with nonusers were 0.79 (95% CI 0.63-0.98) for men and 0.66 (95% CI 0.48-0.91) for women. This inverse association was not modified by such healthy lifestyle habits as consumption of fruits and vegetables, intake of dietary fiber, smoking habits and level of physical activity, although never smoking appeared to outweigh the association in women. Findings from this study indicate that use of low dose multivitamin supplements may aid in the primary prevention of MI.
Multivitamin study 5
Rates of vitamin-mineral supplement use by US female physicians are unknown but are of particular interest for several epidemiologic and clinical reasons. The objective was to determine rates of and variations in vitamin-mineral supplement use among US female physicians. We used data from the Women Physicians’ Health Study, a large (n = 4501) national, randomly sampled mail survey of female physicians aged 30-70 y. Half of the physicians took a multivitamin-mineral supplement; 35.5% of these did so regularly. However, </=33% took any supplement other than calcium and <20% did so regularly. Regular vitamin-mineral supplement use increased with age, and antioxidant intake was higher in those at high risk of heart disease. Those with a history of osteoporosis were nearly 3 times as likely as those with no history to take supplemental calcium regularly. Those who took any supplement regularly also consumed more fruit and vegetables daily than did occasional users or nonusers (P: < 0.0001). Regular users of any supplement also consumed less fat than did occasional users or nonusers (P: < 0.01). Additionally, vegetarians were more likely than were nonvegetarians to regularly consume any supplement (59.9% compared with 46.3%; P: < 0.001) and those who regularly consumed any supplement were more likely to comply with US Preventive Services Task Force guidelines than were those who were occasional users or nonusers (72.4% compared with 66.5% and 60.2%; P: < 0.0001). In conclusion, female physicians, particularly those who were especially health conscious or at higher risk of heart disease or osteoporosis, used supplements at rates at least equal to those of women in the general population.
Multivitamin study 6
To investigate the effect of supplementation with multivitamin and mineral on blood pressure and C-reactive protein (CRP) in obese women with increased cardiovascular disease risk as having hypertension, hyperglycemia or hyperlipemia. 128 obese Chinese women aged 18-55 years with increased cardiovascular disease risk participated in a 26-week randomized, double-blind, placebo-controlled trial. Subjects were randomized to four groups, and received either one tablet of high-dose multivitamin and mineral supplement (MMS), or one tablet of low-dose MMS (Low MMS), or calcium 162 mg (Calcium) or identical placebo (Placebo) daily during the study. Diastolic blood pressure (DBP), systolic blood pressure (SBP) and serum concentrations of CRP were measured at baseline and end-trial. The results showed that, at baseline, the subjects had an average age of 42.0+/-7.1 years and BMI of 30.9+/-2.8 kg/m2. There were no significant differences between the four groups in baseline characteristics. One hundred and seventeen subjects completed the study. After 26-week supplementation, both SBP and DBP were significantly lower in the MMS group compared to the placebo group (p < 0.05). There was also a non-significant trend of lower DBP at 26-week in the MMS and calcium groups compared to baseline (p < 0.08). At 26-week, the MMS group also had significantly lower serum concentrations of CRP compared with that of baseline and the placebo group (p < 0.05). In conclusion, supplementation with adequate multivitamin and mineral supplement could reduce blood pressure and serum CRP in obese women with increased cardiovascular disease risk.
Multivitamin study 7
The objective of this study was to examine the association between multivitamin use and myocardial infarction (MI) in a prospective, population-based cohort of women. The study included 31,671 women with no history of cardiovascular disease (CVD) and 2262 women with a history of CVD aged 49-83 y from Sweden. Women completed a self-administered questionnaire in 1997 regarding dietary supplement use, diet, and lifestyle factors. Multivitamins were estimated to contain nutrients close to recommended daily allowances: vitamin A (0.9 mg), vitamin C (60 mg), vitamin D (5 μg), vitamin E (9 mg), thiamine (1.2 mg), riboflavin (1.4 mg), vitamin B-6 (1.8 mg), vitamin B-12 (3 μg), and folic acid (400 μg). Results showed that during an average of 10.2 y of follow-up, 932 MI cases were identified in the CVD-free group and 269 cases in the CVD group. In the CVD-free group, use of multivitamins only, compared with no use of supplements, was associated with a multivariable-adjusted hazard ratio (HR) of 0.73 (95% CI: 0.57, 0.93). The HR for multivitamin use together with other supplements was 0.70 (95% CI: 0.57, 0.87). The HR for use of supplements other than multivitamins was 0.93 (95% CI: 0.81, 1.08). The use of multivitamins for ≥5 y was associated with an HR of 0.59 (95% CI: 0.44, 0.80). In the CVD group, use of multivitamins alone or together with other supplements was not associated with MI. In conclusion, the use of multivitamins was inversely associated with MI, especially long-term use among women with no CVD. Further prospective studies with detailed information on the content of preparations and the duration of use are needed to confirm or refute our findings.
B vitamins study 1
The objective of this study was to determine whether oral folic acid (FA) + vitamin B-12 supplementation prevented cognitive decline in a cohort of community-dwelling older adults with elevated psychological distress. This randomized controlled trial (RCT) with a completely crossed 2 · 2 · 2 factorial design comprised daily oral 400 mcg FA + 100 mcg vitamin B-12 supplementation (compared with placebo), physical activity promotion, and depression literacy with comparator control interventions for reducing depressive symptoms was conducted in 900 adults aged 60–74 y with elevated psychological distress (Kessler Distress 10–Scale; scores .15). The 2-y intervention was delivered in 10 modules via mail with concurrent telephone tracking calls. Main outcome measures examined change in cognitive functioning at 12 and 24 mo by using the Telephone Interview for Cognitive Status–Modified (TICS-M) and the Brief Test of Adult Cognition by Telephone (processing speed); the Informant Questionnaire on Cognitive Decline in the Elderly was administered at 24 mo. The results were that FA + vitamin B-12 improved the TICS-M total (P = 0.032; effect size d = 0.17), TICS-M immediate (P = 0.046; d = 0.15), and TICS-M delayed recall (P = 0.013; effect size d = 0.18) scores at 24 mo in comparison with placebo. Researchers concluded that long-term supplementation of daily oral 400 mcg FA + 100 mcg vitamin B-12 promotes improvement in cognitive functioning after 24 mo, particularly in immediate and delayed memory performance. This trial was registered at linicaltrials.gov as NCT00214682.
B vitamins study 2
Physicians are frequently confronted with patients complaining of fatigue, tiredness and low energy levels. In the absence of underlying disease, these symptoms could be caused by a lack of vitamins, especially B-vitamins, and minerals. Certain risk groups like the elderly and pregnant women are well-recognized. This review describes the inter-relationship between micronutrients, energy metabolism and well-being, especially the role of B-vitamins in energy metabolism, an overview of which follows is shown in Table 1. The review also identifies risk groups for inadequate micronutrient intake. The authors indicated that micronutrient supplementation can alleviate deficiencies, but supplements must be taken for an adequate period of time.
B vitamins study 3
B-vitamins function as cofactors in fundamental pathways, such as glycolysis, the Krebs cycle, the respiratory chain and amino acid metabolism. Although all tissues have these vitamin-dependent pathways, they take on increased importance in the brain because of its high metabolic rate and dependence on continuous metabolism. In fact, the discovery of vitamins was closely linked to the sensitivity of the brain to deficiency, specifically that of thiamine. Furthermore, in the brain these pathways are linked to neurotransmitter synthesis.
B vitamins study 4
In the brain, the synthesis of the neurotransmitter, serotonin, from the amino acid, tryptophan, is catalyzed by a pyridoxal 5′-phosphate-dependent enzyme (pyridoxal 5′-phosphate is the metabolized, principle coenzyme form of vitamin B6). Other neurotransmitters, such as dopamine, norepinephrine and gamma-aminobutyric acid (GABA), are also synthesized using PLP-dependent enzymes.
B vitamins study 5
The current study examined the relation of plasma IL-6 to anger, hostility, and severity of depressive symptoms [which are associated with stress—see following two citations for substantiation] as a function of multivitamin supplement use (providing a source of B vitamins) in 96 healthy, nonsmoking men (aged 18-46). Plasma IL-6 was independently associated with anger, hostility, and severity of depressive symptoms, as well as with a composite factor score, but only among nonusers. Among users, these associations were not significant. Multivitamin use was associated with lower plasma IL-6 levels, but only among men with high composite factor scores. Statistical adjustments for age, body mass index, resting diastolic blood pressure, fasting total cholesterol, high-density lipoprotein cholesterol, alcohol use, exercise frequency, and educational level did not alter these results. These data suggest that plasma IL-6 is elevated among healthy men characterized by a propensity for anger, a hostile disposition, and greater severity of depressive symptoms and that multivitamin supplements could ameliorate plasma IL-6 levels among these men.
Stress study 1
Stress can come from any event or thought that makes you feel frustrated, angry, or nervous.
Stress study 2
The body responds to each type of stress in similar ways. Different people may feel it in different ways. For example, some people experience mainly digestive symptoms, while others may have headaches, sleeplessness, depressed mood, anger and irritability. People under chronic stress are prone to more frequent and severe viral infections, such as the flu or common cold, and vaccines, such as the flu shot, are less effective for them.
B vitamins study 6
Correlation of actual consumption of vitamins B1, B2 and B6 with biochemical parameters of their utilization has been studied in two groups of workers (one group was engaged in the synthetic leather industry, the second one in the diamond treatment industry). It is shown that the actual utilization of vitamins B1, B2 and B6 correlated well with the stimulation coefficients (SC) of the basal activity of the corresponding erythrocytic enzymes. This correlation can be expressed in an equation of linear regression with a preset SC. Solution of this equation gives the values that can be used in the diagnosis of changes in the vitamins B1, B2 and B6 requirement in certain population groups. The results of the study evidence that vitamin B1 and B6 are especially necessary for workers whose activity is associated with manifest nervous-emotional stress, while the workers engaged in the synthetic leather industry being exposed to dimethyl formamide are in need of vitamin B2.
B vitamins study 7
Previous research has demonstrated that a theoretical model including measures of life stressors, social support, and coping style significantly predicts psychological distress. This study tested plasma pyridoxine (vitamin B6) deficiency status as a predictor of overall psychological distress and specific mood states in this model, controlling for HIV-1 serostatus. Subjects included HIV-1+ (N = 76) and HIV-1- (N = 58) recently bereaved homosexual men. At baseline, subjects completed a battery of psychosocial questionnaires, together with a physical examination and venipuncture. The Profile of Mood States (POMS) provided measures of overall psychological distress as well as specific mood states. Pyridoxine deficiency status (a categorical measure of deficient vs. adequate status) was determined with a bioassay of erythrocyte aspartate aminotransferase activity. Pyridoxine deficiency was a significant predictor of increased overall psychological distress in this model, controlling for life stressors, social support, coping style, and HIV-1 serostatus. In post hoc analyses of specific mood state effects, pyridoxine deficiency status was significantly associated with increases in depressed, fatigued, and confused mood levels, but not with those of anxiety, anger, or vigor. These findings suggest that adequate pyridoxine status may be necessary to avert psychological distress in the setting of bereavement. Inasmuch as pyridoxine is a cofactor for 5-hydroxytryptophan decarboxylase–an enzyme in the biosynthesis pathway of serotonin–serotonin level in the brain is implicated as the mediating factor.
B vitamins study 8
Biochemical processes in the brain affect mood. Minor dietary inadequacies, which are responsible for a small decline in an enzyme’s efficiency, could cumulatively influence mood states. When diet does not provide an optimal intake of micronutrients, supplementation is expected to benefit mood. This meta-analysis evaluated the influence of diet supplementation on mood in nonclinical samples. Databases were evaluated and studies were included if they considered aspects of stress, mild psychiatric symptoms, or mood in the general population; were randomized and placebo-controlled; evaluated the influence of multivitamin/mineral supplements for at least 28 days. Eight studies that met the inclusion criteria were integrated using meta-analysis. Supplementation reduced the levels of perceived stress (standard mean difference [SMD]=0.35; 95% confidence interval [CI]=0.47-0.22; p=.001), mild psychiatric symptoms (SMD=0.30; 95% CI=0.43-0.18; p=.001), and anxiety (SMD=0.32; 95% CI=0.48-0.16; p<.001), but not depression (SMD=0.20; 95% CI=0.42-0.030; p<.089). Fatigue (SMD=0.27; 95% CI=0.40-0.146; p<.001) and confusion (SMD=0.225; 95% CI=0.38-0.07; p<.003) were also reduced. Micronutrient supplementation has a beneficial effect on perceived stress, mild psychiatric symptoms, and aspects of everyday mood in apparently healthy individuals. Supplements containing high doses of B vitamins may be more effective in improving mood states. Questions about optimal levels of micronutrient intake, optimal doses, and active ingredients arise.
Riboflavin study 1
Riboflavin is a water-soluble B vitamin, also known as vitamin B2. In the body, riboflavin is primarily found as an integral component of the coenzymes, flavin adenine dinucleotide (FAD) and flavin mononucleotide, also known as or riboflavin-5′-phosphate.
Vitamin B6 study 1
The phosphate ester derivative pyridoxal 5′-phosphate (PLP) is the bioactive coenzyme form of vitamin B6, involved in over 4% of all enzymatic reactions.
Vitamin B12 study 1
Methylcobalamin and 5-deoxyadenosylcobalamin are the coenzyme forms of vitamin B12 used in the human body.
Folic acid/homocysteine study 1
Researchers used a prospective case-cohort design to determine whether total homocysteine (tHcy)-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center-adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5′-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5′-phosphate (a vitamin B6 coenzyme) was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5′-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C677T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene. In conclusion, researchers suggest that vitamin B6 offers independent protection against tHcy-mediated CHD.
Folic acid/homocysteine study 2
In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6. Results showed that lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis.
Folic acid/homocysteine study 3
In a placebo-controlled study, one hundred men with hyperhomocysteinemia were randomly assigned to five groups and treated with a daily dose of placebo, folic acid (0.65 mg), vitamin B12 (0.4 mg), vitamin B6 (10 mg) or a combination of the three vitamins for 6 wk. Folic acid supplementation reduced plasma homocysteine concentrations by 41.7% (P < 0.001), whereas the daily vitamin B12 supplement lowered homocysteine concentrations by 14.8% (P < 0.01). The daily pyridoxine dose did not reduce significantly plasma homocysteine concentrations. The combination of the three vitamins reduced circulating homocysteine concentrations by 49.8%, which was not significantly different (P = 0.48) from the reduction achieved by folate supplementation alone. However, vitamin B6 supplementation was effective in lowering blood homocysteine levels after an oral dose of methionine (methionine load test) was given, suggesting vitamin B6 may play a role in the metabolism of homocysteine after meals.
Folic acid/homocysteine study 4
Increasing folate intake through folate-rich foods or supplements has been found to lower homocysteine levels. Moreover, blood homocysteine levels have declined since the FDA mandated folic acid fortification of the grain supply.
Folic acid/homocysteine study 5
A meta-analysis of 25 randomized controlled trials involving individual data on 2596 subjects assessed the effect of different doses of folic acid and of the addition of vitamins B12 and B6, on plasma homocysteine concentrations. The proportional reductions in plasma homocysteine concentrations produced by folic acid were greater at higher homocysteine (P < 0.001) and lower folate (P < 0.001) pretreatment concentrations; they were also greater in women than in men (P < 0.001). After standardization for sex and to pretreatment plasma concentrations of 12 micromol homocysteine/L and 12 nmol folate/L, daily doses of 0.2, 0.4, 0.8, 2.0, and 5.0 mg folic acid were associated with reductions in homocysteine of 13% (95% CI: 10%, 16%), 20% (17%, 22%), 23% (21%, 26%), 23% (20%, 26%), and 25% (22%, 28%), respectively. Vitamin B-12 (x: 0.4 mg/d) produced 7% (95% CI: 4%, 9%) further reduction in homocysteine concentrations, but vitamin B-6 had no significant effect. Researchers concluded that daily doses of > or =0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect.
Folic acid/homocysteine study 6
A supplement regimen of 400 mcg of folic acid, 2 mg of vitamin B6, and 6 mcg of vitamin B12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet (is not successful in adequately lowering homocysteine levels.
Folic acid/homocysteine study 7
Meta-analysis of 12 randomised controlled trials that included individual data on 1114 people assessed the effects of folic acid based supplements on blood homocysteine concentrations. Results showed that, typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B-12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 mumol/l to 8-9 mumol/l). Folic acid supplementation had the greatest lowering effect on blood homocysteine levels (25% decrease); co-supplementation with folic acid and vitamin B12 (mean 0.5 mg/day or 500 mcg/day) provided an additional 7% reduction (32% decrease) in blood homocysteine concentrations.
Berocca study 1
A significant proportion of the general population report supplementing their diet with one or more vitamins or minerals, with common reasons for doing so being to combat stress and fatigue and to improve mental functioning. Few studies have assessed the relationship between supplementation with vitamins/minerals and psychological functioning in healthy cohorts of non-elderly adults. The present randomized, placebo-controlled, double–blind, parallel groups trial assessed the cognitive and mood effects of a high-dose B-complex vitamin and mineral supplement (Berocca®) in 215 males aged 30 to 55 years, who were in full-time employment. The supplement contained vitamins: B1 (15 mg), B2 (15 mg), B6 (10 mg), B12 (10 mcg), C (500 mg), biotin (150 mcg), folic acid (400 mcg), nicotinamide (50 mg) and pantothenic acid (23 mg) and minerals: calcium (100 mg), magnesium (100 mg) and zinc (10 mg). Participants attended the laboratory prior to and on the last day of a 33-day treatment period where they completed the Profile of Mood States (POMS), Perceived Stress Scale (PSS) and General Health Questionnaire (GHQ-12). Cognitive performance and task-related modulation of mood/fatigue were assessed with the 60 min cognitive demand battery. On the final day, participants also completed the Stroop task for 40 min whilst engaged in inclined treadmill walking and subsequent executive function was assessed. Vitamin/mineral supplementation led to significant improvements in ratings on the PSS, GHQ-12 and the ‘vigor’ subscale of the POMS. The vitamin/mineral group also performed better on the Serial 3s subtractions task and rated themselves as less ‘mentally tired’ both pre- and postcompletion of the cognitive demand battery. Healthy members of the general population may benefit from augmented levels of vitamins/minerals via direct dietary supplementation. Specifically, supplementation led to improved ratings of stress, mental health and vigor and improved cognitive performance during intense mental processing.
Berocca study 2
To assess the effects of a multivitamin-mineral combination (Berocca Calmag) treatment on stress in a large sample of South Africans, a multiple-dose, double-blind, placebo-controlled, double-centre study was conducted. The supplement contained vitamins: B1 (15 mg), B2 (15 mg), B6 (10 mg), B12 (10 mcg), C (500 mg), biotin (150 mcg), folic acid (400 mcg), nicotinamide (50 mg) and pantothenic acid (23 mg) and minerals: calcium (100 mg), magnesium (100 mg) and zinc (10 mg). Patients were drawn from two centres with high stress levels (Durban and Johannesburg), each study recruiting the same number of patients (150) from 1,000 adults with predetermined high stress levels. Dropouts from the study were replaced. Study medication safety was evaluated by recording adverse events. On day 1 (baseline) patients were subjected to an individual in-depth assessment that included a biographical questionnaire, four psychological scales, and collateral information from close relatives. On day 30 (end of the study period) or at the latest 7 days after the last planned medication intake, the assessment was repeated for purposes of pre- and post-response comparison. Thirty-three patients dropped out and were replaced, leaving 300 patients who completed the study–151 in group 1 (multivitamin-mineral combination), and 149 in group 2 (placebo). There were no statistically significant differences between the two groups regarding demographics and baseline stress scores at study entry. Both groups improved between baseline and the end of treatment as assessed. The degree of improvement was statistically significant and greatest in group 1 for all psychometric instruments, with this beneficial effect increasing over the course of the day. Subgroup analyses for age (18-44 and 45-65 years), gender and ethnicity showed no general effect on the overall study outcome. The multivitamin-mineral combination tested is well tolerated and can be used as part of a treatment programme for stress-related symptoms at the recommended dose.
Berocca study 3
Vitamin and mineral supplements may be associated with improved psychological status. The present study tested the effects of a multivitamin and mineral supplement (Berocca) on psychological well-being. In a double-blind randomised-control trial, 80 healthy male volunteers were assigned to either Berocca or placebo. Questionnaires measuring psychological state were completed and a blood sample taken to determine plasma zinc concentration on day 1 (pre-treatment) and again on day 28 (post-treatment), following 28 days of treatments, which were administered at a dosage of one tablet daily. At the end of the study, the acceptability of the treatment and participants’ awareness of treatment condition were assessed, as was habitual dietary behaviour. Relative to placebo, treatment with Berocca was associated with consistent and statistically significant reductions in anxiety and perceived stress. Participants in the Berocca group also tended to rate themselves as less tired and better able to concentrate following treatment. In addition, participants registered more somatic symptoms following placebo than following Berocca. These effects cannot be attributed to differences in the acceptability of the two treatments or to participants guessing what treatment they received. These findings demonstrate that Berocca significantly reduces anxiety and perceived stress.
Berocca study 4
Previous work has identified the positive effects of the acute administration of a multivitamin-guaraná preparation during an effortful executive/working memory task. Here, we aimed to differentiate the effects of multivitamins with and without guaraná and to examine the neural substrates of such effects using functional magnetic resonance imaging (fMRI). Following a double-blind, placebo-controlled, randomised, balanced crossover design, 20 participants (mean age 29 ± 5.54 years) consumed multivitamin preparations with or without guaraná (Berocca® Performance and Boost, respectively) and a placebo. Thirty minutes post-treatment, they underwent neurocognitive assessment, consisting of a 10 min Cognitive Demand Battery, with mood ratings taken immediately before and after the battery. Five additional participants underwent post-treatment fMRI scanning during Rapid Visual Information Processing and Inspection Time activation tasks. The multivitamin with guaraná treatment was associated with significantly enhanced Serial Threes performance and self-rated contentment. fMRI revealed that both multivitamin treatments increased activation in areas associated with working memory and attentional processing, with the effect being greater in the multivitamin with guaraná condition. These data confirm the acute benefits of multivitamins with guaraná on mood and cognitive performance. Furthermore, they demonstrate for the first time increased brain activation from multivitamin preparations both with and without guaraná, as measured using fMRI.
Berocca study 5
Biochemical processes in the brain affect mood. Minor dietary inadequacies, which are responsible for a small decline in an enzyme’s efficiency, could cumulatively influence mood states. When diet does not provide an optimal intake of micronutrients, supplementation is expected to benefit mood. This meta-analysis evaluated the influence of diet supplementation on mood in nonclinical samples. Databases were evaluated and studies were included if they considered aspects of stress, mild psychiatric symptoms, or mood in the general population; were randomized and placebo-controlled; evaluated the influence of multivitamin/mineral supplements for at least 28 days. Eight studies that met the inclusion criteria were integrated using meta-analysis. Results were that supplementation reduced the levels of perceived stress (standard mean difference [SMD]=0.35; 95% confidence interval [CI]=0.47-0.22; p=.001), mild psychiatric symptoms (SMD=0.30; 95% CI=0.43-0.18; p=.001), and anxiety (SMD=0.32; 95% CI=0.48-0.16; p<.001), but not depression (SMD=0.20; 95% CI=0.42-0.030; p<.089). Fatigue (SMD=0.27; 95% CI=0.40-0.146; p<.001) and confusion (SMD=0.225; 95% CI=0.38-0.07; p<.003) were also reduced.
In conclusion, micronutrient supplementation has a beneficial effect on perceived stress, mild psychiatric symptoms, and aspects of everyday mood in apparently healthy individuals. Supplements containing high doses of B vitamins may be more effective in improving mood states. Questions about optimal levels of micronutrient intake, optimal doses, and active ingredients arise.
Approved health claim
Guidance for Industry: A Food Labeling Guide (11. Appendix C: Health Claims), (21 CFR 101.79). January 2013
Model Claim: “Healthful diets with adequate folate (or folic acid) may reduce a woman’s risk of having a child with a brain or spinal cord defect.”
Folic acid/birth defects study 1
Folic acid plays a critical role in protecting against some serious birth defects, including neural tube defects, when taken by women of childbearing age before and during pregnancy. The Food and Nutrition Board of the Institute of Medicine recognized these findings when it issued new dietary recommendations for the B vitamins in 1998, recommending “that women capable of becoming pregnant should obtain 400 mcg/day of folic acid from dietary supplements and/or fortified foods in addition to the folate present in a varied diet.” The Food and Nutrition Board added, “At this time the evidence for a protective effect from folate supplements is much stronger than that for food folate.”
Folic acid/birth defects study 2
The Centers for Disease Control and Prevention (CDC) started even earlier by issuing a public health recommendation in 1992 urging all women of childbearing age to get 400 mcg of folic acid daily to help neural tube defects.
Vitamin K2 study 1
In a population-based study, 4807 subjects were analyzed for their vitamin K intake as well as its relationship to aortic calcification and coronary heart disease (CHD). The risk of incident CHD, all-cause mortality, and aortic atherosclerosis was studied in tertiles of energy-adjusted vitamin K intake after adjustment for age, gender, BMI, smoking, diabetes, education, and dietary factors. The relative risk (RR) of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone (vitamin K2), particularly in those consuming about 45 mcg menaquinone daily, compared to the lower tertile [RR = 0.73 (95% CI: 0.45, 1.17) and 0.43 (0.24, 0.77), respectively]. Intake of menaquinone was also inversely related to all-cause mortality [RR = 0.91 (0.75, 1.09) and 0.74 (0.59, 0.92), respectively] and severe aortic calcification [odds ratio of 0.71 (0.50, 1.00) and 0.48 (0.32, 0.71), respectively]. Phylloquinone (vitamin K1) intake was not related to any of the outcomes.
Note: In the following studies, 930 mg of dry Echinacea root was used. A 4:1 extract has 4 times the potency, so requires one-fourth of the dose for efficacy. Therefore, 233 mg of the extract is equivalent to 930 mg of the dry herb.
Echinacea study 1
This phase 0, double-blind, repeated within subject, randomized pilot study examined CD25 expression on T cells after ingestion of three commonly used herbs: Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra, administered singly and in combination. Echinacea tincture (Echinacea purpurea root, 0.93 g expressed as dry herb), Astragalus and Glycyrrhiza greatly increase the number of activated CD25 + CD4 T cells in human subjects within 24 h of ingestion. When comparing levels at 24 h with baseline values, Echinacea had the greatest effect on activation of CD4+ T cells, with a value of p = 0.003, significant at a 95% confidence level. At 7 days, the Echinacea subjects continued to have higher levels of CD25 expression compared with the initial levels (p < 0.07). No other single herbs, nor the combination, showed continued CD25 expression at 7 days.
Echinacea study 2
The increasing use of medicinal herbs among the general public has piqued the need for scientific-based research to determine the mechanism of action of herbs administered orally in human subjects. The ability of three herbs, Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra, to activate immune cells in human subjects was assessed in this pilot study. The effect of these herbs when ingested for 7 days was measured both when administered singly, and in combination, using flow cytometry. The primary cell activation marker measured was CD69. The results demonstrate that Echinacea purpurea root tincture, 0.93 g expressed as dry herb, as well as Astragalus and Glycyrrhiza, stimulated immune cells as quantified by CD69 expression on CD4 and CD8 T cells. This activation took place within 24 h of ingestion, and continued for at least 7 days. In addition, these three herbs had an additive effect on CD69 expression when used in combination.
Echinacea study 3
The Health Canada monograph indicates that the traditional uses of Echinacea purpurea in Herbal Medicine include helping to fight off infections, especially of the upper respiratory tract, and helping relieve cold symptoms. It also states that Echinacea purpurea provides supportive therapy in the treatment of upper respiratory tract infections (e.g. common colds), and helps to relieve the symptoms and shorten the duration of upper respiratory tract infections. The monograph identifies the part of the plant used as herb top, root, or a combination of top and root. For Echinacea purpurea root, the dose recommended is 0.9 – 4.5 grams per day, dried root. The directions for use are to take at the first sign of infection.
- Murphy SP, White KK, Park SY, Sharma S. Multivitamin-multimineral supplements’ effect on total nutrient intake. Am J Clin Nutr. 2007 Jan;85(1):280S-284S.
- Gaziano JM, Sesso HD, Christen WG, Bubes V, Smith JP, MacFadyen J, Schvartz M, Manson JE, Glynn RJ, Buring JE. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012 Nov 14;308(18):1871-80.
- Park Y, Spiegelman D, Hunter DJ, et al. Intakes of vitamins A, C, and E and use of multiple vitamin supplements and risk of colon cancer: a pooled analysis of prospective cohort studies. Cancer Causes Control. 2010 Nov;21(11):1745-57.
- Holmquist C, Larsson S, Wolk A, de Faire U. Multivitamin supplements are inversely associated with risk of myocardial infarction in men and women–Stockholm Heart Epidemiology Program (SHEEP). J Nutr. 2003 Aug;133(8):2650-4.
- Frank E, Bendich A, Denniston M. Use of vitamin-mineral supplements by female physicians in the United States. Am J Clin Nutr. 2000 Oct;72(4):969-75.
- Wang C, Li Y, Zhu K, Dong YM, Sun CH. Effects of supplementation with multivitamin and mineral on blood pressure and C-reactive protein in obese Chinese women with increased cardiovascular disease risk. Asia Pac J Clin Nutr. 2009;18(1):121-30.
- Rautiainen S, Akesson A, Levitan EB, Morgenstern R, Mittleman MA, Wolk A. Multivitamin use and the risk of myocardial infarction: a population-based cohort of Swedish women. Am J Clin Nutr. 2010 Nov;92(5):1251-6.
- Walker JG, Batterham PJ, Mackinnon AJ, Jorm AF, Hickie I, Fenech M, Kljakovic M, Crisp D, Christensen H. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms—the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr. 2012;95:194–203.
- Huskisson E, Maggini S, Ruf M. The role of vitamins and minerals in energy metabolism and well-being. J Int Med Res. 2007 May-Jun;35(3):277-89.
- Gibson GE, Blass JP. Nutrition and Functional Neurochemistry. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999. Available from: http://www.ncbi.nlm.nih.gov/books/NBK28242/
- Leklem JE. Vitamin B6. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:413-422.
- Suarez EC. Plasma interleukin-6 is associated with psychological coronary risk factors: moderation by use of multivitamin supplements. Brain Behav Immun. 2003 Aug;17(4):296-303.
- Stress and anxiety. MedlinePlus. A service of the U.S. National Library of Medicine, National Institutes of Health. Retrieved April 17, 2013 from http://www.nlm.nih.gov/medlineplus/ency/article/003211.htm.
- Adult Stress—Frequently Asked Questions: How it affects your health and what you can do about it. National Institute of Mental Health. Retrieved April 17, 2013 from http://www.nimh.nih.gov/health/publications/stress/fact-sheet-on-stress.shtml.
- Bondarev GI, Martinchik AN, Khotimchenko SA, et al. [Correlation of the actual vitamin B1, B2 and B6 consumption with the biochemical indices of their body allowance] Korreliativnaia vzaimosviaz’ fakticheskogo potrebleniia vitaminov B1, B2 i B6 s biokhimicheskimi pokazateliami obespechennosti imi organizma. Vopr Pitan 1986; (2):34-7.
- Baldewicz T, Goodkin K, Feaster DJ, et al. Plasma pyridoxine deficiency is related to increased psychological distress in recently bereaved homosexual men. Psychosom Med 1998; 60(3):297-308.
- Long SJ, Benton D. Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: a meta-analysis. Psychosom Med. 2013 Feb;75(2):144-53.
- Food and Nutrition Board, Institute of Medicine. Riboflavin. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:87-122.
- Dakshinamurti S, Dakshinamurti K. Vitamin B6. In: Zempleni J, Rucker RB, McCormick DB, Suttie JW, eds. Handbook of Vitamins. 4th ed. New York: CRC Press (Taylor & Fracis Group); 2007:315-359.
- Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999.
- Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98(3):204-210.
- Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group.Circulation. 1998;97(5):437-443
- Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994;124(10):1927-1933.
- Shane B. Folic acid, vitamin B-12, and vitamin B-6. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483-518.
- Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005;82(4):806-812.
- Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999;99(1):178-182.
- Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ. 1998;316(7135):894-898.
- Kennedy DO, Veasey R, Watson A, Dodd F, Jones E, Maggini S, Haskell CF. Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males. Psychopharmacology (Berl). 2010 Jul;211(1):55-68.
- Schlebusch L, Bosch BA, Polglase G, Kleinschmidt I, Pillay BJ, Cassimjee MH. A double-blind, placebo-controlled, double-centre study of the effects of an oral multivitamin-mineral combination on stress. S Afr Med J. 2000 Dec;90(12):1216-23.
- Carroll D, Ring C, Suter M, Willemsen G. The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind placebo-controlled trial. Psychopharmacology (Berl). 2000 Jun;150(2):220-5.
- Scholey A, Bauer I, Neale C, et al. Acute effects of different multivitamin mineral preparations with and without Guaraná on mood, cognitive performance and functional brain activation. Nutrients. 2013 Sep 13;5(9):3589-604.
- Long S-J, Benton D. Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: a meta-analysis. Psychosom Med. 2013 Feb;75(2):144-53.
- Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, vitamin B-6, Folate, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press, 1998.
- CDC (Centers for Disease Control). Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992; 41 (No. RR-14).
- Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. J Nutr 2004;134:3100-5.
- Zwickey H, Brush J, Iacullo CM, Connelly E, Gregory WL, Soumyanath A, Buresh R. The effect of Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra on CD25 expression in humans: a pilot study. Phytother Res. 2007 Nov;21(11):1109-12.
- Brush J, Mendenhall E, Guggenheim A, Chan T, Connelly E, Soumyanath A, Buresh R, Barrett R, Zwickey H. The effect of Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra on CD69 expression and immune cell activation in humans. Phytother Res. 2006 Aug;20(8):687-95.
- Monograph: Echinacea Purpurea. Health Canada, Natural Health Products Ingredients Database. Date Modified: 2013-07-10.