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Dietary Supplements: Beneficial to Human Health of Just Peace of Mind? A Critical Review on the Issue of Benefit/Risk of Dietary Supplements

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Abstract

Summary. Dietary supplement can be defined as any vitamin, mineral, added chemical substances, botanical or herbal products that is added to the diet to improve human health. Scientists and health professionals agree that dietary supplements can be under certain conditions beneficial to human health, but should not replace complete and balanced daily meals of foods which are necessary for a healthful diet. The most authoritative national agency U.S. Food and Drug Administration (FDA) emphasized that “…unlike drugs, dietary supplements are not intended to treat, diagnose, prevent, or cure diseases. Dietary supplements should not make claims, such as “reduces pain” or “treats heart disease”, etc…”. Globally, dietary supplement market stood at over US$90 billion in 2013, and on top is the US market with over 30 billion every year. For many years informed medical sources like doctors, nurses, pharmacists, nutritionists and medical authorities agree that there’s a lot of wrong information in the supplements market. Many dietary supplements, even in the USA that has some of the most experienced health agencies, managed to escape the safety tests, labeling and health regulations. From 2007, some of the most well known scientists in the USA on nutrition, metabolism and epidemiology reviewed the evidence on multivitamin/mineral supplements and concluded that there was not sufficient evidence to recommend for or against for the prevention of chronic disease. Randomized Control Trials of dietary supplements increased substantially in the last decade in many developed countries. The results are mixed but the majority is negative for health benefits or for preventing diseases. In 2013 three papers and an overall review of the results for the last decade with the title “Enough is enough. Stop wasting money on vitamin and mineral supplements” was published in the prestigious medical journal Annals of Internal Medicine in the USA. The influence of these research results was spread to other developed countries and more critical appraisals were published on dietary supplements. This review covers the most important aspects of dietary supplements, the trends in global market, the national and international regulations of various products. Also, examines the debate and arguments of health professionals. The review examines in a systematic way the most important studies that were published in the scientific literature in the last few years on the most widespread dietary supplements and their results on benefits or risk to human health. It covers dietary supplements taken by young, elderly, pregnant women, athletes and people with deficiencies which were self-prescribed and on the international market. KEY WORDS : Dietary Supplements, Balancer Diet, Vitamins, Minerals, Randomized Control Trials, Health Benefit, Risk, Global Dietary Supplements Market ……………………………………………….. Pharmakeftiki 28(II): 60-83, 2016, available at http://www.hsmc.gr/index.php/pharmakeftiki
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ΦΑΡΜΑΚΕΥΤΙΚH, 28, II: 69-92, 2016 ΑΡΘΡΟ ΕΠΙ΢ΚΟΠΗ΢Η΢/ REVIEW ARTICLE
PHARMAKEFTIKI, 28, II: 69-92, 2016
Dietary Supplements: Beneficial to Human Health or Just
Peace of Mind? A Critical Review on the Issue
of Benefit/ Risk of Dietary Supplements
Athanasios Valavanidis
Department of Chemistry, University of Athens, University Campus Zografou,
15784 Athens, Greece
Summary. Dietary supplement can be defined as any vitamin, mineral, added chemical substances,
botanical or herbal products that is added to the diet to improve human health. Scientists and health
professionals agree that dietary supplements can be under certain conditions beneficial to human
health, but should not replace complete and balanced daily meals of foods which are necessary for a
healthful diet. The most authoritative national agency U.S. Food and Drug Administration (FDA)
emphasized that “…unlike drugs, dietary supplements are not intended to treat, diagnose, prevent, or
cure diseases. Dietary supplements should not make claims, such as “reduces pain” or “treats heart
disease”, etc…”. Globally, dietary supplement market stood at over US$90 billion in 2013, and on top is
the US market with over 30 billion every year. For many years informed medical sources like doctors,
nurses, pharmacists, nutritionists and medical authorities agree that tt of wrong information in
the supplements market. Many dietary supplements, even in the USA that has some of the most
experienced health agencies, managed to escape the safety tests, labeling and health regulations. From
2007, some of the most well known scientists in the USA on nutrition, metabolism and epidemiology
reviewed the evidence on multivitamin/mineral supplements and concluded that there was not sufficient
evidence to recommend for or against for the prevention of chronic disease. Randomized Control Trials
of dietary supplements increased substantially in the last decade in many developed countries. The
results are mixed but the majority is negative for health benefits or for preventing diseases. In 2013
three papers and an overall review of the results for the last decade Enough is enough.
Stop wasting money on vitamin and mineral supplements was published in the prestigious medical
journal Annals of Internal Medicine in the USA. The influence of these research results was spread to
other developed countries and more critical appraisals were published on dietary supplements. This
review covers the most important aspects of dietary supplements, the trends in global market, the
national and international regulations of various products. Also, examines the debate and arguments of
health professionals. The review examines in a systematic way the most important studies that were
published in the scientific literature in the last few years on the most widespread dietary supplements
and their results on benefits or risk to human health. It covers dietary supplements taken by young,
elderly, pregnant women, athletes and people with deficiencies which were self-prescribed and on the
international market.
KEY WORDS : Dietary Supplements, Balancer Diet, Vitamins, Minerals, Randomized Control Trials, Health
Benefit, Risk, Global Dietary Supplements Market
………………………………………………..
Corresponding author: Prof. Athanasios Valavanidis, E-mail : valavanidis@chem.uoa.gr

1. Introduction : balanced diet and dietary supplements
Dietary supplement can be defined as any vitamin, mineral, added chemical substance, herbal
product, botanicals, amino acids, or other ingestible preparation that is added to the diet to benefit
human health. Dietary supplements are used worldwide and represent a broad category of ingestible
products that are distinguishable from conventional foods and drugs.1-5
All developed countries have special legislation concerning dietary supplement (for example,
U.S. Dietary Supplement Health and Education Act, 1994). In countries, such as Australia and Canada,
2
dietary supplements and drugs are regulated similarly, and only ingredients deemed acceptable by the
Therapeutic Goods Administration of Australia or the Natural Health Products Directorate of Canada can
be sold as dietary supplements. In the European Union (EU), dietary supplement regulations (Directive
2002/46/EC) often follow a case-by-case basis, depending upon the individual country and the available
safety evidence for the ingredient. In China, India and Japan, where plants, herbs, botanicals and
animal extracts have a long history of use as traditional medicine, regulations are different but relatively
stringent in terms of safety and side effects to humans.6-11 Japan has no legal definition of dietary
supplements, mostly are classified into food products or drugs. The Ministry of Health and Welfare set
up the Food for Specified Health Uses (FOSHU) to provide people with accurate health information
about dietary supplements and the current Japanese system for regulation of health foods is called
Food with Health Claims and is made up of two categories:   and
.12
The Healthy Eating Pyramid
Figure 1. Conventional, balanced and healthy eating can cover all needs of the human body in terms of
energy, basic nutrients (carbohydrates, proteins, fatty acids, water) and micronutrients (vitamins,
minerals, antioxidants, etc).
A fundamental question that everybody asks these days that most people are very aware that
nutrition plays a very important role in health is, if conventional, balanced and without supplements diet
can cover all the needs of the human body for a healthy lifestyle until old age. Nutritionists and health
professionals argued for years that people can get the most important food requirements that their body
needs each day from a conventional, balanced and regular daily diet. T from
health and nutrition agencies cover more than 40 nutrients that are subdivided into 6 categories:
carbohydrates, fats, proteins, vitamins, minerals and water. Daily nutrient recommendations are
collectively known as dietary reference intakes (DRIs). A healthy diet is one that favours  fresh
whole foods that have been sustaining people throughout the millenniums. Whole foods supply the
needed vitamins, minerals, protein, carbohydrates, fats, and fiber that are essential to good health. In
contrast, commercially prepared and fast foods are often lacking nutrients and contain inordinate
amounts of sugar, salt, saturated and trans-fats, all of which are associated with the development of
diseases. A balanced diet is a mix of food from the different food groups (vegetables, legumes, fruits,
grains, protein foods, meat, and dairy). Variety involves eating different foods from all the food groups
that helps to ensure that you receive all the nutrients necessary for a healthy diet. The components of
the Mediterranean diet have been evaluated as substantially beneficial to human health.13-15
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The World Health Organization (WHO) makes the following recommendations for a balanced and
healthy diet: a. eat roughly the same amount of calories that your body is using, b. a healthy weight is a
balance between energy consumed and energy that is 'burnt off', c. limit intake of fats, and prefer
unsaturated, than saturated fats and trans fats, d. increase consumption of plant foods, particularly
fruits, vegetables, legumes, whole grains and nuts, e. limit the intake of sugar, salt/sodium consumption
from all sources and ensure that salt is iodized, f. eat a diet with essential micronutrients such as
vitamins and certain minerals.16,17
2. Dietary supplements: short historical overview
From the beginning of human civilization diet was mostly plant foods that could be easily gathered and
seafoods. Hunter-gatherers later contributed meat products by big game. This was the diet of most
humans until about 10,000 BC, at which time the development of agriculture and animal husbandry
provided more meat and grains for the whole family. Nobody knew about vitamins, minerals, proteins,
carbohydrates and fats and their role in human nutrition. The various people in the continents of the
Earth developed nutritious local cuisines with mostly local products that sustained their health, whereas
by trial and error choose a variety of foods and cooking methods that lead to physical strength, health,
and fertility. The common wisdom of native cultures knew which foods and herbs had special properties
for energy, nutrition and extra health benefits for children, pregnant women and elders. Everyday diets
 up for deficiencies as far back as native cultures. Native Americans, for
example, knew to drink a tea made from pine bark and needles for scurvy containing high concentration
of ascorbic acid, which was later found by science to be a vitamin C deficiency disease. In 1749, Dr.
James Lind discovered citrus fruits prevented scurvy (high in vitamin C content).18-20
The discovery of the role of vitamins was a major scientific achievement in the understanding on
the association of nutrition, health and disease. By the 1920s and 1930s, significant strides were being
made in the world of vitamin research and mass marketing (synthesized vitamin C in 1935 and
marketed as vitamin C supplement under the name Redoxon). In the nearly 75 years since the vitamin
C pill was marketed, large steps have been made in the vitamin and other dietary supplement products.
Increased public interest was stimulated as a result of claims (proved to be false later) made in the USA
by Nobel-laureate Linus Pauling (1901-1994)  of at least 10 times the
RDA (Recommended Dietary Allowances) of ascorbic acid could prevent or cure the common cold, flu,
and cancer.21 In 1976, Pauling and Dr. E. Cameron contacted experiments and reported that a majority
of 100 "terminal" cancer patients treated with 10,000 mg of vitamin C daily survived three to four times
longer than similar patients who did not receive vitamin C supplements. Nevertheless, to test whether
Pauling might be correct, the Mayo Clinic conducted three double-blind studies involving a total of 367
patients with advanced cancer. The studies, reported in 1979, 1983, and 1985, found that patients given
10,000 mg of vitamin C daily did no better than those given a placebo.22-25 In fact, recent laboratory
studies have found that vitamin C may interfere with the effectiveness of five anti-cancer drugs. 26
Although health claims for a variety of vitamin supplements proved to be controversial, popular
books, consumer and sport magazines, popular newspapers and TV advertisements in developed
countries advertise spurious claims for various botanical herbs, and constituents of food for health
 of diseases. The majority of these claims are not supported by
scientific studies. The mainstream scientific community gradually became intrigued by the potential
health benefits of dietary supplements and numerous research projects (epidemiologic, clinical, in vivo
and in vitro) were initiated in the 1980s. This interest was fueled in part by studies demonstrating that
nutrient antioxidants, (vitamins C and A, E and b-carotene, Selenium), have a role in protecting cells
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from oxidative free radical damage. Furthermore, epidemiological studies suggested that a diet rich in
fruits and vegetables and abundant in antioxidants, nutrients, and other substances, reduced the risk of
coronary heart disease and certain cancers. These initial promising results were not materialized by the
more accurate and larger randomized controlled trials taking into account confounding factors.27-30
There are more than 54,000 dietary supplement products in the Natural Medicines.
Comprehensive Database (USA), of which only about 1/3 have some level of safety and effectiveness
that is supported by scientific evidence. Consumer Reports magazine). Reuters 3/8/2010
[http://www.reuters.com/article/us-usa-supplements-idUSTRE6721F520100803 ].
          -fortified dietary
supplements and a large range of special foods and plants appeared on the market with incredibly
superficial health benefits. According to the estimates of the Nutrition Business Journal report, the global
nutrition and supplements market stood at US$96 billion in 2012. A year later, it was approximately
US$104 billion globally. U.S.A market of dietary supplements was estimated in 2015 at US$27.2 billion.
China is also another important consumer in the market. With rising disposable incomes and increasing
health awareness among the Chinese people, vitamins and dietary supplements are deemed a
convenient choice for consumers looking to improve their health and wellbeing. In 2016 Chinese
regulators released draft regulations governing nutritional supplements, a modest step toward
 
Food and Drug Administration (CFDA) would create a notification or recording system for the
introduction of nutritional supplements, according to the U.S.-China Health Products Association
(USCHPA), 2015 [http://www.naturalproductsinsider.com/Articles/2015/01/China-Adopts-Proposed-
Notification-System-for-Nut.aspx ].
Another trend in the last decades, which is characteristic of American consumers and people
from Western developed countries (Canada, W. Europe, Australia), is that increasingly large numbers of
middle class people became disenchanted with rising health care costs and the perceived impersonal
nature of coany countries there is a dramatic rise in the popularity of
various complementary and alternative practices, including Chinese herbal medicine, Ayurvedic
medicine (an Indian holistic medical system incorporating foods and herbs), acupuncture, and
homeopathy. During the last decade the U.S. FDA and the EU attempted to increase regulation of
herbal products and other botanicals and dietary supplements, as well as health labeling and list of
contents, creating a platform of basic information among consumers and forcing dietary supplements
manufacturers to follow hygiene practices and safety regulations. In the USA, the Dietary Supplement
Health and Education Act (DSHEA) of 1994 classifies herbs as dietary supplements. In the EU countries
the European Traditional Herbal Medicinal Products Directive (2004/24/EC) has provided a simplified
registration scheme for traditional herbal medicinal products suitable for self-medication.31-36
3. Dietary supplements global marketing with strong growth
Globally, the nutrition and supplements market stood at over US$90 billion and in 2013 it was
estimated at approximately US$104 billion. The U.S.A market of dietary supplements was estimated in
2015 at US$27.2 billion. Growth is expected to remain strong through the next years with expected
increase between 5-6% per year. For comparison global sales of pharmaceuticals have reached a
milestone of $1 trillion in 2014 and forecasts continued growth with the expectation of sales reaching
$1.3 trillion by 2018.37-39
Research analysis of various sections markets with large nutrition and dietary supplements
industry show interesting sale numbers and growth projections. The global sports supplements market
5
in 2013 was worth US$6.8 billion and growth 9%. These supplements include: whey, casein, egg white
and soy proteins, amino acids, performance enhancers creatine, beta-alanine, D-ribose, Nitric oxide,
testosterone, zinc and magnesium aspartate, green tea extracts for fat burning, raspberry ketones,
caffeine, etc). The global fatty acids supplements (linoleic acid, eicosapentanoic , docosahexanoic, fish
oil omega-3 fatty acids, flax seed oil, evening primrose oil, etc) market was estimated with value of
US$1.9 billion in 2013 and is expected to reach in 2020 value of 4.7 billion.38,39
Figure 2. Global sales of dietary supplements are over US$ 90- billion (source Euromonitor). The
countries with the highest consumption rates are: USA 28%, China 21%, Japan, 20%, W. Europe 12%.
ReportLinker [http://www.reportlinker.com/ci02037/Vitamin-and-Supplement.html ]. The market is full of
advertisements of nutritional supplements with excessive and controversial health claims.
The global mineral supplements market is increasing due to a growing geriatric population,
increasing demand from pregnant women, and rising urban population. With the increasing population of
baby boomers, spending on mineral supplements is anticipated to increase. The mineral supplements
market are: macrominerals, calcium, phosphorous, zinc, alkaline pH booster, sodium, potassium,
chlorine, sulfur, magnesium, and trace minerals: iron, boron, manganese, chromium, copper, iodine,
cobalt, fluoride, selenium, colloidal silver. The global mineral supplements market was valued at $9.9
million in 2014 and was expected to grow at 7.5% during the period 2015 - 2020.40
Vitamin and polyvitamin supplements are very popular and their use as supplements,
supported by increasing promotion adverts in growing every year. The global vitamin supplements
market, estimated to be valued at US$37 billion in 2014, and is expected to grow at 6.5% during 2014 to
2020. This is mainly attributed to growing demand among consumer about preventative healthcare.
Research on the vitamin supplement demand showed that is due to the increasing cost of healthcare,
with people are turning towards vitamin supplements. Vitamin supplements included Vitamin C, E, B, A,
beta-carotene, K, niacin, folic acid etc).41
The growing popularity and widespread use of internet has made finding health information and
dietary supplements easier and faster. Although much of the information on the internet is valuable, at
the same time it allows false and misleading information and advertisements with excessive
therapeutics claims. Consumers may be misled by vendors' claims that herbal products can treat,
prevent, diagnose, or cure specific diseases, despite regulations prohibiting such statements.
Physicians should be aware of this widespread and easily accessible information. More effective
regulation is required to put this class of therapeutics on the same evidence-based footing as other
medicinal products.42,43 According to recent FDA testimony, dietary supplements, including vitamins,
were consumed by 158 million Americans in the year 2000, that is more than 50% the US population.
6
Surveys showed that alternative medical therapies and herbal supplements were used by over 80
million people in the USA.44.45
4. Concern among health professionals for the excessive use of dietary
supplements
In the last decade national medical authorities, health professionals and nutritionists in developed
countries became aware of the widespread and rapid increase of dietary supplements (DS) and
excessive consumption by a wide range of the population. The global market is flooded with a variety of
dietary supplements that have false therapeutic claims (difficult to test experimentally) and products
which can be imported and distributed through the internet advertisements. Like drugs, dietary

prove that a dietary supplements are safe. And unlike drugs, DS are mostly self-prescribed with no input
from informed medical sources like doctors, nurses, or pharmacists. Medical authorities agree that
t  t of wrong information in the supplements market. Even for those who are usually well
informed, it can be hard to find reliable information about the safe use and potential risks of DS.46-48
            
overall health. Women used calcium         
appearance              
. Young people use supplements to enhance body function in sports. Older adults report
motivations related to heart, bone and joint, and eye health. The consumption of DS is excessive in the
USA with most Americans taking multivitamins. The primary reasons given for supplement use are for
overall health and wellness or to fill nutrient gaps.49,50
The concern of health professionals is that very little is known about the efficacy of DS for
disease prevention and health needs. American scientists emphasize that randomized clinical trials are
difficult because they tend to be short in duration, whereas many of the chronic diseases of public health
concern have a long latency period (i.e., allergies, cancer, cardiovascular disease). Also, more
investigations on the complex interplay of social, psychological, and economic determinants that
motivate supplement choices are needed. At the same time the US FDA tracks reports of illness, injury,
or reactions from dietary supplements. Recent FDA information of adverse or side effects shows that the
number of reports has continued to climb each calendar year: 2010: 1,009 reports of DS for adverse
health events to consumers, 2011: 2,047 reports and 2012: 2,844 reports. Exposures to supplements
accounted for more than 100,000 calls to US poison control centers in 2013. Of these calls, more than
8,000 people were reportedly treated in health care facilities and 2 deaths reported to poison control
centers.51 Emergency health departments in the USA between 2004-2013 received 23.000
emergency visits per year attributed to adverse health events related to DS consumption, with 2,154
cases needing hospitalization.52 Also, from 2012 to 2014 the FDA received 114 reports of adverse
events (hepatitis outbreak, liver damage) involving consumers who ingested OxyELITEPro (promotes
weight loss) supplements.53
From 2007, some of the most well known scientists in the USA on nutrition, metabolism and
epidemiology (professors Stampfer, Willett , Harvard, School of Public Health, and Bruce Ames and
Joyce McCann, Nutrition and Metabolism Center,     
following a National Institutes of Health, reviewed the evidence on multivitamin/mineral (MVM)
supplements and concluded that there was not sufficient evidence to recommend for or against for the
prevention of chronic disease. Their bottom line   everyone would agree that all persons
7
should be encouraged to eat a good diet, but we are far from achieving this goal, especially among the
poor. In most cases, a simple way to improve micronutrient status is to take an MVM. However, even if
one eats an ideal diet and takes an MVM, some vitamins can remain below recommended
concentrations in some groups.... The panel excluded this highly relevant body of evidence from
consideration, and       present evidence is insufficient to recommend
eit 
that, by conveying the impression that long-term Randomized Controlled Trials (RCTs), which are
inherently limited, represent the only scientific evidence rel -
the panel presents a highly biased and misleading picture.... 54
Many dietary supplements, even in the USA that has some of the most experienced health
agencies, managed to escape the safety tests, labeling and regulations. The American agencies every
year find toxic DS products in the US market that were finally recalled because they were found to
contain banned toxic substances. Between 2009 and 2012, the FDA recalled 274 dietary supplements.
The analysis of these DS were performed by GC-MS and found to contain toxic substances or additional
pharmaceutical adulterants which were banned.55,56
5. Scientific papers on the role of vitamin and mineral supplements in 2013
In the last decade the Randomized Control Trials (RCTs) of dietary supplements increased
substantially in many developed countries. The results are mixed but the majority was negative for DS
promoting health or preventing diseases. In 2013 three papers and an overall review of the results for
the last decade on DS   Enough is enough. Stop wasting money on vitamin and mineral
supplements    prestigious and influential medical journal Annals of Internal
Medicine in the USA.
In the first paper scientists reviewed in a systematic way all trial evidence (carried by the U.S.
Preventive Services Task Force) for the recommendation on the efficacy of vitamin supplements for
primary prevention for adults with no nutritional deficiencies. The review contained 3 trials of
multivitamin supplements and 24 trials of single or paired vitamins that randomly assigned to more than
400,000 participants, the authors concluded that there was no clear evidence of a beneficial effect of
supplements on all-cause mortality, cardiovascular disease, or cancer.57
In the second paper, researchers evaluated the efficacy of a daily multivitamin to prevent
cognitive decline among 5,947 men aged 65 years or older participating in the  Health Study
II. After 12 years of follow-up, there were no differences between the multivitamin and placebo groups in
overall cognitive performance or verbal memory.58 These findings were compatible with a recent review
of 12 fair- to good-quality trials that evaluated dietary supplements, including multivitamins, B vitamins,
vitamins E and C, and omega-3 fatty acids, in persons with mild cognitive impairment or mild to
moderate dementia. None of the supplements improved cognitive function.59
In the third paper, Lamas and associates60, assessed the potential benefits of a high-dose, 28-
component multivitamin supplement in 1,708 men and women with a previous myocardial infarction
participating in TACT (Trial to Assess Chelation Therapy). After a median follow-up of 4.6 years, there
was no significant difference in recurrent cardiovascular events with multivitamins compared with
placebo (hazard ratio, 0.89).60
The supporting editorial in the same journal,61 added some previous highly relevant research
papers, reviews and guidelines that have appraised the role of vitamin and mineral supplements in
primary or secondary prevention of chronic disease but have consistently found null results or possible
8
harms.62,63 Evidence involving tens of thousands of people randomly assigned in many clinical trials
shows that -carotene, vitamin E, and possibly high doses of vitamin A supplements increase mortality
and that other antioxidants, folic acid and B vitamins, and multivitamin supplements have no clear health
benefit.62,64-66 Despite sobering evidence of no benefit or possible harm, use of multivitamin supplements
increased among U.S. adults in the last decade (reaching over 30 billion in 2013). Similar trends have
been observed in the United Kingdom and in other European countries.67 The editorial concludes he
message is simple conclude the scientists: Most supplements do not prevent chronic disease or death,
their use is not justified, and they should be avoided.
6. Arguments in support of dietary supplements and health benefits
After the publication of the scientific papers in Annals of Internal Medicine and the editorial
Enough Is enough: Stop wasting money on vitamin and mineral supplements" (2013) scientists of
Oregon State University, Linus Pauling Institute (December 2013), an institute specializing on nutrition
benefits of DS, carried a supporting note in their website for the balanced diet and prudent use of DS to
fill the gap of useful micronutrients, vitamins and minerals for humans. Under the title 
.68
-
  he National Health and Nutrition
               -
             eir diet in levels
recommended.e shown that people who take multivitamin/mineral (MVM) supplement
with the recommended doses of the most vitamins and minerals can fill most of these nutritional gaps
safety and at very low cost.69,70,71 Contrary to the impression that the authors (of th
eno           vitamins and minerals, a
result of the energy dense and nutrient-poor dietary pattern of Western populations, rather than over-
consuming MVM and other DS. The known biological functions of vitamins and nutritionally-essential
minerals are to maintain normal cell function, metabolism, growth and development, through their roles
as essential cofactors in hundred of enzyme reactions and other biological processes-not to prevent or
treat chronic disease. Nevertheless, the largest and longest randomized controlled trial (RCT) of MVM
supplements conducted to date           
reduction in total and epithelial cell cancer incidence in male physicians, and a 12% reduction in total
cancer incidence excluding prostate cancer. The PHS II also found a significant 9% reduction in the
incidence of total cataract. The findings are consistent with those of several other RCTs, and are even
more impressive given the fact that the conventional RCT design is strongly biased against showing
benefits of essential nutrients, in contrast to pharmaceutical drugs.72-77
 , taking a daily MVM
supplement will not only help fill the known nutritional gaps in the average American diet, thereby
assuming normal biological function and metabolism and supporting good health, but may also have the
added benefit of reducing cancer and cataract risk-which no existing pharmaceutical drug can do. To

and unscientific, and does not serve public health
In the last few years numerous books and collections of scientific results were published or
projected on websites of health agencies on dietary supplements, safety, cost, efficacy and health
benefits vs risks.78-80
9
7. Recent scientific studies on vitamin and multivitamin supplements
Vitamin and multivitamin supplements in combination with calcium and antioxidants are the most
widespread dietary supplements used by elderly people, pregnant women and people with disabilities
for improving health, perinatal depression, improvement for neurologic and cognitive function,
osteoporosis and progression of cancer. However, clinical trials on the use of vitamin supplements for
promotion of health and prevention of disease have failed to demonstrate the strong associations seen
in observational studies.
In Western countries (US and W. Europe) it is fairly common the consumption of multivitamins
among the elderly to prevent disease and improve health. In the US half of adults report using one or
more DS. Although epidemiologic evidence suggests that a diet rich in fruits and vegetables does have
a protective effect on health, clinical trials on the use of vitamin supplements have failed to demonstrate
their health or protective benefits.81
Other scientific data summarized in a recent review (29 clinical trials involving 24,300 women) do
not support that routine vitamin C supplementation alone or in combination with other supplements for
the prevention of fetal or neonatal death, poor fetal growth, preterm birth or pre-eclampsia. Additionally,
further research is required to elucidate the possible role of vitamin C in the prevention of placental
abruption and prelabour rupture of membranes.82
A recent review examined 35 studies on diet, essential nutrients, and DS and their role in
perinatal depression. The studies were grouped into four main categories based on the analysis of
dietary intake: adherence to dietary patterns (9 studies); full panel of essential nutrients (6 studies);
specific nutrients (including B vitamins, Vitamin D, calcium and zinc; 8 studies); and intake of fish
PUFAs (12 studies). While 13 studies found no evidence of an association, 22 studies showed
protective effects from healthy dietary patterns, multivitamin supplementation, fish and PUFA intake,
calcium, Vitamin D, zinc and possibly selenium. Given the methodological limitations of existing studies
and inconsistencies in findings across studies, the evidence on whether nutritional factors influence the
risk of perinatal depression is still inconclusive.83
Another randomized controlled trial (RCT) investigated the B-12 supplementation benefits on
neurologic and cognitive function in moderately vitamin B-12-deficient people. Results of the RCT study
did not support the hypothesis that the correction of moderate vitamin B-12 deficiency, in the absence of
anemia and of neurologic and cognitive signs or symptoms, has beneficial effects on neurologic or
cognitive function in later life.84 Supplementation of vitamin B (folate, B6 and B12) has been investigated
by a meta-analysis of 4 RCTs, for prevention or reduction in osteoporotic fracture and bone turnover.
The results of this analysis failed to identify a risk-reducing effect of daily supplementation of B vitamins
on osteoporotic fracture in patients with vascular disease and with relatively normal plasma Hcy (a blood
test used to detect levels of homocysteine). In addition, the study did not find any positive effects of B
vitamin supplementation on bone turnover.85
Older adults in most countries use vitamin supplements (vitamins A, B, C, D and E) on the
promise for health improvements and prevention of degenerative diseases (mortality, cancer,
cardiovascular and cerebrovascular diseases, cataracts, age-related macular degeneration and bone
diseases). The results of the most important studies on vitamins were summarized in a recent review.
Data from studies demonstrate considerable variations, most confirming little to no benefit following
supplementation in healthy adults. However, clear roles exist for vitamin supplementation in states of
deficiency and in subgroups of older adults at high risk for deficiency of specific or multiple vitamins.86
10
The prevention of cancer with vitamin supplements has been investigated extensively. Vitamin
D is well known for its beneficial effects on health. A recent study included RCTs that compared vitamin
D at any dose, duration, and route of administration versus placebo or no intervention in adults who
were healthy or were recruited among the general population, or diagnosed with a specific disease.
Vitamin D have been administered as supplemental vitamin D (vitamin D (cholecalciferol) or vitamin D
(ergocalciferol), or an active form of vitamin D (1-hydroxyvitamin D (alfacalcidol), or 1,25-
dihydroxyvitamin D (calcitriol)). Scientists concluded that,   there is currently no firm evidence that
vitamin D supplementation decreases or increases cancer occurrence in predominantly elderly
community-dwelling women87 Another recent review examined (from a systematic search of
scientific literature) recent RCTs on the assessment of the effect of vitamin D supplementation on the
prevention of childhood acute respiratory infections. The findings of the review indicated a lack of
evidence supporting the routine use of vitamin D supplementation for the prevention of infections in
healthy children; however, the findings suggested that such supplementation may benefit children
previously diagnosed with asthma.88
Prostate cancer is a very important cancer for men and increasing in the last decades due to
diet of red meat, processed meat products and dietary fat. Long time ago it has been advocated that
vitamin and selenium supplements might play a beneficial role for the prevention of prostate cancer. A
recent review collected data from a PubMed search from 1990 to 2013. Results showed that dietary
supplementation did not have any beneficial effects for the prevention of prostate cancer and indeed
higher doses may be associated with a worse prognosis. There is no specific evidence regarding
benefits of probiotics or prebiotics in prostate cancer.89
Vitamin E supplementation and other vitamins have been advocated for positive benefits in
pregnancy. A review collected 21 RCTs, involving 22,129 women, which assessed vitamin E in
combination with vitamin C and/or other antioxidant agents. The data from these studies did not support
routine vitamin E supplementation in combination with other supplements for the prevention of stillbirth,
neonatal death, preterm birth, pre-eclampsia, preterm or term PROM or poor fetal growth.90
8. Calcium, vitamin D, cardiovascular risk, osteoporosis, bone fractures, etc
Calcium (Ca) is an essential element in the human diet, but there is continuing controversy
regarding its optimal intake, and its role in the pathogenesis of cardiovascular diseases, osteoporosis
and bone fractures. Most studies show little evidence of a relationship between calcium intake and bone
density, or the rate of bone loss. Very few food contain vitamin D. Synthesis of vitamin D occurs in the
skin, after exposure to sun light (especially UV-B radiation), is the major natural source in humans.91
Vitamin D refers to a group of fat-soluble secosteroid compounds responsible for enhancing intestinal
absorption of calcium, iron, magnesium, phosphate, and zinc. In humans, the most important
compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol).
A diet deficient in vitamin D in conjunction with inadequate sun exposure causes osteomalacia (or
rickets in children). Dietary supplements containing Ca and vitamin D are widespread but there is a
controversy regarding their optimal intake and their role in osteoporosis.92
Studies demonstrated no relationship between dietary Ca intake and rate of bone loss over 5
years in healthy older women. A recent review analysed data from 5 recent large studies that have
failed to demonstrate fracture prevention in their primary analyses. It was concluded that Ca
supplements appear to have a negative risk-benefit effect, and so should not be used routinely in the
prevention or treatment of osteoporosis.93 In the other hand, if there deficiencies (Ca and vitamin D) in
11
older adults health professionals recommend as a cost-effective the daily supplementation with vitamin
D to prevent or decrease the rate of osteoporotic fractures. A recent study concluded that the
recommendation to use dairy products as the preferred source of calcium and vitamin D in aging males
and females is supported by public health and health economic analyses.94
A scientific meta-analysis investigated data from 9 trials in order to provide a quantitative
assessment of the efficiency of intermittent, high dose vitamin D treatment on falls, fractures, and
mortality among older adults. The high dose, intermittent vitamin D therapy did not decrease all-cause
mortality among older adults. No benefit was seen in fracture or fall prevention. The risk ratio for hip
fractures was 1.17 (95% Confidence Interval), while for non-vertebral fractures it was 1.06 and the risk
ratio for falls was 1.02. All these results showed very small beneficial effects. Scientists concluded that
supplementation of intermittent, high dose vitamin D may not be effective in preventing overall mortality,
fractures, or falls among older adults.95
The Womens Health Initiative for Calcium and vitamin D supplementation Study, was a 7 year,
randomized, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in
36, community dwelling postmenopausal women. The study followed the Incidence of four
cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death
from coronary heart disease, and stroke) assessed with patient-level data and trial-level data. In meta-
analyses of placebo controlled trials of Ca or Ca and vitamin D data were available for 2
participants from 8 trials. In total 1,384 individuals had an incident myocardial infarction or stroke. Ca or
combination of Ca and vitamin D increased the risk of myocardial infarction (relative risk 1.24) and the
composite of myocardial infarction or stroke (1.15). Scientists concluded that Ca supplements with or
without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction.96
9. Balanced diet and dietary supplements of omega-3 fatty acids
Omega-3 and omega-6 fatty acids (-3 & -6 FAs) are polyunsaturated fatty acids (PUFAs)
considered to be important in human physiology. The most widely available dietary source of omega-3
FAs is oily fish, such as salmon, herring, mackerel, anchovies, menhaden, and sardines. Omega FAs
have significant influence on the ratio and rate of production of eicosanoids, a group of hormones
intimately involved in the body's inflammatory and homeostatic processes, which include the
prostaglandins, leukotrienes, and thromboxanes. A recent trend has been to fortify food with omega-3
FAs supplements, such fortified bread, pizza, yogurt, orange juice, children's pasta, milk, eggs,
confections, and infant formula to reduce mainly the risk for CVDs.
A review investigated a series of 11 studies for the association of dietary supplements of omega-
3 fatty and risk to cardiovascular deaths with a total of 39,044 patients (after myocardial infarction, heart
failure, peripheral vascular disease, etc) The average dose of EPA/DHA (fish oil containing
EicosaPentaenoic Acid/ DocosaHexaenoic Acid) was 1.8 g/day and the mean duration of follow-up was
2.2 years. Dietary supplementation with omega-3 fatty acids significantly reduced the risk of
cardiovascular deaths at 0.87, sudden cardiac death 0.87, all-cause mortality 0.92, and nonfatal
cardiovascular events 0.92. The mortality benefit was largely due to the studies which enrolled high risk
patients. Meta-regression failed to demonstrate a relationship between the daily dose of omega-3 fatty
acid and clinical outcome. The scientists concluded that dietary supplementation with omega-3 fatty
acids should be considered in the secondary prevention of cardiovascular events. 97
A systematic review explored more than 15,000 articles in the scientific literature, including 48
randomized control trials (with 36,913 participants) and 41 epidemiological cohort studies that focused
12
on health benefits and risks from diets with additional omega-3 (-3) fatty acids. The health effects were
concerned with cardiovascular diseases, general mortality and malignant neoplasms. The pooled
estimate showed no strong evidence of reduced risk of total mortality (relative risk 0.87) or combined
cardiovascular events (0.95) in participants taking additional omega-3 fatty acids. Scientists concluded
that long chain and shorter chain omega-3 fatty acids do not have a clear effect on total mortality,
combined cardiovascular events, or cancer.98
Many studies in the last decade showed that long-chain omega-3 polyunsaturated fatty acids
(PUFAs) or omega-3 PUFAs are able to modulate inflammation, hyperlipidemia, platelet aggregation,
and hypertension, under different mechanisms for conditioning cell membrane function and composition
eicosanoid production, and gene expression. A review in 2014 analyzed the influence of omega-3
PUFAs status and intake on brain function, cardiovascular system, immune function, muscle
performance and bone health in older adults. It was found that omega-3 fatty acids can have benefits in
reducing the risk of cognitive decline in older people, but more studies are needed to confirm the role of
omega-3 (-3) in maintaining bone health and preventing the loss of muscle mass and function
associated with ageing.99
Osteoporosis is a global health problem that leads to an increased incidence of fragility
fracture. In the last decade there is medical recommendation of higher fish oil diet intakes. Findings from
human bone cell culture experiments have revealed both benefits and detriments to bone-related
outcomes depending on the quantity and source of PUFAs. Observational and randomized controlled
trials (RCTs) have produced enough data to suggest that higher fatty fish intake is strongly is linked with
reduced risk of fragility fracture. Human studies largely support that a greater intake of total PUFAs, total
n-6 (-6 FAs) fatty acid, and total n-3 (-3) fatty acid, contributed for higher bone mineral density and
reduced risk of fragility fracture.100 Also, omega fatty acids in combination with other antioxidants, such
as resveratrol, can have a major therapeutic role. A recent review collected some of the key studies
involving the health benefits supported by a combination of resveratrol and -3 FAs intake. Many
studies showed that resveratrol, as a potent antioxidant reduces oxidative stress in endoplasmic
reticulum, and proved to have a significantly protective role in most important pathophysiological factors
associated with CVD conditions. Numerous research projects demonstrated the reduction of the risk of
coronary heart disease, hypertension, and stroke, by a combination of resveratrol and -3 fatty acids
derived from fish oils.101
Many studies support the notion that omega-3 fatty acids are essential for a balanced human
diet, and a certain amount of omega-3 is needed in human daily diet. Currently, there is increasing
evidence of the benefits of omega-3 by different medical professional bodies with the stronger evidence
for cardiovascular disease (CVDs). There is a broad consensus among scientists that fish and seafood
are the optimal sources of n-3 FAs and consumption of approximately 2-3 servings per week is
recommended for good health. But it has been noted that the scientific evidence of benefits from n-3
FAs supplementation has diminished over time, probably due to a general increase in seafood
consumption in developed countries, better pharmacological intervention and acute treatment of patients
with CVD diseases.102-104
10. Dietary zinc, iron and selenium supplementation, health benefits/risks
Zinc is essential trace element for normal biological growth, reproduction and immune function.
In addition, Zn is vital for the functionality of more than 300 enzymes, for the stabilization of DNA, and
for gene expression. Zinc deficiency is estimated to be responsible for 4% of global child morbidity and
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mortality. The adult human contains 23 g of zinc (Zn). Conservative estimates suggest that around
25% of the world's population is at risk of zinc deficiency.105 Most of the affected are poor, and rarely
consume foods rich in highly bioavailable zinc, while subsisting on foods that are rich in inhibitors of zinc
absorption and/or contain relatively small amounts of bioavailable zinc. Food choice is a major factor
affecting risk of zinc deficiency. A major challenge that has not been resolved for maximum health
benefit is the proximity of the recommended dietary allowance (RDA) and the reference dose (RfD) for
safe intake of zinc. The current assumed range between safe and unsafe intakes of zinc is relatively
narrow.106
A recent review included data from 21 randomized controlled trials (RCTs) reported in 54 papers
involving over 17,000 women and their babies. The results showed that there was a 14% relative
reduction in preterm birth for zinc compared with placebo. These results appeared in primarily in trials
involving women of low income and this has some relevance in areas of high perinatal mortality. There
was no convincing evidence that Zn supplementation during pregnancy resulted in other useful and
important health benefits. According to the scientists these results reflected poor nutrition in
impoverished areas and the need for a balanced diet than dietary Zn supplements.107
Scientists experimented with Zinc supplementation that may remodel the immune alterations in
elderly leading to healthy ageing. Several zinc trials have been carried out with contradictory data,
perhaps due to incorrect choice of an effective zinc supplementation in old subjects showing subsequent
zinc toxic effects on immunity. Old subjects with specific IL-6 polymorphism were more prone for zinc
supplementation than the entire old population, in whom correct dietary habits with foods containing zinc
(Mediterranean diet) may be sufficient in restoring zinc deficiency and impaired immune response.108
It is well known that Zinc (Zn) and Iron (Fe) are essential minerals often present in similar food
sources. A review analysed the current medical and nutritional literature on Zn and Fe supplementation
and its impact on mood or cognition in pre-menopausal women. 10 RCTs and one non-randomized
controlled trial were found to meet the inclusion criteria. The results showed that 7 studies found
improvements in aspects of mood and cognition after iron supplementation. Iron supplementation
appeared to improve memory and intellectual ability in participants aged between 12 and 55 years of
age regardless of whether the participant was initially iron insufficient or iron-deficient with anaemia.
Also, 3 RTCs provided evidence to suggest a role for Zn supplementation as a treatment for depressive
symptoms. Overall, the current scientific literature indicated a positive effect of improving Zn status on
enhanced cognitive and emotional functioning. However, further study involving well-designed
randomized controlled trials is needed to identify the impact of improving iron and zinc status on mood
and cognition.109
Many children in developing countries have inadequate zinc nutrition. It has been shown that
outline zinc supplementation reduces the risk of respiratory infections and diarrhea, the two leading
causes of morbidity and mortality in young children worldwide. In childhood diarrhea oral zinc also
reduces illness duration. Oral Zn is therefore recommended for the treatment of acute diarrhea in young
children. An updated review showed that the results from the studies that have measured the
therapeutic effect of zinc on acute respiratory infections, however, are conflicting. Also, the results of
therapeutic Zn for childhood malaria are so far not promising.110
Selenium is another very important trace element (micronutrient) incorporated into
selenoproteins that have a wide range of pleiotropic effects, ranging from antioxidant and anti-
inflammatory effects to the production of active thyroid hormone. In the past 10 years, the discovery of
disease-associated polymorphisms in selenoprotein genes has drawn attention to the relevance of
selenoproteins to health. Low selenium status has been associated with increased risk of mortality, poor
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immune function, and cognitive decline. Higher selenium status or selenium supplementation has
antiviral effects, is essential for successful male and female reproduction, and reduces the risk of
autoimmune thyroid disease. Prospective studies have generally shown some benefit of higher selenium
status on the risk of prostate, lung, colorectal, and bladder cancers, but findings from trials have been
mixed, which probably emphasises the fact that supplementation will confer benefit only if intake of a
nutrient is inadequate. Supplementation of people who already have adequate intake with additional
selenium might increase their risk of type-2 diabetes. The crucial factor that needs to be emphasised
with regard to the health effects of selenium is the inextricable U-shaped link with status; whereas
additional selenium intake may benefit people with low status, those with adequate-to-high status might
be affected adversely and should not take selenium supplements.111
Selenium supplementation and cancer has been investigated by various epidemiological
studies. A recent extensive review analysed data from 55 prospective observational studies (including
more than 1,100,000 participants) and 8 RCTs (with a total of 44,743 participants). Although an inverse
association between selenium exposure and the risk of some types of cancer was found in some
observational studies, this cannot be taken as evidence of a causal relation, and these results should be
interpreted with caution. These studies have many limitations, including issues with assessment of
exposure to selenium and to its various chemical forms, heterogeneity, confounding and other biases.
Conflicting results including inverse, null and direct associations have been reported for some cancer
types. RCT studies have yielded inconsistent results, although the most recent studies, characterized
by a low risk of bias, found no beneficial effect on cancer risk, more specifically on risk of prostate
cancer. Some RCTs suggested harmful effects of selenium exposure. The reviewers concluded that
there is no convincing evidence that selenium supplements can prevent cancer in humans.112
Iron deficiency anemia in humans is an important public health issue, especially for infants,
children, and women with menorrhagia. Oral iron supplements are the cheapest, safest, and most
effective treatment. A retrospective study collected for two years 41 patients with iron deficiency anemia
who continuously took oral ferric for over one month and then switched to oral ferrous due to poor
therapeutic effects. The results showed that the mean blood test values for all patients significantly
increased after switching to ferrous iron. This study found that blood test values improved after iron
deficiency anemia female patients who displayed poor therapeutic effects with oral ferric switched to
ferrous. A literature review in the same study showed that the risk for gastrointestinal problems with
ferrous is higher than that with ferric.113
Randomised Control Trials or quasi-randomised trials evaluating the effects of oral preventive
supplementation with daily iron, iron + folic acid or iron + other vitamins and minerals during pregnancy.
The study concluded that iron supplementation reduces the risk of maternal anaemia and iron deficiency
in pregnancy but the positive effect on other maternal and infant outcomes is less clear. Implementation
of iron supplementation recommendations may produce heterogeneous results depending on the
populations' background risk for low birthweight and anaemia, as well as the level of adherence to the
intervention. 114
Recent studies showed that intermittent iron supplementation is a promising strategy in
reducing iron deficiency and iron deficiency anaemia. Also, a small number of studies investigated the
effect of iron interventions on developmental outcomes, such as growth and cognition, and provided
mixed results. Some studies reported that iron intervention increased morbidity and caused
unfavourable shifts in the gut microbial composition along with increases in intestinal inflammation,
particularly in children with a high infectious disease burden. Scientists suggested that that there is a
need for studies in children from low and middle-income populations to provide evidence for the
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beneficial effects of iron interventions on functional outcomes (iron deficiency and anaemia), and to
explore potential mechanisms underlying the negative effects of iron reported in recent trials.115
11. Dietary phytochemicals, herbs, loss of weight and supplements
The global market of Dietary Supplements (DS)       
incredulous claims and very little evidence of health benefits. Dietary supplements involving flavonoids,
polyphenols, herbal therapies (Ginkgo, ginseng, Echinacea, etc), and for reduction of body weight
(chitosan, picolinate, Ephedra sinica, Garcinia cambogia, etc) are claiming beneficial biological effects
without risk of adverse effects.
But the scientific evidence is very different. Numerous studies have shown that although
consumption of dietary phytochemicals such as flavonoids has been suggested to have beneficial
biological effects including the prevention of cancer and heart disease, there is considerable evidence to
suggest that such compounds are not without risk of adverse effects. The risk of adverse effects is likely
increased by the use of pharmacological doses in prevention/treatment and supplement situations and
genetic polymorphisms or drug-drug interactions that increase the bioavailability of test compounds.116
The DS market is full of popular herbal remedies. Scientific studies investigated the efficacy and
safety of ginkgo, St. John's wort, ginseng, echinacea, saw palmetto, and kava. The safety assessments
were based on systematic reviews of RCTs. Although data supported the efficacy of some of these
popular herbal medicinal products, the published evidence suggests that ginkgo is of questionable use
for memory loss and tinnitus but has some effect on dementia and intermittent claudication. St. John's
wort was efficacious for mild to moderate depression, but serious concerns exist about its interactions
with several conventional drugs. Well-conducted clinical trials do not support the efficacy of ginseng to
treat any condition. Echinacea may be helpful in the treatment or prevention of upper respiratory tract
infections, but trial data are not fully convincing. Saw palmetto has been shown in short-term trials to be
efficacious in reducing the symptoms of benign prostatic hyperplasia. Kava is an efficacious short-term
treatment for anxiety. Studies showed that none of these herbal medicines were free of adverse effects.
Because the evidence is incomplete, risk-benefit assessments are not completely reliable, and much
knowledge is still lacking.117
Numerous supplements are used in the global market for body weight reduction without evidence
of effective effects and some of them containing risks. An overall critical review assessed the efficacy by
using 5 systematic reviews and meta-analyses and 25 additional trials. Data on the following dietary
supplements were identified: chitosan, chromium picolinate, Ephedra sinica, Garcinia cambogia,
glucomannan, guar gum, hydroxy-      
yohimbe. The reviewers identified some encouraging data but no evidence beyond a reasonable doubt
that any specific DS was effective for reducing body weight. The only exceptions were for E. sinica and
ephedrine-containing supplements, which have been associated with an increased risk of adverse
events. Reviewers concluded that the evidence for most DS as aids in reducing body weight was not
convincing. None of the reviewed DS can be recommended for over-the-counter use.118
A large study involving086 men and women [Health Professionals Follow-up Study (HPFS),
    ] measured self reported change in
weight over multiple four year time intervals between 1986 and 2011. Results showed that Increased
consumption of most flavonoid (flavonols, flavan-3-ols, anthocyanins, flavonoid polymers) was
inversely associated with weight change over four year time intervals, after adjustment for simultaneous
changes in other lifestyle factors including other aspects of diet, smoking status, and physical activity.
16
Scientists concluded that intake of food rich in flavonoids may contribute to weight maintenance in
adulthood and prevent obesity.119
The use of herbal or alternative medicine as therapeutic supplements for neuropathy diseases
has garnered rising interest in recent years. The Internet is a ubiquitous source of information/market for
these supplements. A study investigated 184 websites, 28% claimed to decrease CKD (chronic kidney
diseases) progression, 60% did not advise to consult a doctor before taking the supplement, and >90%
did not mention any potential drug interaction, disease interaction, or caution in use during pregnancy or
in children. Scientists concluded that nephrologists need to be cognizant of the lack of substantiated
proven benefits of these substances (in internet sites) and of the potential adverse effects in the animal
models that can translate to the patients. Regulation of these products must change to prevent patient
harm and misinformation.120
12. Dietary supplements and prevention of cancer
Dietary supplements are widely used among patients with cancer who perceive them to have
strong anticancer and antioxidant properties. Large-scale, randomized cancer prevention trials have
mainly been negative, with some notable adverse and beneficial effects. These trials showed that -
carotene increase the risk of lung and stomach cancer, vitamin E increase prostate cancer and
colorectal adenoma, and selenium reduced gastric and lung cancer in populations with low selenium
levels but increased rates in those with higher levels. Both -carotene and vitamin E supplementation
increase overall mortality. A recent review examined phase II and III trials that investigated the effects of
multivitamins, antioxidants, vitamin D, and n-3 supplements on outcome and toxicity from cancer
treatments. Although vitamin E and -carotene reduced toxicity from radiotherapy among patients with
head and neck cancer, it has been found to increase recurrence, especially among smokers.
Antioxidants have mixed effects on chemotherapy toxicity, but there are no data on outcome. Vitamin D
deficiency is relatively common among patients with cancer, and ongoing phase III trials are studying
the effect of vitamin D on outcome as well as optimum vitamin D and calcium intakes for bone health.
Docosahexanoic and eicosopentanoic acid supplements have mixed effects on cachexia and are
currently being tested as potential adjuncts to maximize response to chemotherapy. Dietary
supplementation tailored to an individual's background diet, genetics, tumor histology, and treatments
may yield benefits in subsets of patients.121,122
In the last decade numerous studies investigated the anticancer properties for Resveratrol
(antioxidant polyphenol in red wine). Studies in experimental animals showed that resveratrol can
protects against angiogenesis, inflammation, and cancer, but dietary sources of resveratrol are not
enough to have an impact on health. Pre-clinical findings have provided mounting evidence that
resveratrol may confer health benefits and protect against a variety of medical conditions and cancer,
but there is no consistent evidence. Most of the studies that have investigated the effect of resveratrol
administration on patient outcomes have been limited by their sample sizes for diseases, such as
cancer, diabetes, neurodegeneration, CVDs and other age-related ailments. There is an open question
as to resveratrol supplementation for therapeutic anticancer benefits, especially for prostate.123 The
relationship between dietary polyphenols and the prevention of prostate cancer has been examined by a
great number of clinical trials. Although results are sometimes inconsistent and variable, there is a
general agreement that polyphenols hold great promise as chemopreventive agents for the future
management of prostate cancer, including resveratrol. Dietary supplements of polyphenols can act as
key modulators of signaling pathways and affect post-translational modifications and microRNA
expressions.124
17
Dietary supplementation for cancer prevention or for therapeutic intervention (market claims not
consistent with supplements) has become a multibillion-dollar industry all over the world. There is a
widespread belief that nutritional supplements can ward off chronic disease, including cancer, although
there is little to no scientific evidence. To the contrary, there is now evidence that high doses of some
supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry
continue to imply anticancer benefits. Scientists and medical professionals agree that insufficient
government regulation of the marketing of DS products resulted in unsound advice to cancer patients
and consumers. According to the most recent National Health and Nutrition Examination Survey (2003
2006), 50% of the US adult population uses one or more dietary supplements; most of those are
multivitamin and/or multimineral supplements despite the results of observational studies that provide
little evidence that multivitamins reduce cancer risk, and there have been no randomized studies of
multivitamins for cancer prevention.125
13. Conclusion
Scientists and health professionals agree that dietary supplements (DS) can be under certain
conditions beneficial to human health, but should not replace complete and balanced daily meals of
foods. For the last decades informed medical agencies, doctors, pharmacists and nutritionists inform the
consumers that tt of wrong information in the global supplements market. Many DS even in
developed countries managed to escape the safety tests, labeling and health regulations. Scientists in
the USA and Western Europe specializing on nutrition, metabolism and epidemiology reviewed the
evidence for DS supplements and concluded that there was not sufficient evidence to recommend for or
against for the prevention of chronic disease. Results from Randomized Control Trials of DS showed
that the majority are negative for health benefits or for preventing diseases. Self-prescription of DS
should be avoided and patients, older people, pregnant women, young and people with disabilities
should be informed and advised by their doctors or pharmacists for dietary supplementation.
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ΦΑΡΜΑΚΕΤΣΙΚΗ, 28, II:69-92, 2016
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PHARMAKEFTIKI, 28, ΙI:69-92, 2016 ………………... ΑΡΘΡΟ ΕΠΙ΢ΚΟΠΗ΢Η΢/ REVIEW ARTICLE
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            
    Food and Drug Administration (FDA)       
         
 
            

US$    
     
            
  
18
  
          
          ,    
        



         
  (Randomized Control Trials, RCTs) 
   placebo         
 
. 
          
           
  
    Annals of Internal Medicine    ..  
         

            
    
  
          
 
     



-  
 

 e-mail : valavanidis@chem.uoa.gr
 .
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... Taking into account the complexity of the mechanisms and potency of phytoestrogens, it is not known what their effect on a particular organism might be when the recommended doses are exceeded or when they are used simultaneously with other drugs. Many people, without prior consultation with a physician, pharmacist or dietitian, use supplements containing phytoestrogens as a remedy for their ailments, even though the definition of a dietary supplement clearly emphasizes that it should not be used as a treatment, but can only contribute to the improvement in the functioning of the body (11). ...
... Ze względu na złożoność mechanizmów i siłę działania fitoestrogenów, nie wiadomo, jaki będzie ich wpływ na konkretny organizm przy przekraczaniu zalecanych dawek lub stosowaniu ich jednocześnie z innymi lekami. Wiele osób, bez uprzedniej konsultacji z lekarzem, farmaceutą czy dietetykiem stosuje suplementy zawierające fitoestrogeny jako remedium na swoje dolegliwości, mimo iż definicja suplementu diety wyraźnie podkreśla, iż nie służy on do leczenia, a jedynie usprawnia funkcjonowanie organizmu (11). ...
... Dietary supplements may be vitamins, minerals, or herbal products that are known to improve the well-being of humans [1]. is clearly denotes the use of these supplements as an addition to dietary requirements that may not be met by daily meals. ...
... However, under no circumstance should dietary supplements be used as a replacement for daily meals. e United States Food and Drugs Administration also prohibits the indication of dietary supplements as a treatment for diseases or any indication that connotes dietary supplements as primary therapeutic agents [1]. ...
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... Suplemen adalah produk kesehatan yang mengandung satu atau lebih bahan yang bersifat nutrisi suplemen dikemas dalam bentuk kapsul, tablet, serbuk atau cairan yang berfungsi sebagai pelengkap kekurangan gizi dalam tubuh. Suplemen digolongkan sebagai nutraceutical, oleh karena itu suplemen dijual bebas karena untuk memenuhi kebutuhan (Valavanidis, 2016). Suplemen makanan dapat didefinisikan sebagai vitamin, mineral, zat kimia, produk herbal, tumbuhan, asam amino, atau olahan yang dapat dimakan lainnya. ...
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... Generally, dietary supplements have been massively advertised and commercialized as miraculous products that can contribute to many health benefits, and these over-the-counter products have also been widely available in various places, as they can be purchased without a prescription from a healthcare professional [5,6]. Nevertheless, several systematic reviews of randomized control trials have stated that there is still little and inconclusive evidence indicating the significant beneficial health effects of dietary supplements and that irrational use of these products might lead to several health risks [7,8]. In addition, the safety of using dietary supplements is still of concern, as these products may contain active ingredients, which could interact with medications or could contain other nutrients or excessive doses of potentially harmful ingredients and illegal substances that are not marked on the nutrition label [8]. ...
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The use of dietary supplements is prevalent among many groups worldwide. However, few studies have examined their use among government employees. The aim of this cross-sectional study was to determine the association among sociodemographic characteristics, body weight status, and energy intake with dietary supplement use among government employees in Putrajaya, Malaysia. Simple random sampling was used to select a sample of 460 government employees from six ministries in Putrajaya, Malaysia. The data used in this study were collected through anthropometric measurements (height, weight, % body fat, waist and hip circumferences), a self-administered questionnaire (sociodemographic characteristics and dietary supplements use), and an interviewer-administered questionnaire (24-hour dietary recall; fruit and vegetable intake). The results indicated that the prevalence of dietary supplement use was 55.4%, with vitamin C (38.4%) being the most popular type of dietary supplement. Health issues (80.8%) were the most common reason for usage, internet (59.2%) was the main source of information, and pharmacies (71.8%) were the most indicated places to purchase dietary supplements. A multivariate analysis showed that participants who were female, married, had better monthly income, lived within a smaller household size, had a normal body mass index, classified as having unhealthily high body fat percentage, did not skip breakfast, and consumed at least five servings of fruits and vegetables per day were significantly more likely to use dietary supplements. In conclusion, health-conscious groups were more prone to consume dietary supplements, and due to the high prevalence of dietary supplement use, dissemination of accurate scientific information regarding dietary supplements is highly recommended among government employees.
... Imarc (2019), in their latest report stated how the altered eating habits among individuals and their increasingly sedentary lifestyles paved the way for various lifestyle diseases like diabetes, blood pressure, and obesity; the fear of which triggers the market of dietary supplements. Valavanidis (2016) explained how the rising health consciousness, change in the population demographics and growth of urban population acts as the catalyst for the growth of nutraceutical products like mineral supplements. The researcher further stated multi-vitamin supplements to be very popular due to its higher degree of promotion and estimated its market to grow at a pace of 6.5% from 2014 to 2020 globally. ...
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Introduction: Vitamins and micronutrients are essential organic substances in the metabolic processes of living things, and supplementation is only recommended in conditions of nutritional deficits. Objective: To determine the prescription patterns of vitamins and supplements in a group of patients enrolled in the Colombian Health System in 2016. Methodology: This was a cross-sectional study based on a population database. Vitamin-prescribed patients of both sexes and all ages were selected for 3 consecutive months. A database was designed using the dispensing records. SPSS 23.0 was used for the univariate, bivariate and multivariate analyses. A p-value <0.05 was considered statistically significant. Results: In total, 9998 patients receiving vitamin supplementation were identified. A female predominance was observed (n=8341, 83.4%). The mean age was 57.7±18.7 years. The most commonly formulated vitamins and micronutrients were vitamin D (58.0%), calcium (55.0%) and folic acid (25.0%). Overall, 60.8% of patients were prescribed more than one vitamin. The most frequent multiple-nutrient association was between calcium and vitamin D (n=5505); 77.3% received concurrent treatment with other medications to manage comorbidities. The probability of comedication in the multivariate analysis was higher for folic acid (OR:3.10, 95%CI 2.69-3.59), thiamine (OR:2.75, 95%CI:2.15-3.5) and calcium + vitamin D (OR:1.61, 95%CI: 1.42-1.82) and for those individuals older than 65 years (OR:1.24, 95%CI:1.02-1.51). Conclusions: Vitamins are widely used in the Colombian population. The results of this study elucidate the patterns of use of these supplements and offer proposed strategies to the future and to evaluate and minimize prescriptions that are potentially inappropriate or of little therapeutic value. MÉD.UIS. 2020;33(2):41-8.
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Background: There is considerable evidence that many patients concurrently administer dietary supplements with conventional drugs, creating a risk for potential drug-supplement interaction. The aim of this study was to determine the effect of Cellgevity® supplement on selected rat liver cytochrome P450 (CYP) enzymes. Also, we sought to deternine the effect of Cellgevity® on the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Methods: Male Sprague-Dawley (SD) rats were randomly put into 5 groups and administered (per os) either distilled water (negative control), Cellgevity® (3 separate doses) or phenobarbital (positive control). Modulation of liver CYP enzyme activity was evaluated after 30 days of treatment, using probe substrates, spectroscopic and high-performance liquid chromatographic methods. In the pharmacokinetic study, 12 SD rats were divided into 2 groups administered (per os) carbamazepine plus Cellgevity®, or carbamazepine plus normal saline, both over a period of 14 days. Blood samples from rats in the same group were collected after treatment. Serum samples were prepared and pooled together at each specific sampling time point. Levels of carbamazepine were determined using a fluorescence polarization immunoassay. Results: Activities of rat liver CYP1A1/2, CYP2C9 and CYP2D6 were significantly increased by Cellgevity® after 30-day treament. Pharmacokinetic parameters for rats administered carbamazepine with Cellgevity® vis-a-vis carbamazepine with normal saline were as follows: Cmax; 20 μmol/L vs 11 μmol/L, AUC0→24; 347 μmol.h/L vs 170 μmol.h/L, Ke; 0.28 h⁻¹ vs 0.41 h⁻¹, and t1/2; 2.3 h vs 1.7 h, respectively. Conclusions: Cellgevity® increased the activity of rat CYP1A1/2, CYP2C9 and CYP2D6 enzymes, and altered the pharmacokinetics of carbamazepine in rats.
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Objective To examine whether dietary intake of specific flavonoid subclasses (including flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and flavonoid polymers) is associated with weight change over time. Design Three prospective cohort studies. Setting Health professionals in the United States. Participants 124 086 men and women participating in the Health Professionals Follow-up Study (HPFS), Nurses’ Health Study (NHS), and Nurses’ Health Study II (NHS II). Main outcome measure Self reported change in weight over multiple four year time intervals between 1986 and 2011. Results Increased consumption of most flavonoid subclasses, including flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers, was inversely associated with weight change over four year time intervals, after adjustment for simultaneous changes in other lifestyle factors including other aspects of diet, smoking status, and physical activity. In the pooled results, the greatest magnitude of association was observed for anthocyanins (−0.23 (95% confidence interval −0.30 to −0.15) lbs per additional standard deviation/day, 10 mg), flavonoid polymers (−0.18 (−0.28 to −0.08) lbs per additional SD/day, 138 mg), and flavonols (−0.16 (−0.26 to −0.06) lbs per additional SD/day, 7 mg). After additional adjustment for fiber intake, associations remained significant for anthocyanins, proanthocyanidins, and total flavonoid polymers but were attenuated and no longer statistically significant for other subclasses. Conclusions Higher intake of foods rich in flavonols, flavan-3-ols, anthocyanins, and flavonoid polymers may contribute to weight maintenance in adulthood and may help to refine dietary recommendations for the prevention of obesity and its potential consequences.
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The present review aims at summarizing the major therapeutic roles of resveratrol and omega-3 fatty acids (O3FAs) along with their related pathways. This article reviews some of the key studies involving the health benefits of resveratrol and O3FAs. Oxidative stress has been considered as one of the most important pathophysiological factors associated with various cardiovascular disease conditions. Resveratrol, with the potent antioxidant and free radical scavenging properties, has been proven to be a significantly protective compound in restoring the normal cardiac health. A plethora of research also demonstrated the reduction of the risk of coronary heart disease, hypertension, and stroke, and their complications by O3FAs derived from fish and fish oils. This review describes the potential cardioprotective role of resveratrol and O3FAs in ameliorating the endoplasmic reticulum stress.
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Background: Dietary sources of calcium and vitamin D are recommended as a first-line strategy in prevention of osteoporosis-related fractures but their public health and economic impact has never been studied. Methods: We designed a population-based model to forecast the potential health outcomes and medical effectiveness of the daily administration of dairy supplements containing 800 IU of vitamin D and 1 g of calcium in cohorts of subjects, from both genders, aged 50, 60, 70 and 80 years. Annual costs of dairy products were tested at €150, €250 and €350. Results: In total, the daily intake of vitamin-D rich dairy products reduces by 30,376 and 16,105 events the number of osteoporotic fractures in women and men respectively and permits to gain 6605 and 6144 life-years, in women and men respectively. This intervention is cost-effective from 70 years on in the general population and from 60 years on in patients at increased risk of osteoporotic fractures. Conclusion: The recommendation to use dairy products as the preferred source of calcium and vitamin D in aging males and females is supported by public health and health economic analyses.
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Background Dietary supplements are used by more than half of adults, although to our knowledge, the reasons motivating use have not been previously examined in US adults using nationally representative data. The purpose of this analysis was to examine motivations for dietary supplement use, characterize the types of products used for the most commonly reported motivations, and to examine the role of physicians and health care practitioners in guiding choices about dietary supplements. Methods Data from adults (≥20 years; n = 11 956) were examined in the 2007-2010 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional, population-based survey. Results The most commonly reported reasons for using supplements were to “improve” (45%) or “maintain” (33%) overall health. Women used calcium products for “bone health” (36%), whereas men were more likely to report supplement use for “heart health or to lower cholesterol” (18%). Older adults (≥60 years) were more likely than younger individuals to report motivations related to site-specific reasons like heart, bone and joint, and eye health. Only 23% of products were used based on recommendations of a health care provider. Multivitamin-mineral products were the most frequently reported type of supplement taken, followed by calcium and ω-3 or fish oil supplements. Supplement users are more likely to report very good or excellent health, have health insurance, use alcohol moderately, eschew cigarette smoking, and exercise more frequently than nonusers. Conclusions Supplement users reported motivations related to overall health more commonly than for supplementing nutrients from food intakes. Use of supplements was related to more favorable health and lifestyle choices. Less than a quarter of supplements used by adults were recommended by a physician or health care provider.
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Nutrients, Dietary Supplements, and Nutriceuticals: Cost Analysis Versus Clinical Benefits provides the most current, concise, scientific appraisal and economic analysis (costs vs. benefit) of nutritional supplements and bioactive components (nutriceuticals) of foods in improving the quality of life. It fills a much-needed gap to have a single volume provide a synopsis of cost analysis of dietary supplements and nutritional products as well as therapies for treatment and prevention of disease. Chapters include emerging fields of science and important discoveries relating to early stages of new nutriceuticals in cancer prevention, prior to clinical trials. Written by international and national standing leaders in the field, Nutrients, Dietary Supplements, and Nutriceuticals: Cost Analysis Versus Clinical Benefits is essential reading for nutritionists, pharmacologists, health care professionals, research scientists, cancer workers, pathologists, molecular and cellular biochemists, physicians, general practitioners as well as those interested in diet and nutrition in disease resistance via immune regulation.
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Osteoporosis is a global health problem that leads to an increased incidence of fragility fracture. Recent dietary patterns of Western populations include higher than recommended intakes of n-6 (ω-6) polyunsaturated fatty acids (PUFAs) relative to n-3 (ω-3) PUFAs that may result in a chronic state of sterile whole body inflammation. Findings from human bone cell culture experiments have revealed both benefits and detriments to bone-related outcomes depending on the quantity and source of PUFAs. Findings from observational and randomized controlled trials suggest that higher fatty fish intake is strongly linked with reduced risk of fragility fracture. Moreover, human studies largely support a greater intake of total PUFAs, total n-6 (ω-6) fatty acid, and total n-3 (ω-3) fatty acid for higher bone mineral density and reduced risk of fragility fracture. Less consistent evidence has been observed when investigating the role of long chain n-3 (ω-3) PUFAs or the ratio of n-6 (ω-6) PUFAs to n-3 (ω-3) PUFAs. Aspects to consider when interpreting the current literature involve participant characteristics, study duration, diet assessment tools, and the primary outcome measure.
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A collection of current knowledge of phytochemicals and health. Interest in phenolic phytochemicals has increased as scientific studies indicate these compounds exhibit potential health benefits. With contributions from world leaders in this research area, Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology offers an essential survey of the current knowledge on the capacity of specific micronutrients present in ordinary diets to fight disease. The coverage in this resource: Explains the presence and biochemical properties of phenolics present in fruits and vegetables, as well as in foods derived from their plant sources. Provides biochemical explanations on how certain plant phenolics fight cardiovascular and neurodegenerative diseases, cancer, and other widespread pathologies. Focuses on certain phenolics, e.g., flavonoids, stilbenes, and curcuminoids, and provides insights on the biochemical bases used to define their significance in the diet as well as their recommended consumption requirements and toxicity. Appropriate for graduate and upper-level undergraduate courses in human and animal nutrition, basic nutritional biology, physiology, pharmacology, and other health-related disciplines, Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology serves as both an invaluable supplementary classroom text and a self-teaching guide for professionals interested in defining the association between diet and health from classical, alternative, and complementary biomedical perspectives.
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Key messages: Depression in pregnancy and post-partum is common and can have adverse consequences. During pregnancy and lactation, nutritional demand increases. Lack of key nutrients may negatively impact neurotransmission and increase the risk of perinatal depression. We conducted a systematic literature review and present a synthesis of the evidence on whether dietary intake influences perinatal depression. The evidence is still inconclusive, because of both mixed results of studies and a lack of high-quality investigations. Further research is needed using robust, longitudinal measurement of nutritional exposures and depression outcomes, including low-income settings.
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Objective: Iron deficiency anemia is an important public health issue, especially for infants, children, and women with menorrhagia. Oral iron supplements are the cheapest, safest, and most effective treatment. This study compared the therapeutic and side effects of ferrous and ferric in iron deficiency anemia. Methods: This was a retrospective study on data collected between April 2012 and October 2013 for patients with iron deficiency anemia who continuously took oral ferric for over one month and then switched to oral ferrous due to poor therapeutic effects. The exclusion criteria were the use of other oral or injected iron preparations, erythropoietin, or vitamin B12. Results: A total of 41 participants were recruited. The average participant age was 44.76±16.89 years; most participants were females (95.1%; 39/41); the average daily dose of oral ferric (139.02±49.39 mg) was higher than that of ferrous (96.34±23.43 mg). Repeated measures: mixed model analyses were conducted to examine patients’ clinical blood test values. The results showed that the mean blood test values for all patients significantly increased after switching to ferrous (p<0.01, with the exception of mean corpuscular hemoglobin). One patient experienced gastrointestinal discomfort and diarrhea after switching to ferrous. Conclusion: This study found that blood test values improved after iron deficiency anemia female patients who displayed poor therapeutic effects with oral ferric switched to ferrous. Literature review showed that the risk for gastrointestinal problems with ferrous is higher than that with ferric. However, no significant difference was found in this study.
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Background: Dietary supplements, such as herbal or complementary nutritional products and micronutrients (vitamins and minerals), are commonly used in the United States, yet national data on adverse effects are limited. Methods: We used nationally representative surveillance data from 63 emergency departments obtained from 2004 through 2013 to describe visits to U.S. emergency departments because of adverse events related to dietary supplements. Results: On the basis of 3667 cases, we estimated that 23,005 (95% confidence interval [CI], 18,611 to 27,398) emergency department visits per year were attributed to adverse events related to dietary supplements. These visits resulted in an estimated 2154 hospitalizations (95% CI, 1342 to 2967) annually. Such visits frequently involved young adults between the ages of 20 and 34 years (28.0% of visits; 95% CI, 25.1 to 30.8) and unsupervised children (21.2% of visits; 95% CI, 18.4 to 24.0). After the exclusion of unsupervised ingestion of dietary supplements by children, 65.9% (95% CI, 63.2 to 68.5) of emergency department visits for single-supplement-related adverse events involved herbal or complementary nutritional products; 31.8% (95% CI, 29.2 to 34.3) involved micronutrients. Herbal or complementary nutritional products for weight loss (25.5%; 95% CI, 23.1 to 27.9) and increased energy (10.0%; 95% CI, 8.0 to 11.9) were commonly implicated. Weight-loss or energy products caused 71.8% (95% CI, 67.6 to 76.1) of supplement-related adverse events involving palpitations, chest pain, or tachycardia, and 58.0% (95% CI, 52.2 to 63.7) involved persons 20 to 34 years of age. Among adults 65 years of age or older, choking or pill-induced dysphagia or globus caused 37.6% (95% CI, 29.1 to 46.2) of all emergency department visits for supplement-related adverse events; micronutrients were implicated in 83.1% (95% CI, 73.3 to 92.9) of these visits. Conclusions: An estimated 23,000 emergency department visits in the United States every year are attributed to adverse events related to dietary supplements. Such visits commonly involve cardiovascular manifestations from weight-loss or energy products among young adults and swallowing problems, often associated with micronutrients, among older adults. (Funded by the Department of Health and Human Services.).