European Journal of Pharmacology 668 (2011) S2–S9

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European Journal of Pharmacology

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Functional foods and dietary supplements: Products at the interface between pharma
and nutrition
Simone R.B.M. Eussen a, b,⁎, Hans Verhagen a, c, d, Olaf H. Klungel b, Johan Garssen b, Henk van Loveren a, c,
Henk J. van Kranen a, Cathy J.M. Rompelberg a, 1
a
National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands
b
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands
c
Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
d
University of Ulster, Northern Ireland Centre for Food and Health (NICHE), Cromore Road, Coleraine, BT52 1SA, Northern Ireland, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history: It is increasingly recognized that most chronic diseases of concern today are multifactorial in origin. To combat
Accepted 13 July 2011 such diseases and adverse health conditions, a treatment approach where medicines and nutrition
Available online 27 July 2011 complement each other may prove to be the most successful. Within nutrition, apart from (disease-related)
dietetic regimes, an increasing number of functional foods and dietary supplements, each with their own
Keywords:
health claim, are marketed. These food items are considered to be positioned between traditional foods and
Pharma-nutrition
Food-pharma
medicines at the so-called ‘Pharma-Nutrition Interface’. This paper encompasses aspects related to the
Functional food regulatory framework and health claims of functional foods and dietary supplements. The use of functional
Dietary supplement foods or dietary supplements may offer opportunities to reduce health risk factors and risk of diseases, both as
EU regulation monotherapy and in combination with prescription drugs. Nevertheless, the potential caveats of these
Claim products should not be overlooked. These caveats include the increased risk for food-drug interactions due to
the elevated amounts of specific functional ingredients in the diet, and the stimulation of self-medication
potentially resulting in lower adherence to drug therapy. Health technology assessments should be used more
to compare the cost-effectiveness and benefit–risk ratios of drugs, functional foods and dietary supplements,
and to evaluate the added value of functional foods or dietary supplements to drug therapy.
© 2011 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S2
2. Regulatory framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S3
2.1. Safety and efficacy of drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S3
2.2. Safety of food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S3
2.3. Efficacy of food: nutrition and health claims . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S4
2.4. Dietary supplements: regulated as food or drug? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5
3. Opportunities and caveats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5
3.1. Opportunities of functional foods and dietary supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5
3.2. Caveats of functional foods and dietary supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6
4. Health technology assessments of food and drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7

⁎ Corresponding author at: P.O. Box 80082, 3508 TB Utrecht, The Netherlands. 1. Introduction
Tel.: + 31 30 253 6966; fax: + 31 30 253 9166.
E-mail addresses: S.Eussen@uu.nl (S.R.B.M. Eussen), Cathy.Rompelberg@rivm.nl
Since ancient times plants, herbs and other natural products have
(C.J.M. Rompelberg).
1
P.O. Box 1, 3720 BA Bilthoven, The Netherlands. Tel.: + 31 30 274 2387; fax: + 31 30 been used as healing agents. Advances in organic chemistry from the
274 4466. early 19th century have enabled the preparation of numerous synthetic

0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2011.07.008
 S.R.B.M. Eussen et al. / European Journal of Pharmacology 668 (2011) S2–S9
Fig. 1. Pharma-Nutrition Interface.
medicines. Yet, the majority of the medicinal substances available today
have their origin in natural compounds. The best known example is
aspirin (acetylsalicylic acid), originally derived from the bark of the
white willow tree (Leroux, 1830; Mahdi et al., 2006). Other examples
include the immunosuppressive cyclosporines (Borel et al., 1990), the
anthracycline antibiotics (Nadas and Sun, 2006) and the HMG-CoA
reductase inhibitors, commonly known as statins (Endo, 2004).
Traditionally, pharmaceuticals have been used to cure diseases or
to alleviate the symptoms of disease. Nutrition, on the other hand, is
primarily aimed to prevent diseases by providing the body with the
optimal balance of macro- and micronutrients needed for good health.
Due to the emerging knowledge of disease, medicines are now
increasingly being used to lower risk factors, and thereby to prevent
chronic diseases. Prime examples are blood pressure lowering and
blood lipid-lowering agents which reduce the risk of cardiovascular
disease. The appearance of functional foods and dietary supplements
on the market has further blurred the distinction between pharma
and nutrition (Fig. 1). Functional foods are foods that are claimed to
improve health, quality of life or well-being beyond basic nutritional
functions (Henry, 2010; Howlett, 2008; ILSI Europe, 1999; van Kreijl
et al., 2006). Examples of functional foods are margarines enriched
with cholesterol-lowering phytosterols, cereals fortified with soluble
fibres and yoghurts with specific bacterial cultures added. Thus,
functional foods resemble conventional food products in appearance
and are consumed as part of the usual diet. In contrast, dietary
supplements are typically marketed in the form of a capsule, pill,
powder or gel and are not presented for use as a conventional food,
meal or diet. Dietary supplements contain one or more dietary
ingredients (e.g., vitamins, minerals, amino acids, herbs or other
botanicals) and are intended to supplement the diet (http://ods.od.
nih.gov/) (U.S. Food and Drug Administration, 1994; van Kreijl et al.,
2006).
Today's functional foods and dietary supplements are typically
marketed to large (sub)groups of the total population. For example,
phytosterol-enriched functional foods are targeted to all adults with
(moderately) elevated cholesterol levels and products with claimed
pre- and probiotic activity are aimed at general healthy populations.
The recent advances in pharmaco- and nutrigenomics have formed
the basis for developing the concepts of ‘personalized medicine’
(Personalized Medicine Coalition, 2009) and ‘personalized nutrition’
(Kaput, 2008; Kussmann and Fay, 2008). These emerging fields rely
on targeted therapies based on a person's genetic risk profile.
Pharmaceuticals (Caskey, 2010; Pravenec and Kurtz, 2007), as well
as several dietary components (Afman and Müller, 2006), have been
recognized to modulate gene and protein expression and thereby
metabolic pathways, homeostatic regulation, and presumably health
and disease. In addition, genes also contribute largely to different
responses to diet or drug exposure, including interindividual
variations in the occurrence of adverse drug reactions (Friso and
Choi, 2002; Lee et al., 2010).
S3
In the following sections we will first address the regulatory
framework for drug and food safety and efficacy. In particular, we will
focus on functional foods and dietary supplements, and the health
claims related to these food products (Section 2.1 to 2.3). Within the
extensive regulatory framework, some (herbal) dietary supplements
fall in between food and drug regulations, though (Section 2.4).
Subsequently we describe the opportunities for functional foods and
dietary supplements to reduce health risk factors and risk of diseases
(Section 3.1), and discuss potential caveats of these food products
(Section 3.2). Section 4 explains how health technology assessments,
i.e. cost-effectiveness and risk-benefit analyses, can be used to make
evidence-based decisions about which therapy, or combination of
therapies, will result in the most successful and cost-effective
management of health risk factors and chronic diseases. Finally,
conclusions are drawn at the end of this paper (Section 5).
2. Regulatory framework
2.1. Safety and efficacy of drugs
An extensive legal regulatory system is in place for pharmaceutical
products. Already shortly after the thalidomide affair in the 1960s,
national and international regulatory authorities were established to
monitor drug safety (Lisman and Lekkerkerker, 2005). Since 1995, the
European Medicines Agency (EMA) is responsible for the scientific
evaluation and monitoring of the safety and efficacy of pharmaceuticals
in Europe (http://www.ema.europa.eu/ema/index.jsp?curl=/pages/
home/Home_Page.jsp). The agency was set up to reduce disparities in
drug regulation across the different European Member States. Yet, the
majority of the existing pharmaceuticals throughout the European
Member States remain authorized nationally, whereas the majority of
novel medicines are authorized through the European Medicines
Agency. Directive 2001/83/EC requires that all medicinal products are
registered before they are placed on the European market (European
Commission, 2001a). Registration involves standard procedures to
examine the efficacy, safety and quality of the product. In exceptional
circumstances, individual Member States may grant permission for the
availability of pharmaceuticals without market authorization under the
compassionate use program (European Commission, 2001b). This
program makes promising therapies available to select patients with a
seriously debilitating or life-threatening disease when no alternative
authorized treatment exists (European Commission, 2001b). A differ-
ent, simplified registration procedure (‘traditional-use registration’) is
in place regarding the efficacy of traditional herbal medicinal products.
For these medicinal products the provision of data from pre-clinical tests
and clinical trials is not required, as long as their efficacy is ‘plausible on
the basis of longstanding use and experience’ (European Commission,
2004b).
2.2. Safety of food
Food safety has long been a matter of national policy (Szawlowska,
2001). Following the bovine spongiform encephalopathy (BSE) crisis
and other food scares in the 1990s, in January 2000 the European
Commission published a White Paper on Food Safety (European
Commission, 2000a). The Paper outlines a comprehensive range of
actions needed to complement and modernise existing European food
legislation, and led to the introduction of the General Food Law
(Regulation (EC) 178/2002) (European Commission, 2002). This
regulation formed the basis for the establishment of the independent
European Food Safety Authority (EFSA) in 2002. This Authority is
responsible for providing the European Commission with indepen-
dent scientific advice on all matters with a direct or indirect impact on
food safety (http://ec.europa.eu/food/efsa_en.htm). Nowadays, the
European Commission has established a legal framework regulating
the food supplements market, the fortified food market and the
S4 S.R.B.M. Eussen et al. / European Journal of Pharmacology 668 (2011) S2–S9

market for so-called ‘novel foods’ (Schwitters et al., 2007; Verhagen et
al., 2009). The Food Supplements Directive 2002/46/EC specifies
permitted vitamin and mineral substances, and provides maximum
and minimum levels of vitamins and minerals in food supplements.
Regulation (EC) 1925/2006 (Food Fortification Regulation) provides a
positive list of vitamins, minerals and specific other substances (e.g.
herbal extracts) that may be added to foods. When a functional food
contains novel ingredients or is produced by a novel process it may
fall under Regulation (EC) 258/97 (currently under revision (European
Commission, 2008)). This regulation requires that all novel foods or
novel food ingredients, i.e. food (ingredients) without a history of
significant consumption in the European Union prior to 15 May 1997
(European Commission, 1997), undergo a science-based safety
assessment before being placed on the European market.
In the USA, functional foods are regulated as a category of foods and
must meet all provisions for conventional foods as specified in the
Federal Food Drug and Cosmetic Act. Dietary supplement ingredients
sold in the USA before implementation of the Dietary Supplement Health
and Education Act (DSHEA) on October 15, 1994 are considered old
dietary ingredients and are presumed to be safe, whereas dietary
ingredients marketed after October 15, 1994 are new ingredients
requiring pre-market review of safety by the Food and Drug Adminis-
tration (Taylor, 2004; U.S. Food and Drug Administration, 2009).
Unlike the European situation where food and drug safety are
regulated by distinct agencies, in the USA the U.S. Food and Drug
Administration is responsible for both drug regulation and food safety.
2.3. Efficacy of food: nutrition and health claims
Dietary supplements and functional foods are meant to benefit
health. Consequently, such food products typically contain claims on
their label stating their benefits. In order to harmonize those claims at
the European level, in December 2006 the European Union published
Regulation No 1924/2006 on nutrition and health claims made on
foods (European Commission, 2006). This regulation distinguishes
two categories of claims: nutrition claims and health claims. Nutrition
claims are claims that state, suggest or imply that a food has particular
nutritional properties. Such claims may, e.g. state that a product
contains calcium, or is low in salt or sugar. Health claims are
statements that imply that a relationship exists between a food
product and a health condition. Examples are general function claims
(Article 13(5) claims), reduction of disease risk claims (Article 14(1)
(a) claims) and claims referring to the growth and development of
children (Article 14(1)(b) claims) (Verhagen et al., 2010). The
European Food Safety Authority evaluates the scientific data related
to food and food ingredients that contain a nutrition or health claim
into an opinion which is put forward to the European Commission for
approval and authorization (see Table 1 for an overview of authorized
health claims). In the European Union medical claims, i.e. claims for
the prevention, treatment or cure of human disease, are reserved for
medical products (European Commission, 2000b). For example, an
authorized health claim states that ‘Phytostanol/-sterol esters have
been shown to lower/reduce blood cholesterol. High cholesterol is a risk
factor in the development of coronary heart disease’ (EFSA, 2009a;
European Commission, 2009a, 2010a). This does not explicitly claim
that phytostanol and phytosterol esters reduce the risk of coronary
heart disease, although this assumption may easily be made by most
consumers (Katan and de Roos, 2003). Thus, the European Union
differentiates between ‘reduction of disease risk factor’ and ‘preven-
tion’ to acknowledge that diet and certain foods can make important
contributions to maintain health and manage disease risk factors, but
they may not bear a claim that they can prevent disease (European

Table 1
Health claims authorized by the European Commission (March 2010) divided into general functional claims (Table 1a), reduction of disease risk claims (Table 1b) and claims
referring to the growth and development of children (Table 1c) (European Commission, 2011).

Panel a. Function claim (Article 13(5))

Substance, nutrient, food Claim European Commission Decision EFSA opinion

reference

Water-soluble tomato Water-Soluble Tomato Concentrate (WSTC) I and II No 2009/980/EU (European Commission, 2009c) (EFSA, 2009e,
concentrate helps maintain normal platelet aggregation, which 2010b)
(WSTC I and II) contributes to a healthy blood flow

Panel b. Reduction of a disease risk claim (Article 14(1)(a))

Substance, nutrient, food Claim European Commission Regulation EFSA opinion

reference

Plant sterols/plant stanol
esters
Chewing gum sweetened
with 100% xylitol
Plant sterols and plant stanol esters have been shown to lower/ No 384/2010 (European Commission, 2010a) No 983/2009 (EFSA, 2008a,b,
reduce blood cholesterol. High cholesterol is a risk factor in the (European Commission, 2009a) 2009a,b)
development of coronary heart disease.
Chewing gum sweetened with 100% xylitol has been shown to No 1024/2009 (European Commission, 2009b) (EFSA, 2008c)
reduce dental plaque. High content/level of dental plaque is a
risk factor in the development of caries in children

Panel c. Claims referring to the growth and development of children (Article 14(1)(b))

Substance, nutrient, food Claim European Commission Regulation EFSA opinion

reference

α-linolenic acid & linoleic acid, Essential fatty acids are needed for normal growth and No 983/2009 (European Commission, 2009a) (EFSA, 2008d)
essential fatty acids development of children.
Calcium Calcium is needed for normal growth and development No 983/2009 (European Commission, 2009a) (EFSA, 2008e,f)
of bone in children.
Vitamin D Vitamin D is needed for normal growth and development No 983/2009 (European Commission, 2009a) (EFSA, 2008e,g)
of bone in children.
Phosphorus Phosphorus is needed for the normal growth and No 1024/2009 (European Commission, 2009b) (EFSA, 2008h)
development of bone in children.
Iodine Iodine contributes to the normal growth of children No 957/2010 (European Commission, 2010b) (EFSA, 2009c)
Iron Iron contributes to normal cognitive development of children No 957/2010 (European Commission, 2010b) (EFSA, 2009d)
Protein Protein is needed for normal growth and development No 983/2009 (European Commission, 2009a) (EFSA, 2008i)
of bone in children.

EFSA; European Food Safety Authority.

 S.R.B.M. Eussen et al. / European Journal of Pharmacology 668 (2011) S2–S9 S5

Commission, 2003). Also in the United States, medical claims on foods
and dietary supplements with regard to diagnosis, treatment, curing
or prevention of specific diseases or classes of diseases are not allowed
(U.S. Food and Drug Administration, 2005).
2.4. Dietary supplements: regulated as food or drug?
Herbs and botanicals are often proposed as functional ingredients
in functional foods and dietary supplements. Also medicines fre-
quently contain ingredients derived from plant material. A product
containing herbs or botanicals will be considered a medicinal product
when presented as having properties for treating or preventing
disease in humans, or when it may be used in or is administered to
humans either with a view to restore, correct or modify physiological
functions by exerting a pharmacological, immunological or metabolic
action, or to make a medical diagnosis (European Commission,
2004a). It is the competence and responsibility of the Member States
to decide, on a case-by-case basis, whether an herbal or botanical
product falls within the definition of a medicinal product. This may
lead to a situation in which a product containing exactly the same
bioactive ingredients and in the same dosage is considered a dietary
supplement in some European Member States, but is registered as a
medicine in others. Since the way of presentation of a product and its
anticipated pharmacological, immunological or metabolic action
determine its classification as food or drug it is also possible that
herbs and botanicals are exploited both as a dietary supplement as
well as a medicine within a Member State, depending on dosage and
form. E.g., in the Netherlands, the herbals Ginkgo biloba, Valerian and
St. John's Wort are sold both as food and as drugs.
The distinction between a food item and a medicine is of great
significance for legal practice, since medicines are more tightly
regulated than foods. The recognized therapeutic active level of
substances may be used as a cut-off point to differentiate between a
food item and a medicine (Coppens et al., 2006a). Products with a
recommended daily intake level that is higher than this cut-off point
would be classified as a medicinal product, whereas products with a
recommended daily dosage that is lower than this cut-off point would
be regarded as a dietary supplement. This is in agreement with the
view taken by the European Court of Justice. According to the Court,
the medicines legislation only applies to a product if the product at the
recommended dosage is capable of modifying human physiological
functions by exerting a pharmacological, immunological or metabolic
action (Baeyens and Goffin, 2009). In the case of Hecht-Pharma, red
rice capsules were judged to be classified as a food agent. Although the
capsules contained monacolin K, which is identical to the prescription
drug lovastatin, the recommended daily dosage (1.33-4 mg/day) was
lower than what is considered effective for lovastatin (20–80 mg/day)
(Bradford et al., 1994). Nevertheless, differences in the production
process, auxiliary agents and ratio of active and auxiliary ingredients
between food products and medicines may contribute to differences
in effectiveness.
3. Opportunities and caveats
3.1. Opportunities of functional foods and dietary supplements
Functional foods or dietary supplements, i.e. those that carry
substantiated health claims, can be helpful in reducing health risk
factors and may thereby contribute to prevent chronic diseases. They
are generally intended to be used by two categories of consumers. The
first category comprises persons with modestly elevated risk factors
who can take functional foods or dietary supplements as part of a
healthy lifestyle, or to compensate for an unhealthy one. However,
persons in this first category will often be unaware of their increased
risk (de Jong et al., 2007). The second category comprises persons that
are eligible for drug therapy in order to reduce a particular risk factor.
They can take functional foods or dietary supplements as add-on to
their therapy. This might be especially beneficial for patients who do
not achieve optimal treatment goals with drug monotherapy.
Examples are phytosterol/-stanol-enriched products in addition to
statin therapy for the prevention of cardiovascular disease (EFSA,
2008a,b), calcium-fortified foods or drinks in addition to hormone
replacement therapy for the prevention/minimization of osteoporosis
(EFSA, 2010c) and products containing the long-chain ω-3 polyun-
saturated fatty acids, eicosapentaenoic acid (EPA) or docosahexaenoic
acid (DHA) in addition to antihypertensive agents to reduce blood
pressure (EFSA, 2009f). Thus, functional foods and dietary supple-
ments are not meant to replace drug therapy, since they cannot equal
the health effects of pharmaceuticals. However, persons who
consistently use the food products may be able to lower the dose of

Table 2
Clinically important food-drug interactions.

Substance, nutrient, food Drug(s) Possible mechanism Result of interaction

Grapefruit (Dahan and Altman, 2004;
Ulbricht et al., 2008)
St. John's wort (Borrelli and Izzo,
2009; Ulbricht et al., 2008)
Vitamin K (Rohde et al., 2007)
Soluble dietary fibre, e.g. guar gum and
β-glucan (Brown et al., 1978; Huupponen et al.,
1984; Richter et al., 1991)
Calcium (Maton and Burton, 1999; Neuhofel et al., Antibiotics, e.g. quinolones and tetracyclines, Interfering with drug absorption due to the
2002; Schneyer, 1998; Wallace et al., 2003)
Ginkgo (Abad et al., 2010; Ulbricht et al., 2008) Anticoagulant drugs, e.g. warfarin, and
Allicin-containing garlic (Colalto, 2010)
CYP3A4 substrates, e.g. some benzodiazepines,
calcium channel antagonists, statins, and
cyclosporine
CYP3A4 and/or P-glycoprotein substrates, e.g.
some anticancer drugs, antiretroviral drugs,
oral contraceptives, and cyclosporine
Anticoagulant drugs, e.g. warfarin, and
antiplatelet drugs, e.g. aspirin
Digoxin, some statins
and levothyroxine
antiplatelet drugs, e.g. aspirin
CYP3A4, CYP2E1 and P-glycoprotein substrates, Induction of P-glycoprotein and CYP3A4 by
e.g. some anaesthetics, calcium channel
blockers, antiretroviral drugs
Inhibition of intestinal CYP3A4 by grapefruit
Induction of CYP3A4 and P-glycoprotein by St.
John's wort
Direct antagonism by vitamin K content
in food
Interfering with drug absorption due to
binding of the drug to fibre or forming
an unstirred
water layer in intestinal lumen
formation of insoluble complexes between
the drug and calcium
Decreased platelet aggregation due to
interactions with platelet-activating factor
and collagen
allicin-containing garlic
Increased bioavailability and
peak levels of CYP3A4
substrates
Decreased activity of CYP3A4
substrates
Decreased drug effectiveness,
decreased International
Normalised Ratio (INR)
Decreased drug effectiveness
Decreased drug effectiveness
Increased risk of bleeding
Decreased activity of CYP3A4
substrates
S6 S.R.B.M. Eussen et al. / European Journal of Pharmacology 668 (2011) S2–S9
medicine needed to control risk factors. Since side effects of drugs are
often correlated to higher doses, lowering the dose of the drug may
consequently lead to less drug-associated side effects (Eussen et al.,
2010a).
3.2. Caveats of functional foods and dietary supplements
Persons who use functional foods or dietary supplements may be
able to lower the dose of their prescribed drug without decreasing the
therapeutic effect. Nonetheless, persons should only lower the drug
dose after consulting a doctor or pharmacist. This immediately reveals
one of the caveats of functional foods and dietary supplements: the
stimulation of self-medication. In a recent study performed by
Alevizos et al. (2007), almost 90% of the patients who acknowledged
to have heard of phytosterols declared that they were willing to
switch statin therapy with phytosterol/-stanol-enriched products.
Moreover, in a retrospective study it has been observed that patients
who use margarines enriched with phytosterols/-stanols in addition
to their prescribed statins were more likely to discontinue drug
therapy (Eussen et al., 2010b), thereby increasing rather than
decreasing their disease status. This underscores the importance of
thorough communication between patients and their health care
providers about combination therapies in order to urge the patient
not to take functional foods as replacement for their prescribed
medication.
Even if patients use their medicines and functional foods or dietary
supplements as intended, the combined intake may have caveats. Due
to the elevated amounts of specific functional ingredients in the diet,
there is an increased risk for food-drug interactions (see Table 2 for
important interactions). For example, functional foods enriched with
water-soluble dietary fibres, e.g. guar gum or β-glucan, might
decrease the intestinal absorption, and thereby the cholesterol-
lowering effects, of statins (Richter et al., 1991; Eussen et al., 2011).
St. John's wort might diminish the clinical effectiveness of medicines
which are substrates of cytochrome P450 3A4 (Markowitz et al., 2003)
and dietary supplements rich in vitamin K might decrease the
anticoagulant effects of oral anticoagulants (Booth and Centurelli,
1999; Franco et al., 2004). It should be noted, however, that also non-
supplemented intake levels of certain food products, e.g., grapefruit
(juice), can give raise to a food-drug interaction. Additionally,
interactions between drugs in multidrug regimens are more common
and possibly more serious than food-drug interactions (Cannon, 2008;
Scheen, 2007). Nevertheless, whereas in most pharmacies drug
prescriptions are computer-checked for drug-drug interactions,
most pharmacists do not inquire about patients' use of functional
foods or dietary supplements.
The European Commission requests that all adverse drug reactions
and drug-drug interactions are reported to the Union Pharmacov-
igilance database (http://eudravigilance.ema.europa.eu/human/
index.asp). Moreover, post-authorization safety studies on medicines
are required to ensure adequate ongoing pharmacovigilance moni-
toring (European Commission, 2001a). In contrast, there is currently
no post-market monitoring system for functional foods or dietary
supplements that deals with adverse effects after market-launch. Such
a monitoring system may provide the means to evaluate the (long-
term) exposure and safety under customary conditions of use, such as
overconsumption of specific nutrients, adverse effects in potential risk
groups, unforeseen long-term health effects and interaction effects
with nutrients and/or drugs, and as such has been proposed for novel
foods (de Jong et al., 2008; Hepburn et al., 2008).
4. Health technology assessments of food and drugs
The aging of the population together with the rising health care
costs underline the need to consider the cost-effectiveness of a
treatment. It has been suggested that functional foods and dietary
supplements, as part of healthy eating habits, can have a substantial
effect on health care costs (Milner, 2000). Although cost-effectiveness
assessments for pharmaceuticals are being used increasingly (Taylor
et al., 2004), the cost-effectiveness of the use of functional foods or
dietary supplements remains largely unexamined (Kotilainen et al.,
2006). Moreover, to help policy-makers in making reimbursement
decisions, comparative cost-effectiveness analyses of drugs v. func-
tional foods/dietary supplements in persons with a modestly elevated
risk profile are indicated. Comparing the cost-effectiveness of drugs
plus functional foods/dietary supplements v. drug therapy alone can
be useful in assessing the additive value of a functional food or dietary
supplement in patients with a high risk profile.
Besides the importance of considering the cost-effectiveness of
health care interventions, regulators also focus on their benefit–risk
profile. The European Commission requires manufactures of pharma-
ceuticals to supply the European Medicines Agency with all information
relevant for the evaluation of the benefits and risks related to a medical
product. When therapeutic alternatives are available, one should
perform a comparative benefit–risk assessment (European Commission,
2001a; Garattini, 2010). So far, no benefit–risk assessment is required
for the approval and market introduction of (novel) functional foods or
dietary supplements (Tijhuis et al., Epub ahead of print). Nonetheless,
potential health benefits of these products are currently being assessed
under Regulation (EC) 1924/2006 (Section 2.3.), and evaluating food
safety is an established field of research (Section 2.2.) (Coppens et al.,
2006b; European Commission, 2000a). The concept of integrated
benefit–risk assessments of food (products) and nutrition is new
(Fransen et al., 2010; Hoekstra et al., 2010; Pascal, 2009). It envisages
expressing both benefits and risks in similar units, e.g., quality- or
disability-adjusted-life-years, thereby permitting direct comparisons of
adverse and beneficial effects. The European Food Safety Authority has
recently developed guidance for performing benefit–risk assessment of
foods (EFSA, 2010a). This guidance is applicable to all foods, but might
be especially appropriate for (novel) functional foods or dietary
supplements that may be beneficial to health, but may also cause
health risks due to the over- or underconsumption of specific nutrients,
unforeseen adverse health effects or long-term effects, and interactions
(Section 3.2.). Due to the absence of a history of safe use, novel
functional foods and dietary supplements may be more frequently
related to adverse health effects. Phytosterol-enriched products, for
example, are effective in reducing total and LDL cholesterol levels, but
have been associated with a reduction in β-carotene levels (Katan et al.,
2003). Moreover, the increased serum phytosterol concentration might
contribute to a higher atherosclerotic risk (Patel and Thompson, 2006).
The changes in dietary intake level after the introduction of a (novel)
functional food or dietary supplement provide for assessing a benefit–
risk balance both before and after market introduction.
Several major European initiatives are currently ongoing in the
area of benefit–risk assessment of foods, including BEPRARIBEAN
(http://en.opasnet.org/w/Bepraribean), BRAFO (http://www.ilsi.org/
europe/pages/brafo.aspx) and PLANTLIBRA (http://cordis.europa.eu/
fp7/projects_en.html). The BEPRARIBEAN (Best Practices in Risk
Benefit Analysis) project aims to push forth the area of benefit–risk
analysis for foods by approaching benefit–risk analysis for food and
nutrition from perspectives and experience in other areas, i.e.
medicines, food microbiology, environmental health, economic and
marketing-finance and consumer perception. In the BRAFO (Benefit–
risk Analysis for Foods) project a tiered (‘stepwise’) approach for
performing a benefit–risk assessment of foods is established. The
approach consists of four tiers, including the individual assessment of
benefits and risks and a qualitative and quantitative integration of
benefits and risks (Hoekstra et al., 2010). PLANTLIBRA (PLANT food
supplements: Levels of Intake, Benefit and Risk Assessment) focuses
on the safe use of food supplements containing plants or herbal
extracts by collecting food supplement intake data and developing
methodologies for benefit and risk assessment.
 S.R.B.M. Eussen et al. / European Journal of Pharmacology 668 (2011) S2–S9
5. Conclusion
Most chronic diseases of concern today are multifactorial in origin.
For control, an approach in which medicines and nutrition are
considered together and complement each other may result in the
most successful and cost-effective management of health risk factors
and chronic diseases. Functional foods and dietary supplements may
become important players at the interface between pharma and
nutrition, and merit attention from both a public health and a
marketing perspective. The attention of the European Union and USA
regarding functional foods and dietary supplements has been
principally directed to food safety and (claims of) efficacy, and most
of the research focuses on these two areas. Currently little is known
about the opportunities and caveats of functional foods and dietary
supplements under customary conditions of use. Relevant issues for
further research comprise the beneficial and harmful effects of the
combined use of functional foods/dietary supplements and medicines,
the stimulation of self-medication with the use of functional foods and
dietary supplements, and the long-term safety of these products. A
post-launch monitoring system assessing the effectiveness and safety
of a food product after it has been placed on the market may be
valuable in this respect. Health technology assessment is a useful tool
to make evidence-based (reimbursement) decisions about which
therapy, or combination of therapies, provides the most favourable
benefit–risk and cost-effectiveness ratio.
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