Nutraceuticals - shedding light on the grey area between pharmaceuticals and food

KEYWORDS:

• Food
• regulation
• food supplements
• nutraceuticals
• pharmaceuticals

1. Nutraceuticals: beyond the diet before the drugs

The term ‘nutraceutical’, originally coined in 1989 by Stephen DeFelice, founder and chairman of the Foundation for Innovation in Medicine (DeFelice, 1989), is a portmanteau of the words ‘nutrition’ (indicating a nourishing food or food component) and ‘pharmaceutical’ (with reference to a drug), the concept of nutraceutical and potential has been described and widely assessed in the following years since 1995 [1]. It identifies a food or part of a food, which can be of vegetal or animal origin, and has a potential pharmaceutical activity. Food is the source of nutrients (macro and micro) for the body metabolism. In some circumstances, however, there is the lack of some of them so to require the addition to the regular diet of food supplements. These last are food-derived products which can compensate and/or can have a beneficial effect on health due to the addition of specific components (minerals, vitamins, etc.) if there is a lack of them in daily diet. Food supplements may not have any proven pharmacological effect. On the opposite, nutraceuticals should have proven health beneficial effect as a requirement [2,3].

Recently, a redefinition of the concept on nutraceuticals has been proposed to differentiate them from food supplements and from pharmaceuticals in a sharp way. In particular, nutraceuticals are defined as: i) for food of vegetal origin, a nutraceutical is the phytocomplex; and ii) for food of animal origin, a nutraceutical is the pool of the secondary metabolites. Both are concentrated and administered in the proper pharmaceutical form. They are capable of providing beneficial health effects, including the prevention and/or the treatment of a disease [3].

Nutraceuticals define hence a new category, which shades the frontier between drugs and food and could be imagined as the evolution of the concept of food supplement.

While the pharmaceuticals must follow specific legislation on efficacy, safety, production, and use in therapy to be authorized and marketed, these rules are not in general followed for food supplements and nutraceuticals.

To mark the difference existing between food supplements and nutraceuticals, a proper starting step could be the identification of an appropriate epidemiological target. While food supplements are addressed to compensate, if any, a lack of micro/macro nutrients in the body, a nutraceutical must have a proven pharmacological effect and rationale to be used in a pathological condition. Nutraceuticals are generally reported to have good safety profile with few unwanted side effects and better bioavailability, even if new studies stress the possible adverse effects of both food supplements and nutraceuticals with reference to interactions with pharmaceuticals and/or food [4]. Their application area ranges from metabolic syndrome and inflammation control to Alzheimer’s disease [5–11]. The adoption of nutraceuticals in daily diet may help to prevent the onset of pathological conditions by possibly delaying or avoiding the need to use pharmaceuticals in subjects who qualify for an alternative non-pharmacological approach to a pathological condition.

Nonetheless, there is lack of clear information, and often the claimed health benefits of food supplements may not be properly substantiated by safety and efficacy information which can induce false expectations and miss the target for a product to be effective as claimed. On the opposite, a growing demand exists for nutraceuticals, and their market is rapidly increasing [12] even if they still seem to reside in the gray area between pharmaceuticals and food, and are experiencing challenges with safety and health claim substantiation due to the lack of regulatory shared system and lack of clinical data substantiating the proposed health claim.

Since a shared definition of nutraceuticals is still missing, nutraceuticals are mostly referred to as pharma-foods, and confused with food supplements, while they could become a powerful toolbox to be used ‘beyond the diet but before the drugs’ to prevent and treat pathological conditions (e.g. dismetabolisms) [13]. It would be strongly advisable to have a proper and unequivocal definition of nutraceuticals and a supra national shared regulation which can allow to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. Nonetheless, it would also be advisable to consider the clinical aspects of any study concerning nutraceuticals as pharma-foods (e.g. in vivo clinical trials) or any possible interactions between food and/or drugs assumed together with nutraceuticals [14,15]. Medical doctor involvement in these studies is a crucial step for proper evaluation of both safety and efficacy assessment.

2. Nutraceuticals: future challenges

The main issue regarding the proper and effective use of nutraceuticals in prevention and therapy is linked to the lack of clinical data substantiating in full their efficacy which prevents the obtainment and use on the label of a health claim. There are some issues: for example, nutraceuticals bioavailability affects their efficacy as disease-preventing agents, and this is another open challenge for further studies. Their oral bioavailability depends mainly on the food composition and structure [13], and only nutraceuticals which reach and distribute to the tissues and organs where they can exert their beneficial health effects are effective. Barriers preventing ingested nutraceuticals from reaching the systemic circulation in an active form, can be indicated in: chemical instability during digestion, poor solubility in fluids, slow absorption from the gastro intestinal tract, and first-pass metabolism [16,17]. Nutraceuticals delivery is a wide-open challenge for producers. Systems currently being studied for labile and poorly permeable hydrophilic nutraceuticals include nanoparticles, intestinal permeation enhancers, and mucolytics [18].

The bioavailability profile of nutraceuticals may be due also to a limited bioaccessibility, poor absorption, or chemical transformation within the gastrointestinal tract. It has been suggested among the others, the use of oil-water emulsions, core-shell (zein-pectin) nanoparticle delivery system [19], nanoencapsulation and/or the use of nanoemulsion [20].

The potential of new delivery systems, and encouraging data are available in the literature (e.g. on possible use of coenzime Q10 in heart failure [21] and of poly unsaturated fatty acids in coronary artery disease) [22]. Current study on potential action of cocoa flavonoids [23] as nutraceutical represents another potential challenge also from a legal point of view. The possible combination of statin with cholesterol lowering nutraceuticals is also a challenge from a regulatory point of view.

Nutraceuticals in fact are actually categorized as food supplements, and the same regulations apply. This causes confusion among consumers and lack of proper information on the market. A shared regulatory framework for nutraceuticals does not exist. As previously mentioned, the key issue is mostly related to the health claim status, and whether a nutraceutical or the phytocomplex itself could be defined ‘a medicinal by function’.

Medicinal products are defined by Directive 2001/83/EC of the European Parliament, which was amended by Directive 2004/27/EC of the Council [24] as ‘any substance or combination of substances presented as having properties for treating or preventing disease in human beings, or any substance or combination of substances that may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis’.

Nutraceuticals require an appropriate description and specific classification. Food supplements and nutraceuticals are both considered to be derived from foodstuffs, which mean that in many cases, the precautionary principle valid for food is applied to food supplements, and the term nutraceutical is often used for products available on the market without proper assessment of their beneficial health effects. This does not address the issue of borderline definitions and classifications between medicinal products, food supplements, and nutraceuticals [25]. In the USA, differently from European regulations where the European Food Safety Authority (EFSA) authorizes a health claim, the US FDA) focuses mainly on safety aspects of food supplements, acknowledges the term nutraceutical, and applies a different set of regulations to them compared to those regarding conventional foods and drugs. The Dietary Supplement Health and Education Act established in 1994 (DSHEA) and the following Food and Drug Administration Modernization Act of 1997 attribute to the manufacturer’s the responsibility to ensure that a nutraceutical is safe before it is put on the market. The manufacturers and/or the stakeholders do not have to register their products with the FDA since there is no need to obtain FDA approval and/or authorization before producing or selling food supplements or nutraceuticals. Health claims and nutrient content claims are enabled on food labeling if authorized based on an authoritative statement from the Academy of Sciences or other federal authorities after notifying the FDA given that any information given is true and not misleading [26,27,28].

3. Concluding remarks

While the definition of a food and of a food supplement is quite understandable as outlined before, the definition of a nutraceutical is still in the gray area between food, food supplements, and pharmaceuticals. Resolving the discrepancies between the different given for definitions of nutraceuticals and their regulatory aspects will be a significant challenge which must be accepted to define and assess the right terms of reference.

The lack of shared regulations regarding nutraceuticals as pharma-foods is needed, and it is of utmost importance to clearly identify their specificity in view of their possible use and utility in the pharmaceutical arena. The current regulatory situation regarding nutraceuticals is far from being satisfactory, and there is the need to open a debate which can lead to a global approach to define for them a specific shared regulatory framework.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.