FOOD SUPPLEMENTS
OF BOTANICAL ORIGIN:
A MULTIDISCIPLINARY
APPROACH TO QUALITY.
The case of turmeric.

Milan,
29th January 2020

[ Consensus Paper

with the endorsement ofwith the endorsement of

INDEXINTRODUCTION
AUTHORSOBJECTIVES AND METHODSCONSENSUS PAPER• What are food supplements of botanical origin?
• Quality, safety and efficacy: a clarification• How to recognise the quality of a botanical food supplement­­­– Quality of the raw material– Control of the supply chain– Quality of the manufacturing processes• How to recognise the efficacy of a botanical food supplement– Availability and reliability of specific preclinical and clinical studies on the ingredient– Pharmacokinetic results– Evidence of clinical studies on healthy physiological activities• Interaction: an important aspect of safety

FOCUS ON THE CASE OF TURMERIC• The plant and its active components• Functioning at cell level• Physiological and side effects• Quality• Safety• Efficacy

CONCLUSIONSREFERENCES AND BIBLIOGRAPHY

ABSTRACTThe botanical supplements sector comprises a huge range of products which varysignificantly from one to another, not least for different degrees of attention andtransparency given to quality and safety. This is why for doctors, pharmacists andconsumers alike, quality should be a defining criterion in the choice of supplement
and an essential requirement for information and transparency.
The need for clarification underlies the establishment of the Advisory Board on
Quality in Food Supplements of Botanic Origin, a multidisciplinary panel of
Italian and international experts dedicated precisely to this topic.
Deliberations on the part of the experts on this Board have led to the draft of the firstConsensus Paper: Food Supplements of Botanical Origin: a Multidisciplinary
Approach to Quality, a document that addresses the issues of quality, efficacy
and safety of botanicals based on scientific evidence and clinical experience.
Turmeric is the the special focus of the Consensus Paper, which offers scientificevidence about the quality, efficacy and safety of one of the most studied andwidely consumed botanical extracts in the world.

INTRODUCTION

According to a report on the social value of the food supplement, published by
the Italian social Studies Institute Censis in 20191, 32 million Italians takefood supplements, of which 18.7 million are regular users. Product consumption
cuts across gender, age, schooling, location and economic condition, and can be
attributed to recognition of their contribution to healthcare.
The Censis Report also highlights two important challenges for the foodsupplement sector:• to provide safe, high quality products, which match the growing expectations of
the populace by drawing on the best knowhow in the field;• to create effective authenticated communication, designed to convey expert
knowledge and medical opinion.
In a sector that includes a very large quantity of very different products not leastfor different degrees of attention and transparency given to quality and safety,
quality is decisive as a criterion of choice for doctors, pharmacists and consumers,
and an essential requirement for correct transparent information.

What do we understand by quality supplements?
What elements allow us to evaluate the quality, safety
and efficacy of the products?
What are the risks of “do it yourself”?
What are the criteria for the correct use of food supplements?
How should proper information be provided?

To clarify these issues and provide common guidelines, supported by rigorous
scientific evidence and clinical experience, the Quality Supplements Advisory Board
has been set up; a multidisciplinary panel of Italian and international experts todeal with botanical supplements.
This Consensus Paper is the first result of the work of the Advisory Board. Its
objective is to address general aspects relating to the quality of botanicalsupplements. There will be deeper exploration in subsequent publications of
the specificities of different plant extracts used in nutraceuticals2. The in-depth
analysis which is the main focus of this first Consensus Paper is related to thewidely used ingredient turmeric; according to IQVIA data, 4.9 million packs ofsupplements containing turmeric were sold in Italy from July 2018 to June 20198.
The Consensus Paper: Food Supplements of Botanical Origin: a Multidisciplinary
Approach to Quality has received the backing of the Italian Society of
Nutraceuticals – (SINut) (an independent non-profit association which undertakes
to develop, encourage and promote nutraceutical research). The scientific value of thePaper is recognised and deemed consistent with the objectives of the association.
The Advisory Board was created on the initiative of Indena, a leading company inthe production of quality botanical ingredients and supplements, and of Scharper, apharmaceutical company also with a history of development and marketing of foodsupplements promoted exclusively to the medical profession.

AUTHORS•

Dr. Pietro Allegrini - R&D Director, Indena SpA•

Prof. Giovanni Appendino - Professor of Organic Chemistry, Faculty of Pharmacy,
University of Eastern Piedmont, - Indena Scientific Advisor•

Prof. Arrigo F.G. Cicero - Associate Professor, Food and Dietetic Sciences,
Department of Medical Science and Surgery, Sant’Orsola Malpighi University
Hospital in Bologna•

Dr. Alessandro Colletti - Department of Drug Science and Technology Universityof Turin; Regional Officer for the Italian Nutraceutical Society (SINUT) andNational Secretary of the Italian Society of Nutraceutical Formulators (SIFNut)•

Prof. Diego Fornasari - Associate Professor of Pharmacology, Departmentof Medical Biotechnology and Translational Medicine University of Milan•

Dr. Parris M. Kidd - Independent Biomedical Consultant, Pinole, CA, USA•

Dr. Ernesto Marco Martinelli - Group Quality Director, Indena SpA•

Dr. Giovanni Musso - Gradenigo Humanitas Hospital, Turin•Dr.ssa Antonella Riva - R&D, Product Research Manager, Indena SpA•

Prof.ssa Mariangela Rondanelli - Associate Professor of Dietary Sciences andTechniques, Operations Manager, Metabolic Rehabilitation Unit, Director of the
School of Specialization in Food Science, Department of Public Health, Faculty of
Medicine and Surgery, University of Pavia.

OBJECTIVES
AND METHODSThe Consensus Paper: Food Supplements of Botanical Origin: a Multidisciplinary
Approach to Quality aims to make available to doctors, pharmacists, consumers,
and the media, a scientifically authoritative source that clarifies the issues of quality,
safety and efficacy of supplements of botanical origin, helping these interlocutors toorient themselves in the vast and varied panorama of food supplements.
The authors of this Consensus Paper, who make up the Advisory Board on quality
supplements, are experts with different specializations chosen from the leading
authorities on botanical extracts and in particular on turmeric, which is the focus of
this document.
Careful analysis of scientific literature and the comparison of clinical practiceexperiences were the basis of the joint work that led the group of experts to formulate
the indications and recommendations contained in this document.

THE CONSENSUS
PAPER

WHAT ARE FOOD SUPPLEMENTS OF BOTANICAL ORIGIN?
The European Directive 2002/46 / EC of 10th June 2002, ratified in Italian Law by
Legislative Decree n°169 of 21st May 2004, defines food supplements as follows:“food products intended to supplement the common diet and which constitutea concentrated source of nutrients, such as vitamins and minerals, or of othersubstances having a nutritional or physiological effect, in particular, but not
exclusively, amino acids, essential fatty acids, fibre and extracts of vegetable
origin, whether single or multi-component, in pre-dosed forms, such as capsules,
tablets, pills, chewing gums and the like, sachet powders, liquids contained inampoules, dropper bottles and other similar forms of liquids and powders in premeasured forms.”
In botanical supplements, the active ingredients are made up of substances andpreparations from a plant base (botanicals), and related derivative preparations.
The use of botanicals in food supplements is currently regulated in Italy by the
Ministerial Decree of 10th August 2018, which also contains plants in the BELFRIT
list, drawn up by the relevant authorities in Belgium and France3.

QUALITY, SAFETY AND EFFECTIVENESS: A CLARIFICATIONHOW TO RECOGNISE THE QUALITY OF A BOTANICAL FOOD SUPPLEMENT

The quality, safety and efficacy of a supplement are not concepts which may besuperimposed:

The quality of botanical supplements is expressed by specific characteristics,
which those who prescribe or recommend the products (doctors and pharmacists)and consumers must be able to verify:• quality is determined by the characteristics of the raw material, the supply chain, thetechnologies and processes used for the processing of the ingredients, the controlson the raw material (botanical ingredients) and on the finished product;•• safety is primarily linked to the verification of the absence of potential contaminants

typical of products of plant origin (eg pesticides, mycotoxins, toxic metals etc.), an
aspect that pertains to quality, but also to the specific conditions of the organismthat assumes the supplement, the dosage and the methods of intake and the possible
interactions with other active ingredients, be they natural or synthetic. Therefore, itis essential to carry out preclinical toxicological studies to guarantee the use of the
botanical ingredient. However, a quality supplement can have different safety profiles
in different subjects and for this reason it is advisable that the intake of botanicalsupplements is preferably recommended and guided by the doctor or pharmacist;•• efficacy is understood to be the ability of a supplement, through its ingredients, tostrengthen physiological processes: supplements containing the same ingredient of
natural origin can have different effectiveness depending on the formulation, which forexample modifies its solubility.

It is clear therefore that the quality, safety and efficacy, as described, are essential
requirements for a supplement to be deemed as being of “quality”.

1. quality of the raw material:
I. identification of the plant (at least its genus and species): the plant fromwhich the ingredient derives must be identified with certainty, throughspecific protocol and analyses, such as botanical checks, chromatographic
profiles, or DNA analysis;
II. purification of the botanical extract: if the plant contains notoriously
toxic or allergenic substances such as ginkgolic acids in the leaves ofGinkgo biloba, or unwanted substances such as simple sugars, it is importantto remove these components and obtain an extract deemed purified;
III. standardization is a process of combining different lots to ensure that the
botanical extract always has the same composition of constituents in orderto reduce the natural variability present at the outset in the plant material aswell as the same titration (i.e. the concentration of the characteristic
chemical class);

2. control of the supply chain:
I. suppliers should be accredited on the basis of rigorous criteria of quality,
sustainability and traceability;
II. GAPC guidelines for good agricultural and harvesting practices should be
implemented in the supply chain;
III. the need for high quality raw materials should be reconciled with theprinciples of biodiversity and sustainability indicated by international conventions
and standards such as the Convention on Biological Diversity (CBD);
IV. the entire supply chain should be under continuous control from cultivation
which is constantly monitored by agronomists and botanists, up to the deliveryof the raw material to the production sites;
3. quality of the manufacturing processes:
I. technologically advanced and safe production plants for both raw materials
and operators;
II. processes compliant with production standards and regulations such as
Good Manufacturing Practices (GMP) and the Hazard Analysis Critical Control
Points manual (HACCP);
III. use of high-quality, precisely defined excipients to optimize the effectivenessof the active ingredient;
IV. meticulous inspection of the finished product.
Ready access to information on the characteristics outlined above would allow
assessment of the actual quality of the products and to make an informed choice
on botanical supplements. The authors of this Consensus Paper therefore hopethat the market will increasingly go in the direction of real transparency, and aim
to serve prescribers and consumers alike.

HOW TO RECOGNISE THE QUALITY OF A BOTANICAL FOOD SUPPLEMENT
Current legislation on botanical supplements does not require evidence of efficacy
based on scientific studies.
Despite this, there are products of botanical origin whose effectiveness isdemonstrated by rigorous preclinical and clinical studies and conducted withmethods similar to those required for drugs4.
The effectiveness of a supplement of botanical origin with respect to thephysiological function it claims to have is therefore verifiable through:1. availability and reliability of specific preclinical and clinical studies
on the ingredientI. the number and reproducibility of studies;II. reliability of the research institutes that conducted them and of the journals
that published them (peer-reviewed international journals);
III. the specific nature of the studies: it is essential that the studies are devoted
to a specific ingredient contained in the supplement, with its characteristicsof origin, extraction, formulation, concentration, and that efficacy is not affirmed
by general reference to existing literature;
2. pharmacokinetic results from studies dedicated to the specific productwith its specific formulation (these studies verify the absorption, distribution,
metabolism and elimination from the body of the ingredients believed to be active
supplements): in fact, albeit with physiological equivalence, products with different
formulations may have a different degree of bioavailability, a different metabolism
and therefore vary in efficacy.
3. evidence of clinical studies on healthy physiological activities, or datathat lead to evidence of the impact on physiological functions performed by the
ingredient and / or by the supplement.
In order to adopt a new claim, or to be able to declare the nutritional and healthclaims of the product being marketed, the studies must then be validated by thetechnical scientific commission of the European Food Safety Authority (EFSA), in
accordance with Regulation 1924/2006.

INTERACTION: A FUNDAMENTAL ASPECT OF SAFETY
The widespread trend among consumers to consider food supplements “naturallygood”, together with the accessibility of these products through distribution channels
where prescriptions are not required, have fostered a “do-it-yourself” habit.
This practice is to be discouraged strongly. The use of supplements of botanicalorigin requires an overall assessment of the condition of the person concerned,
with a technical competence that can only be provided by a doctor or pharmacist.
The reasons for this warning are not dissimilar from those concerning the productsof the official pharmacopoeia, namely:
1. botanically derived ingredients have physiological effects which must be known
and assessed with respect to the specific situation of the individual for whomthey are intended;
2. It is essential that a competent professional should assess and monitor
any possible interaction between the ingredient of botanical origin that theindividual is about to take and any other active ingredient being taken
simultaneously, whether natural or synthetic. The absence or superficiality ofan assessment of possible interaction between active ingredients, in theerroneous belief that “it is natural, therefore it can do no harm”, is actuallya source of potential risk;
3. each organism responds in its own way to the ingredients of a supplement: it istherefore necessary to first analyse the general conditions of the individual in anexpert manner and then evaluate the opportunity to prescribe a specificsupplement and the methods of use, which include the dosage and lengthof treatment. For this reason, it is also necessary that the ingredients are
the subject of human studies, from which their safety and tolerability canbe verified.
It is therefore necessary to reiterate that botanical supplements should preferably
be recommended by the doctor or pharmacist. These professionals must regard
the prescription or recommendation of these products with the same rigorous
approach they apply to all prescriptions, taking into account the general conditionsof the individual subject and any therapies or treatments already in progress toorder to assess any possible interaction and establish the most effective dosage.

FOCUS ON THE
CASE OF TURMERIC

THE PLANT AND ITS ACTIVE COMPONENTS5
Curcuma longa L. (a member of the ginger family, Zingiberaceae) is a perennial
herb plant widespread in South East Asia and extensively cultivated in China, India,
Indonesia and Thailand6.
The golden-orange rhizome from which an intense yellow ingredient is obtained isused for food and for the production of supplements. Turmeric root has been known
since ancient times for its beneficial properties and is one of the most widely
studied botanical products.
The turmeric plant, and in particular its rhizome, first appeared in India as a spice,
as a food and for use in Ayurvedic medicine before 600 BC. Turmeric is part of theginger family and, like ginger, grows easily in tropical climates. It probably reached
China in 700 AD, West Africa from 800 AD. and the Americas around 1700 AD.
Turmeric has many different names in different countries, but is known in many
languages simply as “yellow root”. This iconic colour derives from three chemicallydistinct compounds, which are the active components of the plant: curcumin,monodemetoxicurcumin and bisdemethoxyurcumin.
All three of these curcuminoids are often collectively referred to as curcumin,both on the market and also in scientific literature. However, it is importantto remember that each curcuminoid has its specific chemical structure and its
specific functional profile. Depending on its provenance and growth conditions,the rhizome contains from 2% to 9% of curcuminoids and a volatile oil composed
mainly of sesquiterpenes such as zingiberene, curcumol and α and β turmerone.
The three forms of curcumin have different chemical personalities and colours
and, working together or individually, have been shown to produce important
physiological antioxidant, anti-inflammatory, anti-mutagenic, anti-infectious, anticancer effects.
As of 2019, about 100 human studies have been carried out on curcumin, involving
thousands of subjects.

FUNCTIONING AT CELL LEVEL5QUALITY

The mechanism of action of curcumin is polyvalent in that it “turns off” proinflammatory transcription factors such as NF-κB, AP-1, STAT, thus regulating theexpression of genes involved in cell survival, cell proliferation and angiogenesis.
Curcumin is also able to inhibit various kinase proteins and modulates the
inflammatory response by “turning off” the inflammation enzymes such as COX2, lipoxygenase and NO synthase. Curcumin also inhibits the production of
inflammatory cytokines such as TNFα, IL -1-2-6-8- and -12. In addition, curcumin
is a powerful anti-oxidant that acts as a radical scavenger by inducing antioxidant
cellular defences through the activation of the nuclear factor NrF2.

The quality of turmeric, like all botanical extracts, depends primarily on the qualityof the raw material and the purity of the extract.
The procedure that enables the plant to be unquestionably identified is by DNA
analysis or barcoding of the plant itself.

PHYSIOLOGICAL AND SIDE EFFECTS6
In humans, the main action of curcumin is anti-inflammatory; as such, it has a beneficial
effect on gastrointestinal, cardiovascular, osteoarticular and hepatic health.
Chronic inflammation is the cause of many ailments, especially of people in old age.
However, chronic inflammation may also in fact be defined today as the silent killerof human health. According to the World Health Organization, over a third of the 57
million deaths worldwide each year are caused by chronic diseases (cardiovasculardisease, type 2 diabetes, hypertension, respiratory disease and Alzheimer’s disease)and 90% of these diseases have an inflammatory origin. Chronic inflammation ismainly the result of a typical western lifestyle: understanding its mechanisms andcoping with inflammation has become a crucial goal of modern clinical researchand has in fact recently been defined a priority by the National Institutes of Healthin the US.
In addition to its anti-inflammatory action, curcumin has proven antioxidant,
hepatoprotective, neuroprotective, antihypertensive, antiobesity, antimicrobial andantidiabetic action.
In any case, it should be remembered that the antioxidant effects and joint
functions of turmeric are recognised by the Ministerial Guidelines.
The permissible daily dose of curcumin is 0 - 3 mg / kg body weight, according to
the Joint Committee of Experts for Food Supplements of the United Nations and theWorld Health Organization (JECFA) and the European Safety Authority Food (EFSA).
The only side effects described, mainly resulting from excessive dosage, are reportsof diarrhoea, nausea, dyspepsia, headache and skin rash8.

Furthermore, quality turmeric is free from contamination whether accidental ordeliberate, in particular with9:• species other than Curcuma longa, such as Curcuma zeodaria, Curcuma
aromatica and Curcuma xanthozzhiza;• azo dyes such as Metanil Yellow and Sudan I and IV, organic compounds
not allowed as additives and prohibited for food use but used asturmeric adulterants because the absorption spectrum is similar tothat of curcuminoids, thus mimicking their colour;• turmeric / synthetic curcuminoids.
Attempts of adulteration with synthetic products are known. These adulterations
can be detected using different analytical techniques which reveal the presence ofsynthetic curcumin.
Another area of potential contamination is during the manufacturing processof the raw material. Quality turmeric must not contain process contaminants
such as polycyclic aromatic hydrocarbons or PAHs (Reg. (EU) N. 2015/1933),
pesticides (Reg. (EC) N. 396/2005) or solvents (Dir. 2009/32 / CE) outside thelimits of acceptability, as prescribed by current regulations. Furthermore, it must
not contain GMOs (genetically modified organisms) and must respect precise
microbiological parameters.
The protocols and tools to define the quality of turmeric are therefore many andconsolidated. The conscious prescription of supplements with curcumin meansdemanding exhaustive and transparent information from producers on quality
controls and the methods by which these controls are carried out.

SAFETY
The amount of research conducted since 1815, the year in which curcumin was
isolated by the French pharmacist Pelletier, makes this botanical ingredient one of
the most studied in the world. Based on scientific evidence it can be stated thatthe safety profile of turmeric is very high.
As regards liver safety10, curcumin has been studied all over the world for years indozens of experimental models as a treatment for the protection of the liver against
chemical damage, caused for example by alcohol abuse. In case of changes to theliver function, however, use of the product is not recommended8.
As a general indication, it should be reiterated that botanical supplements should
preferably be recommended by the doctor or pharmacist, who are able to verify
the general condition of the subject, analyse any therapies or additions already inprogress to evaluate possible interactions and identify the most effective dosage.

EFFICACY
Like many botanically derived substances, turmeric has poor solubility in waterand is difficult to absorb by the intestine, with consequent limitation of its
bioavailability.
To overcome this problem, solutions have been found that primarily concern theformulation of the supplement containing curcumin.
In this context, one of the most common formulation solutions is the associationof curcumin with piperine. Piperine is a solid substance that does not dissolve inwater and is able to increase the bioavailability of some nutritional substances.
Piperine in combination with curcumin therefore improves the activity of thelatter in the body, enhancing the amount of substance dissolved in the plasma
and the extent of absorption. It should be noted, however, that piperine increases
the absorption of curcumin but with a non-selective mechanism: so it may also
increase the absorption of other substances, of natural or synthetic origin, foreign
to an organism9.
One of the most innovative solutions in the formulation of curcumin for helping
bioabsorption is with turmeric phytosome.

The phytosome is a formulation developed by Indena to improve the bioavailability
and pharmacokinetic profile of active compounds of natural origin using 100% foodgrade ingredients (lecithin). Lecithins are natural surfactants which, together
with bile salts, participate in the physiological process of absorption of lipophiliccompounds and constitute the lipid double layer of cell membranes, making
compounds, not readily soluble in water, more easily absorbable for example by theintestine.
The efficacy of turmeric phytosome is demonstrated by 35 scientific studies inhumans, of which at least a third were conducted with the randomized controlled
scheme, relating in particular to the areas of cardiovascular, intestinal and ocular
health, nutrition in sports , osteoarthritis, diabetes and the side effects of anticancer therapy. In these studies involving over 2000 subjects, no adverse reactionin the liver has ever been reported. Indeed, positive liver protection data have been
observed and a double-blind, randomized, placebo-controlled study is ongoing inwhich no adverse reaction of this type has been reported to date.
Once again it is emphasised that the correct use of the botanical ingredient –which therefore includes turmeric - according to the specific indications provided
by the manufacturer, is a fundamental condition for the overall safety of foodsupplements, as indeed of any other finished product of which it is part.

CONCLUSIONS

Botanical-based supplements are a valuable aid in maintaining people’s physiologicalwell-being, and this evidence is confirmed by the numerous published studies which
demonstrate the interesting bio-medical properties of plant extracts.
“Quality” is a fundamental requirement for their safe use. In this Consensus Paper
we have tried to clarify what “quality” means; this starts from the raw materialof the botanical ingredient and the industrial controls applied to guarantee theproduct a constant phytochemical profile and titration. In addition, dedicatedpreclinical and clinical studies must define the biological properties and conditionsof use for each specific plant ingredient.
Information on the quality of extracts of botanical origin should ideally be madeavailable to those who prescribe, recommend and use the supplements that
contain them, and that the intake of such supplements should preferably takeplace following the indications of doctors or pharmacists, avoiding “do-it-yourself”
remedies.
Turmeric is internationally one of the most widely studied plants ever. The correct
use of extracts or preparations containing this botanical ingredient is based on thespecific indications that emerge from the preclinical and clinical developments of
the individual products as well as on the directions of the Health authorities.

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