These products are generally considered completely harmless, but their active ingredients exert a biological function in the organism and can, therefore, have side effects or interact with drugs.
Non-conventional medicines in Italy
Non-conventional therapies are therapeutic practices, complementary or alternative to western medicine, used to improve the health and the psychophysics wellbeing of the individual rather than to treat specific diseases, for which there is no evidence of effectiveness.
According to a survey conducted by ISTAT in Italy, in 2013, 4.200.000 people (corresponding to 7% of resident population) resorted to non-conventional medicines. The most popular treatments were homeopathy (4.1%), manual treatments (3.4%), phytotherapy (1.9%) and acupuncture (1.0%). In particular, the survey showed that 6% of children had been treated with a non-conventional therapy.1
Among the reasons that lead to their use, the most frequent is the opinion that they are associated with less side effects and less toxicity in respect to conventional therapies and drugs.2
Natural products: which regulation?
The products present on the market and labelled as “natural”, particularly the plant-based ones, are extremely heterogeneous in their formulation and products with very different marketing characteristics might contain the same vegetal species (see Table 1).
Table 1. Typologies of products containing plant-based substances.
- Phytoderivatives (extracts, mother tinctures, macerated oils, essential oils)
- Foods (dried, whole, grinded or powdered)
- Food supplements
- Medical devices
- Magistral pharmaceutical preparations
It is worth noticing that not every product used by non-conventional therapies has a natural origin, like some homeopathic products that contain dilutions of drugs or other chemical and synthesised substances.
The market expansion, the relative easiness to import exotic species and the use by a vast part of the population have mandatorily raised within the scientific community the issue of these preparations safety and the regulation of their commercialisation.
At the moment, in Italy, most plant-based products used for health purposes are registered as “food supplements” or are sold as “food”, sometimes fortified with vitamins and minerals or enlisted in particular categories such as nutraceutics or “novel foods”.
According to the legislative decree 21 May 2004, n. 169 - promulgated for implementing the Directive 2002/46/CE - food supplements are defined as: “dietary products designed to integrate the normal diet that are a concentrated source of nutrients, such as vitamins and minerals, or of other substances with nutritional or physiological effects, especially but not only amino acids, essential fatty acids, fibres and plant-based extracts, either mono or multi compounds, marked in pre-dosed form.”
Their commercialisation is subordinated to a notification procedure submitted to the Ministry of Health and only some vegetal species are admitted in their compositions.
Food supplements must, also, have no therapeutic purposes and their safety must be guaranteed, in terms of composition, doses and association of different active ingredients; their advertisement and marketing presentation must not attribute to the product any property in terms of preventions, cure or healing of any disease and must not suggest that its use has no side effect.
This situation could disorient and confuse both consumers and health professionals (doctors in particular) who do not have the necessary specific education to use appropriately and safely all the different products present on the market, often recommended on the basis of the indications suggested by the producers. In the case of food supplements, a medical “prescription” would be misleading when the therapeutic properties were associated to products (food supplements or foods) that, according to their regulations, should not have any.
Products containing vegetal substances: the European regulation
The European directives 2001/83/EC (24) e 2004/24/EC (25) and their further modifications have been issued in order to harmonise the use and commercialisation modalities of vegetal derivatives among the member countries of European Community.
The EMA has, also, instituted a panel of experts with the task of preparing monographs on the natural products that are most frequently used,3 in order to facilitate their legal framework in just two categories:
• well-established use (herbal medicinal products): products for which it is possible to demonstrate, besides an acceptable safety level, a certain grade of effectiveness for the clinical indications they will be authorised for;
• traditional use (herbal medicinal products): products that meet safety criteria, but not effectiveness ones, for which an over 30-year use must be demonstrated (at least 15 years within a country member of the European Community) and for which it will be possible to follow a simplified registration procedure for indications that do not need medical supervision.
Because of these norms, the use of many herbal products in children, pregnant or breastfeeding women will be extremely limited or precluded, until valid scientific studies will demonstrate they are harmless.
However, it should be highlighted that many herbal medicinal products (some of which previously commercialised as food supplements or herbal products for topical or cosmetic use) are registered in the category “medical devices” (legislative decree 24th February 1997, no. 46: “Implementation of directive 93/42/CEE, regarding medical devices”) with the advantage, for the producer, of commercialising them without having to provide documentary evidence of the effects of the vegetal derivatives they contain, whilst this is mandatory for the food supplements.
Natural products: what risks?
In the past two decades, it has been registered an increase in the reported adverse reactions, sometimes severe, associated to the use of natural products.
These products are generally considered completely harmless, but their active ingredients have a biological action on the body and can, therefore, have side effects or interfere with synthesised drugs.4
The frequent use of vegetal material from abroad entails the risk that contaminants (chemical substances, drugs, toxic species or different from the declared ones) might be present into these products in a quite unpredictable way and would be hardly detectable through the standard sample exams requested by the companies. For example, the contamination with tropane alkaloids of a stock of Coleus forskolii from India caused severe cases of acute intoxication in Italy in 2005; equally severe was the consume of slimming products containing Aristolochia fangchi (a cancerous and nephrotoxic species, mistaken for Stefania tetrandra), that in the Nineties caused tens of cases of renal failure and urothelial cancer in Belgium.5
An additional risk comes from unlicensed products sold through channel difficult to check, like e-commerce, illegal import or private selling (healers, gurus or personal trainers).
The mass media, also, have often disseminated “poisonous” recipes (like the risotto with Scotch broom or the Lily of the valley tea) and, encouraging the use of wild herbs or plants for health purposes, they have exposed the population to the risk of collecting species that look similar but are toxic, such as the aconite, colchicum or the mandrake; these circumstances have resulted in several cases of acute intoxication, some lethal.6
Evaluation of the adverse events associated to “natural” products
The evaluation of the adverse events can be more complex and difficult in case of a natural product instead of a drug. In plants, several active ingredients may be present at the same time (phytocomplex) and the information on their properties mostly derive from their traditional use and it is not supported by valid scientific studies that demonstrate their pharmacological activity on humans nor the specific pharmacokinetic and pharmacodynamics characteristics.
Besides, very different pharmacological actions could correspond to the same declared composition on the label of two different products, both for the actual difficulty in the extract standardisation and for the possible differences in their bioavailability once the product is completed.
As for the heterogeneity in their formulations and the difficulties in tracing the origin of the raw materials, in some cases it has been necessary to carry out analytical investigation to verify the concentration of the substances declared on the label and exclude the presence of possible contaminants.
For all these reasons, the study of each single case requires a meticulous investigation on the single ingredients and a multidisciplinary approach that involves experts in pharmacology, pharmacognosy and toxicology.
Surveillance in Italy and the role of Poison-Centres
Since 2002, the Italian National Health Institute (ISS) in collaboration with AIFA and the Ministry of Health, has being coordinating a surveillance system on adverse events associated to the use of natural products, in accordance with the WHO guidelines and on the same line with the other European countries.7
The system, which records and analyses spontaneous reports, allows to highlight critical situations linked to the use of specific substances and to act, together with the Ministry of Health or other pertinent bodies, with corrective and sometimes urgent measures, such as discontinuing or withdrawing from the market a product suspected to have caused the event. For the spontaneous report a form similar to the one used for drugs has been adopted, but modified in order to register different information, specific to the different preparations involved in the reactions. The form, that needs to be send by fax to the National Health Institute, can be downloaded by the internet website of “Epicentro”.8 Spontaneous reports are evaluated by a multidisciplinary group of experts in epidemiology, pharmacology, pharmacognosy, toxicology, phytotherapy, homeopathy and pharmacovigilance.
In this context is worth noting the observational activity carried out by the Poison Centre in Milan that, thanks to the large population served and to the high number of consultations, is able to identify possible issues caused by the use of natural products in the population, even when they are correlated to situations usually hard to discover, like the presence, on the national market, of contaminated or adulterated stocks.
The registration of the clinical consultations in a database allows to identify cases of interest and to elaborate the data for epidemiological purposes.
The observational studies carried out in collaboration with the National Health Institute have, also, allowed to analyse and better evaluate the principal critical points linked to the use of natural preparations in Italy.9
The belief that natural products are always safe and beneficial could mislead consumers to use them without precautions and to underestimate possible symptoms that could appear during their use. The widening of the global market has facilitated the commercialisation of preparations derived from vegetal species not traditionally present in Europe and the circulation of illegal products.
Therefore, it is very important that both consumers and health professionals are attentive to report possible harmful effects, as post-marketing monitoring appears to be the best system for evaluating their safety.
The surveillance system coordinated by ISS, in collaboration with AIFA and the Ministry of Health and the Poison Centres, is able both to monitor the adverse events and to actuate corrective or preventive interventions, urgent if necessary, in case of contaminated or dangerous products.
Updating the regulations for preparations and vegetal-based preparations, as established by the directive issued by the European Community, will contribute to a safer and more appropriated use of “natural products”, both for consumers and health professionals.
Poison Centre, Milan
ASST Grande Ospedale Metropolitano Niguarda
- Eur J Clin Pharmacol 2002;58:61-4. CDI NS
- Life Sci 2006;78:2146-57. CDI NS
- N Engl J Med 2000;342:1686-92.
- Urban Forestry & Urban Greening 2009;8:179-86.
- WHO Guidelines on safety monitoring of herbal medicines in pharmacovigilance systems, 2004.
- XVIII Seminario Nazionale “La valutazione dell’uso e della sicurezza dei farmaci: esperienze in Italia ISS ISTISAN Congressi. 2009. 09(C14):15