September 12, 2023 - Tullio Scrimali, Polo Clinico ed Universitario degli Erei

NegEnt Become Galenic after CBD is Considered a Drug in Italy

On 1 October 2020, the Minister of Health, Roberto Speranza, formulated and made operational a decree, relating to the updating of the tables, containing the indication of narcotic and psychotropic substances, according to the decree of the President of the Republic of 9 October 1990, no. 309 and subsequent amendments and additions (Speranza, 2020 a).

Within the framework of this decree, the inclusion in the Table of Medicines, section B, of the compositions for oral administration of cannabidiol, obtained from extracts of Cannabis Sativa L. Section B of the Table of Medicines will now also include preparations of plant origin based on Cannabis, providing for a regime of dispensing to the public with a non-repeatable prescription (RNR). Considering CBD a real psychotropic drug, he had also taken the lead from the introduction, on the Italian market, of Epidiolex, a registered drug, obtained from Cannabis extracts that exhibits, as the only indication, the treatment of certain forms of epilepsy.

Subsequently, following the protests, raised by the representatives of the production and commercial chain, of the so-called light cannabis and, pending further scientific investigations, Minister Speranza withdrew the aforementioned decree and the free sale of preparations for oral intake of cannabidiol resumed immediately (Speranza 2020 b).

Herbal Neurocare, on the basis of the regulatory framework, outlined after the withdrawal of the Speranza decree of 2020, carried out, during 2022 and 2023, the free sale of its found NegEnt, based on liposomal cannabidiol, in drops, as an unregulated product, for Aromatherapy (Scrimali, 2020).

A New Perspective in Italy: Cannabidiol as a Drug

The current Minister of Health, Prof. Orazio Schillaci, resumed, during the summer of 2023, the row of the speech on the regulation of cannabidiol and has implemented a path of scientific and regulatory in-depth study, taking into account, above all, the note of the Italian Drug Agency (AIFA) of 19 March 2021, in which the same Agency reiterated that cannabidiol (CBD) is to be considered, for all purposes, an active substance, within the meaning of art. 1, paragraph 1, letter b-bis of legislative decree no. 219 of 2006, explicitly recalling the provisions of art. 2, paragraph 2, of the same legislative decree, according to which, in case of doubt, if a product, due to its characteristics, can simultaneously fall within the definition of a medicine or in the definition of a product, governed by another Community legislation, the provisions concerning medicines, for human use, apply. Furthermore, AIFA referred to the case of Epidyolex, a cannabidiol-based drug, regularly registered for the treatment of some forms of epilepsy, first in the United States and, subsequently, in Europe.

Based on the conclusion that cannabidiol is a real drug, Minister Schillaci has decided to prepare and publish, on 7 August 2023, a new decree on cannabidiol with which he has revoked the previous decree of the Minister of Health, Roberto Speranza, of 28 October 2020, suspending the entry into force of the previous decree of the Minister of Health of 1 October 2020 and thus restoring the aforementioned first decree Speranza.

In his current decree, Minister Schillaci therefore updates, three years later, the provisions of the Speranza decree of 1 October 2020, namely that cannabidiol, must be considered, for all purposes, a psychotropic therapeutic substance, to be included in the Table of Medicines, Section B, and can only be dispensed upon presentation of a non-repeatable medical prescription.

It seems useful to remember that, while the Honourable Roberto Speranza was an exponent of the left, the current minister, Prof. Orazio Schillaci, is a doctor, University Professor at the Tor Vergata University of Rome and is part of a right-wing government. It can therefore be said that the decision to consider cannabidiol a drug in Italy appears bipartisan and has matured over a three-year process that began in 2020. Furthermore, the determination, by decree, of Minister Schillaci, was taken following the positions, expressed, in this regard, by the Italian Drug Agency and (AIFA) and by the Higher Council of Health, the highest Italian scientific bodies regarding drugs and the protection of public health.

There is no doubt that cannabidiol, although absolutely safe and free of side effects, at a dosage of more than 50 mg per day, constitutes an active drug, both at the level of the central nervous system, as a tranquiliser, antiepileptic and nootropic, and on multiple somatic systems, as an anti-inflammatory and analgesic. The new regulation of cannabidiol, for oral use, which is now outlined, in Italy, as a drug, to be registered on the basis of the Epidiolex precedent or to be proposed as a medicinal galenic drug, according to the Official European Pharmacopoeia and, in particular, following the manual of the German Pharmacopoeia, can constitute a positive opportunity to clear this important therapeutic substance, allowing its positive transition, from an empirical remedy, prepared, proposed and sold by unqualified people, to a drug, possibly registered, but, already currently, saleable in the pharmacy as a medicinal galenic drug, upon presentation of a medical prescription.

Minister Schillaci’s decree provoked an immediate and strong reaction, as already happened at the time of the first implementation of the Speranza decree, which is now restored, and thus opens a very conflictual phase, with a probable state of agitation and protests by the protagonists of the Cannabis Sativa L. supply chain, during which the Associations, which represent the interests of hemp farmers and sellers of edible products, based on cannabidiol, will make the voice of an important economic sector heard, for the wealth produced and the people employed. Sector that has been given the opportunity to develop, without adequate regulation for many years, implementing investments and creating employment. We now rightly ask ourselves what will become of this productive and economic sector?

Herbal Neurocare, and its Scientific Director, Prof. Tullio Scrimali, since the first phase of development of their NegEnt product, have tried to fit into a legislative and regulatory framework, still very confused and lacking, with a severe scientific reference standard (Scrimali, 2022). The NegEnt product, developed and filed, for patenting, by Scrimali, based on liposomal cannabidiol, proposed in the form of drops, as a product for Aromatherapy and as a Class I Medical Device, has been successfully used in hundreds of patients, and a first controlled research, published in an international English journal, has demonstrated the tolerability and safety of the preparation (Scrimali, 2023).

Since the regulatory framework, on cannabidiol, in Italy, from 22 September 2023, the date of entry into force of the Schillaci decree, changes dramatically, Herbal Neurocare has decided to adapt its commercial policies by updating the regulatory profiles of its products.

NegEnt will therefore be proposed, shortly, on the Company’s website, www.herbalneurocare.it, also as a galenic drug according to the Official Pharmacopoeia (F.U.), which can be purchased electronically in a galenic pharmacy where it will be prepared by a galenic pharmacist, upon presentation of a non-repeatable medical prescription. To this end, new procedures are being planned, especially of a computer and telematic nature, and new applications are being set up on the Herbal Neurocare online shop.

These innovations will concern the preparation of the product, which will be implemented in a galenic laboratory, in collaboration with qualified pharmacies. The prescription and the issuance of the prescription, not repeatable, will take place, always on the company’s website, thanks to the collaboration with various doctors who will prescribe NegEnt and issue the prescription, according to the methods of telematic medical consultation and immaterial prescription.

Meanwhile, Herbal Neurocare continues the path, undertaken, for a long time, for the regulation of its products, with the imminent registration of NegEnt Spray, and NegEnt Aromatherapy Drops, as cosmetics, following European legislation.

The Schillaci decree, in fact, does not take into account cannabidiol-based cosmetic products that can therefore be produced and sold, as previously, without a medical prescription, throughout Europe. The preparation and sale of cannabidiol-based cosmetics is covered by European legislation, established by Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009. NegEnt Aromatherapy Drops and NegEnt Spray are being registered, on the European portal, called Cosmetic Product Notification Portal (CPNP).

NegEnt’s complex, onerous and difficult development path appears consistent with the scientific mission of Herbal Neurocare which, since its foundation, by Prof. Tullio Scrimali, has set itself the goal of developing cannabinol-based products, regulated, safe and effective, as well as documented by science and evidence-based procedures. The great potential of cannabidiol, in human and veterinary medicine, is partly compromised by the current state of anarchy in Italy and Europe, the production and sale of CBD. Patients, often afflicted by severe diseases, such as multiple sclerosis, buy expensive CBD products, whose safety and efficacy are not guaranteed by production procedures and rigorous tests and trials. The bioavailability of CBD, in many expensive commercial products, appears minimal and the therapeutic effect almost zero. Pharmacokinetics and dosages are never documented with scientific data. The nomenclatures and description of the products, on free sale, are now completely arbitrary. For example, a website where an expensive CBD is sold, defines an oily suspension of 20% CBD as cannabis seed oil. In fact, cannabis seed oil contains CBD, but in much lower percentages. So, an oily solution of CBD is a drug, and from 22 September 2023 it will fall under the new legislation dictated by the Schillaci decree, cannabis sativa light seed oil is, instead, a food, on free sale according to food legislation.

NegEnt Edible Drops therefore becomes: NegEnt Galenic Drug F.U., a cannabidiol-based medicine, prepared, on input and with the supervision of Herbal Neurocare, at galenic laboratories, by galenic pharmacists. The sale will also take place exclusively in the pharmacy since, according to the Schillaci decree, it is a product that can only be purchased upon presentation of a non-repeatable prescription, framed in Table B and, therefore, not saleable, not even in a parapharmacy.

According to current legislation, recently entered into force, galenic preparations, based on cannabidiol, can be made in galenic form, scrupulously following the provisions of a European Pharmacopoeia but in officinal form; therefore, even before the presentation of the medical prescription, by the patient, with the constitution of small stocks in the pharmacy. Currently, galenic cannabidiol is regulated by the German Pharmacopoeia and its galenic preparation will therefore take place following the relevant manual.

A further element of confusion, present in the current debate on cannabidiol in Italy. Some journalistic sources and some Associations of the Cannabis supply chain have stated that the Schillaci decree declares cannabidiol, not only a psychotropic drug, but also an astonishing. In fact, the Schillaci decree does not speak of cannabidiol, as a drug and could not have done so, given the enormous scientific literature that proves to be cannabidiol absolutely devoid of hedonistic and additive effects. Therefore, products, based on cannabidiol, for oral use, from 22 September 2023 should be considered, in Italy, in the light of the Schillaci decree, psychotropic, included in Table B, to be prepared in galenic laboratories or by pharmaceutical industries after registration with AIFA. It is not understood, however, why many operators speak of the classification of cannabidiol as an astonishing drug.

Materials and Methods

In light of and in compliance with the decree of the Italian Minister of Health, the new production and sale process of NegEnt Liposomal Drops, now become NegEnt, Galenic Cannabidiol FU, will be articulated in a different and innovative way, compared to the past.

The preparation of NegEnt, Cannabidiol Galenic F.U. will take place in galenic laboratories, affiliated pharmacies and active in online sales. The pharmacy shelf will appear on the Herbal Neurocare website, and the patient will be able to observe and evaluate all the characteristics of the NegEnt product, Galenic Cannabidiol FU and the sale price. The production will scrupulously follow all the dictates of the Official Pharmacopoeia (in this case the German one) as well as Italian legislation on the preparation and sale of galenic drugs online.

If the patient is inclined to purchase the product, he/she must, however, undergo, before being able to conclude the purchase, a telematic medical consultation through the NegEnt Medical Care computer application. At the end of the consultation, he will be prescribed, with a non-repeatable prescription, NegEnt Drops, Liposomal Cannabidiol, Galenic drug FU. Once the prescription has been received, the patient can purchase the product directly from the galenic pharmacy, receiving it, at home, in a couple of days. This procedure will take place, quickly, and automatically, online, through the application called NegEnt Medical Care. In this way, Herbal Neurocare will allow patients, who must use cannabidiol-based therapies, to access a cannabidiol-based treatment project, now finally safe, legal, regulated and, above all, science and evidence-based.

The Schillaci decree, it is worth emphasizing, speaks, expressly and specifically, of the inclusion, in the table of medicines, section B, of the compositions for oral administration of cannabidiol, obtained from extracts of Cannabis Sativa L. The question of cannabidiol for use other than oral and its classification, to date, not regulated. In the light of the formulation of the Schillaci decree, it seems that cannabidiol-based preparations for use other than oral use do not fall under the new legislation. Having made two new preparations of NegEnt, for non-oral use, called: NegEnt Liposomal Aromatherapy, NegEnt Liposomal Emulsion Spray, it was planned to regulate the two products as follows:

Aromatherapy Liposomal NegEnt in Drops.

It is a product for external use, not edible. The drops must be dissolved in water, in the tank of an ultrasonic vaporizer and the generated steam is inhaled. If necessary, the drops can be deposited on the buccal mucosa, but not swallowed. NegEnt Liposomal Aromatherapy in Drops will continue to be proposed, as in the last two years, for free sale, since not being a product based on cannabidiol, for oral use, it does not fall under the Schillaci decree. This product is being registered on the European portal, called Cosmetic Product Notification Portal (CPNP).

In this regard, it is important to mention a judicial affair, initiated with the complaint, that a Psychiatrist from Rome, sent to the Italian Drug Agency, claiming that NegEnt was a drug and, moreover, a defective drug. Following the complaint, AIFA ordered an inspection at the headquarters of Herbal Neurocare, in Acicastello, by the Carabinieri of the Anti-Sophistication Unit (NAS in Italiana). The military, at the end of a long inspection, with interrogations of those present, especially the author of this article, Prof. Tullio Scrimali, communicated, to the Prosecutor’s Office of the Republic of Catania, the news of a crime, in their opinion, committed by Scrimali, for the violation of article 443 of the Criminal Code, accusing the researcher who developed NegEnt, of having prepared and sold a defective drug. Subsequently, the Public Prosecutor, in charge of the case, considered that she had to proceed with the referral to trial of Scrimali for the crime of having prepared and sold NegEnt, considered a defective drug (article 443 of the Criminal Code). During the process, held later, Scrimali claimed and demonstrated, with the help of his own lawyers, that NegEnt was not a drug and, even less, a defective drug, obtaining absolution with a full formula, with the reason that the fact does not exist. It is possible, therefore, to conclude, with the support of a judgment of the Criminal Court of Catania, that NegEnt Liposomal Drops, proposed as a product for Aromatherapy, not edible, is not a drug and much less a defective drug but a product for Aromatherapy, for free sale, soon registered on the European Portal for Product Notification (CPNP).

Liposomal NegEnt Spray.

It is also a product for external use, not edible, and with a local effect on the skin, muscles and joints. It will be registered, also in this case, at the European CPNP portal.

With this new phase of development, NegEnt continues the evolutionary path, identifying new promising ways of using cannabidiol and adapting to the evolutions of Italian and European regulations.

Discussion and Conclusions

The decree, by the Italian Minister of Health, Orazio Schillaci, recently issued in Italy, defines, for all purposes, cannabidiol for oral use, a drug, which can only be purchased in a pharmacy, through the presentation of a non-repeatable medical prescription. The new decree, therefore, precludes the free sale of cannabidiol for oral use, so far largely implemented in Italy.

Herbal Neurocare, a pharmaceutical company that produces NegEnt, a preparation in drops, based on liposomal cannabidiol, has developed, under the impulse of its Scientific Director and Cannabis scientist, a new and original procedure for the production and sale of its NegEnt Edible Drops product, based on liposomal cannabidiol with the aim of adapting to the new regulatory framework. This procedure proposes NegEnt Liposomal Drops as a medicinal galenic drug, prepared following the manual of the German Pharmacopoeia and sold by galenic pharmacies, upon presentation of a non-repeatable medical prescription.

Meanwhile, Herbal Neurocare continues to propose NegEnt Liposomal Aromatherapy Drops, based on cannabidiol, for topical use, as a product that does not fall under the Schillaci decree but is proposed as collateral drops, registered with the European Cosmetic Product Notification Portal (CPNP).

The procedures adopted and the methodologies developed, which will be implemented shortly by Herbal Neurocare, should allow, without difficulty, the sale of NegEnt, in its various formulations, ensuring full compliance with the new legislation. The experimentation of innovative prescription and sales methodologies, and of new materials created, has just begun; therefore, the results or necessary corrections can be evaluated in the coming months.

Bibliography

Monograph for Cannabis Extracts (2023). Deutsches Arzneibuch (DAB 2023), Deutscher Apotheker Verlag, Gerlingen.

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Speranza R. (2020 a). Update of the tables containing the indication of narcotic and psychotropic substances, referred to in the decree of the President of the Republic 9 October 1990, n. 309, and subsequent amendments and additions. Inclusion in the table of medicines, section B, of the compositions for the administration for oral use of cannabidiol obtained from extracts of Cannabis. Official Gazette, General Series, no. 255 of 15 October.

Speranza R. (2020 b). Suspension of the entry into force of the decree of 1 October 2020, containing: «Update of the tables containing the indication of narcotic and psychotropic substances, referred to in the decree of the President of the Republic 9 October 1990, n. 309, and subsequent amendments and additions. Inclusion in the Table of Medicinal Products, section B, of the compositions for oral administration of cannabidiol obtained from Cannabis extracts”. Official Gazette, General Series no. 270 of 29-October 2020.

Conflicts of Interest:

The author is C.E.O. and Scientific Director of Herbal Neurocare, an ethical company, manufacturer of NegEnt, as well as the owner of the deposit of the original formula of NegEnt Liposomal.