A regulatory take on cannabis and cannabinoids for medicinal use in the European Union

Ever since the nineteenth century approval of the use of cannabis tincture to relieve pain and nausea in Britain (5), most countries allow medicinal use of cannabinoids as one of the legal treatment options (1). By definition, cannabinoids are substances that bind the cannabinoid receptors of the body and trigger similar effects to those evoked by the plant C. sativa (3). They are most often classified according to their origin and structure.

Endocannabinoids are endogenous neurotransmitters that bind to cannabinoid CB₁ and CB₂ receptors in the mammalian central and peripheral nervous system. In the past 15 years, they have been shown to share metabolic pathways and molecular targets with a number of lipid mediators. They make a complex system, described as endocannabidiome, which regulates several physiological processes. These include pain, cognition, motor activity, appetite, nausea, vomiting, and some endocrine, inflammatory, and immune reactions. Endocannabidiome receptors and metabolic enzyme targets can therefore be useful in the treatment of various symptoms and diseases such as pain, nausea, depression, anxiety, and neurological disorders like multiple sclerosis and epilepsy (6, 7, 8).

Phytocannabinoids are the first known psychoactive cannabinoids. They are components of C. sativa and some other plant species. So far, there are over 100 known phytocannabinoids, some of which are present in plants in very low concentrations. The most abundant phytocannabinoid, readily extracted from C. sativa is the psychoactive Δ9-tetrahydrocannabinol (THC). Other common phytocannabinoids are not psychoactive and include cannabidiol (CBD), cannabigerol (CBG), and cannabichromene (CBC) (9).

Syntethic cannabinoids have been used in medicine since the second half of the 20^th century. Historically, they are based on the structure of phytocannabinoids, but this is not true of newer synthetic compounds. Currently, there are two products containing synthetic cannabinoids that have been approved for medicinal use in some EU member states: dronabinol, which is synthetic THC, and nabilone, which is a synthetic analogue to THC (Table 1). Current drug research is mainly based on synthetic cannabinoids. Besides medicinal use, several CB1 receptor-selective agonists have been developed as psychoactive ingredients in products for recreational use. Since little is known about their effects in humans, and since some of them cause more distress and panic than phytocannabinoids, they represent a significant health risk (10, 11, 12, 13).

Legislation on cannabis issues is nearly 100 years old. When cannabis came under international control under the revised International Opium Convention of 1925, it was referred to as ‘Indian hemp’. The Convention referred only to the dried tops of the pistillate plant, particularly rich in ‘pharmaceutically strong active resin’ and banned the export of cannabis resin to countries that prohibited its use and established domestic control, such as penalties for unauthorised possession of cannabis extract and tincture. The Convention also proposed that any breaches of national laws should be penalised (14).

Three United Nations (UN) conventions, signed by all EU member states, outline the basic framework for controlling the production, trade, and possession of over 240 psychoactive substances, many of which have therapeutic potential. These conventions classify narcotic drugs and psychotropic substances, including cannabis, according to their danger to health, risk of abuse, and therapeutic value.

The first, 1961 Single Convention on Narcotic Drugs (15), classified narcotic drugs and seeks to combat drug abuse through concerted international measures. It proposed two forms of intervention and control with the aim to: a) limit the possession, use, trade, distribution, import, export, and production of drugs exclusively for medical and scientific purposes; and b) combat drug trafficking through international cooperation. The Convention did not differ between industrial hemp and medicinal cannabis and classified cannabis in Schedule I as a substance presenting a serious risk of abuse, whose properties give rise to dependence. Cannabis was also included in Schedule IV among the most dangerous substances due to their particularly harmful characteristics, the risks of abuse, and limited therapeutic value. This significantly limited the use of cannabis and cannabinoids for medicinal purposes, which has later raised a number of controversies (16).

The 1971 UN Convention on Psychotropic Substances (17) included new, synthetic drugs of abuse, such as synthetic cannabinoids, taking into account their abuse potential as well as their therapeutic value.

The 1988 UN Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances (18) has established comprehensive international measures against drug trafficking, money laundering, and abuse of drug precursors. The Convention also binds member countries to prevent illicit cannabis cultivation and to eradicate cannabis plants on their territory.

These three conventions, however, do not specify that drug use should be a punishable offence. Instead, each country is free to regulate this issue. In addition, the conventions do not associate drug types with the severity of penalties and even though the schedules affect the procedures for the legal trade of the drugs, the countries are not bound to use them.

International drug control has evolved, and nowadays it does not ban cannabis or cannabis-based product use in medicine to treat specific indications. While international law provides a general regulatory framework for the cultivation and marketing of cannabis, the EU law sets the criteria for medicinal products, including those containing cannabinoids, to be authorised for marketing in the EU member states. However, magistral and officinal formulas are exempt from the EU marketing authorisation rules and are left to the care of the EU member states. This eventually leads to different access for patients to these medicinal products containing cannabinoids in the EU countries.

Cannabis and cannabinoids have their place in pharmacotherapy in the EU member states. They are mostly indicated for treating chronic pain, nausea, and vomiting due to chemotherapy or to relax muscle stiffening caused by multiple sclerosis (7, 19, 20). They occur in various formulations, yet some products have a marketing authorisation for medicinal use and others do not (Figure 1) (1).

Figure 1

International law does not ban the cultivation of cannabis for medicinal use. Instead, the 1961 UN Convention provides a general system of control, if a country decides to grant cannabis cultivation not intended for industrial or horticultural purposes. Each country has the exclusive right to buy the entire cannabis production on its territory (15). Cultivation and primary processing of cannabis directly influence the quality of active pharmaceutical ingredients and should therefore comply with the provisions of the UN Conventions and the WHO guidelines of good agricultural and collection practices (35) for medicinal plants. For the EU member states EMA additionally provides Guidelines on Good Agricultural and Collection Practices (GACP) (36) that include a system of quality control of medicinal plants and herbal substances from cultivation to distribution.

Cultivation of medicinal cannabis in the EU is currently allowed in Austria, Czech Republic, Italy, Germany, Greece, Malta, the Netherlands, and Portugal. All of these member states have established an authority for cannabis cultivation and defined their responsibilities as summarised in Table 2 (1, 27, 37, 38, 39, 40).

Hemp can also be cultivated in the EU for food, provided that it is registered in the EU’s Common Catalogue of Varieties of Agricultural Plant Species (41) and that its THC content does not exceed 0.2 % w/w. Furthermore, in the Novel Food catalogue (42) the EC has listed C. sativa extracts with cannabidiol content higher than in hemp, and them banned in food, including dietary supplements, until safety assessment is completed.

The growing interest in the use of cannabis and cannabinoid products forces countries to regulate cultivation and safe use of cannabis and its products for medicinal use. The basic regulatory framework is provided by the UN conventions, whereas the EU legislation covers only medicinal products that have been authorised for marketing. The regulation of cannabinoid-containing products without marketing authorisation – magistral and officinal (standardised) preparations – is left to each EU member state and is quite uneven across the EU, mainly due to cultural and historical differences between the countries. There are different approaches to this kind of regulation that cannot be easily transferred from one EU country to another, yet uneven availability of cannabinoid-containing medicinal products calls for some harmonisation of these approaches to level the playing field and avoid issues such as cross-border patient access where EU countries have different regulatory schemes.

Kanabis in kanabinoidi v medicini – zakonodajni vidik