For many centuries, nature’s pharmacy has been an important source of potent therapeutic agents; either by administering parts of plants, eg opium and senna pods, or preparing extracts/tinctures. Over time, the principal active ingredients have been identified and their therapeutic utility established through clinical trials, such as quinine, morphine and digoxin.
Cannabis, from the plant Cannabis sativa or Cannabis indica, has been used for centuries for a very wide range of physical and neurological conditions. The main active ingredients are tetrahydrocannabinol (THC) and cannabidiol (CBD), but recent research shows that, in addition, plants contain at least 113 cannabinoids and between 550-600 other phytocompounds, including phenols, terpenes and flavonoids.
THC is highly psychoactive and can result in impairment, dependency and addiction, whilst pure CBD is non-intoxicating, highlighting the vastly different properties of cannabinoids.
Cannabinoids interact with our endocannabinoid system which, along with other networks, regulates and balances many processes in the body including immune responses, communication between cells, memory, metabolism and more. Optimum therapeutic effect is likely to be the result of the synergistic activity of a number of plant constituents; the so-called ‘entourage’ effect.
The type and number of cannabinoids in a plant (including THC and CBD) depends heavily on the strain and growing conditions (soil, temperature, rainfall, nutrients, etc). Also, the type and quantity of chemical ingredients in extracts varies according to harvesting and storage conditions, as well as the solvents and process conditions (temperature, etc) used for extraction.
In recent years, a number of manufacturers have standardised these variables such that the products they offer are consistent batch to batch and can be provided in specially formulated products. Since their products are ‘unique’, patients should not be switched to products from alternative suppliers unless they are clinically monitored to confirm therapeutic equivalence.
The term ‘medicinal (or medical) cannabis’ has been loosely applied to a range of products associated with possible therapeutic efficacy, particularly the flowering tops of plants (flos), resin and other extracts, but also to pure cannabinoids (THC and CBD) and combinations of these with other cannabinoids/plant constituents.
Growers have standardised cultivation conditions and selected strains that can have high THC content (eg marijuana) and low or no THC (eg hemp). The dried flowering heads can be vaporised and inhaled using validated medical devices. However, ‘medicinal cannabis’ specifically excludes recreational smoking of cannabis leaves and vaping (e-cigarettes).
During the last few years, a considerable number of products have been made available in a number of countries through retail shops and mail order with names such as Hemp Oil and CBD Oil. Independent chemical analysis of a number of these has shown that very few are correctly labelled, with some containing zero CBD and others a relatively high THC content. Further, some suppliers include in their advertisements ‘suggested’ medical benefit for a range of conditions for which adequate clinical studies have yet to be performed.
Medicinal cannabis specifically excludes these products, which are classified as novel foods. New legislation that becomes effective in 2021 in the EU will ensure the quality of these products and regulatory agencies must check that no misleading claims are made for their therapeutic use.
CBD is particularly insoluble in water and at the various pHs in the gastrointestinal tract. So, CBD products (and combination products with other cannabinoids) are usually formulated as oily solutions or suspensions, administered either sublingually or swallowed as a liquid or as a soft gelatin capsule. Even then, oral bioavailability is low. Very few bioavailability studies have been reported despite the many different formulations used in clinical studies. Typically, the amount of CBD absorbed after oral administration is 5-10%.
So, what do we know about medical claims for the therapeutic efficacy of medicinal cannabis?
Products recommended as medicines with such claims must be approved by national regulatory agencies. A few such medicinal cannabis products have been subject to proper clinical trials and have received product licences, eg GW Pharma’s Epidyolex for two rare forms of epilepsy and Sativex for adults with moderate to severe spasticity due to multiple sclerosis.
There are thousands of reports of human studies on the possible therapeutic benefit of medicinal cannabis preparations but virtually all are either anecdotal or are insufficiently powered statistically to justify an efficacy claim.
Several systematic reviews have been published from authoritative sources (such as Cochrane, EU Pain Federation EFIC, NICE) on specific conditions (eg chronic pain) but have concluded that more, well designed clinical studies are needed before such claims can be fully supported, so that patients are not led to believe in unproven benefit and potentially miss the value of currently available medicines.
Clinical studies must be conducted such that the body of data obtained permits an objective determination of claims for safety and therapeutic efficacy and, in parallel, studies should be carried out to prove the quality, reproducibility and stability of the product under investigation.
Whilst classical clinical trials, conducted to full regulatory requirements, are desirable, there is a case for carrying out real-world studies in defined clinical conditions, the data being collected as a non-interventional, observational study for subsequent review by regulatory agencies.
Most countries that have introduced legislation for the use of medicinal cannabis have, correctly, insisted that well characterised products should only be available to patients under the supervision of medical practitioners adequately trained in their potential use, and that comprehensive clinical records are maintained. To date, this supply has been through the use of specially formulated preparations from qualified pharmacies, so called ‘magisterial’ or ‘specials’. But recently a number of proprietary products have become available for the leading suppliers.
One factor complicating the broader clinical use of medicinal cannabis products is their scheduling as controlled drugs. It is appropriate that products containing THC, at least over 0.2%, are regarded as narcotics.
Following judgment by the European Court of Justice in November 2020, the European Commission has noted that CBD should not be considered as a drug within the meaning of the 1961 United Nations Single Convention on Narcotic Drugs. Also, that CBD can be qualified as food, provided that the other conditions of the EU Food Safety Regulation are also met. This should apply whether the CBD is derived and highly purified from plant sources or synthesised. However, since CBD can exist in two isomeric chemical forms, it is essential that when incorporated in a medicinal product that it is the (-) enantiomer that is used.
The medical use of cannabis-based products was legalised in the UK on November 1, 2018, when it was rescheduled to Schedule 2, making it available on prescription. In November 2019, NICE approved GW Pharma’s Epidyolex and Sativex for reimbursement under the NHS.
However, patients have repeatedly complained about a lack of NHS prescriptions. Less than 10% of the cannabis-based medicinal products (CBMPs) prescribed to patients in 2019 came via the NHS, according to a July 2020 report by the Care Quality Commission.
While the data showed an overall increase in the total number of private prescriptions for CBMPs, from four in January 2019 to 42 in December 2019, NHS prescriptions remained stalled with two items and one item prescribed in the same months respectively.
In summary, medicinal cannabis products, which excludes both the recreational use of cannabis and novel foods containing cannabis ingredients, have considerable potential to provide therapeutic benefit for a number of clinical conditions. Dried flowering heads, plant extracts and preparations containing one or more cannabinoid may be regarded as medicinal cannabis but should be shown to be of acceptable quality, stability (shelf life) and bioavailability. The excipients included in formulations should be GRAS (generally recognised as safe) listed and/or recognised by regulatory agencies, pharmacopoeias and the products compounded/manufactured in facilities that are compliant with accepted GMP standards.
Importantly, they should only be available to patients through appropriately qualified medical practitioners and then only provided adequate patient records are maintained and are available for pharmacovigilance, ongoing and retrospective analyses to determine their acceptability in terms of safety and efficacy in defined clinical conditions.
Professor Trevor Jones CBE is former R&D director of Wellcome and director general of the ABPI. He is currently chair of the European Medicinal Cannabis Association: EUMCA.org
