The importance of standardisation
Unlike other medication, cannabis does not have a fixed chemical/molecular composition. A cannabis plant contains hundreds of different substances and each individual plant is different in terms of its composition. THC and CBD are the best-known substances, but there are dozens to hundreds of other known and unknown substances in the plant that may have an effect. No two cannabis plants are the same. Even if the levels of THC and CBD are the same, the substances around them can produce a different effect for the patient; this known as the ‘entourage effect’. There have been various studies of this entourage effect. Ultimately, the complete ‘fingerprint’ of the plant determines its effect.
Four crucial reasons why medicinal cannabis should be standardised
In the Netherlands, there are now five medicinal cannabis varieties available. Each variety has a unique, fully standardised genetic composition that is and remains the same each time, for every batch, year in, year out, because of the unique production process. The result is that the CBD and THC levels are always the same, but the other substances are also always present in the same ratio. The reproducible chemical profile enables doctors to monitor the dose and the effect on the disorder in the same way as for other certified medication. Furthermore, it makes these varieties suitable for carrying out scientific medical research.
Constant availability of a standardised product is extremely important to the patient
Just like ‘normal’ medication, all patients are ‘set’ on a certain variety. Sometimes it can take a long time to get patients on the right variety with exactly the right dose on the basis of the existing five varieties. The same applies to the use of cannabis oil. Changing the dose or administering medication with a different genetic composition can have adverse consequences for individual patients. In some cases medicinal cannabis oil is used for children and adults with serious epilepsy. The Dutch Epilepsy Fund and doctors recommend changing brands as little as possible for epilepsy medication, because somebody can end up with a seizure after changing medication.
Constant availability of a standardised product is extremely important to the doctor
Quite rightly, doctors want to know exactly what they give to their patients and what its effects are. It takes a lot of time and effort for doctors to become used to prescribing cannabis. The reproducible chemical profile of standardised medicinal cannabis enables doctors to monitor the dose and the effectiveness in the same way as for other certified medication. As this medicinal cannabis is also produced in accordance with pharmaceutical standards (GMP), quality and safety are guaranteed as much as possible. As doctors have prescribed the same products from the Office of Medicinal Cannabis for years, they know what it does and they feel comfortable with it. The same applies to the pharmacists who ultimately hand over the product.
Constant availability of a standardised product is extremely important to researchers and clinical research
For the first time, there is now larger scale serious clinical research into the effect of medicinal cannabis. In December 2018, the first results were published of a placebo-controlled, comparative study of 3 of the 5 varieties available in the Netherlands, carried out by the University Medical Centre Leiden. Different doctors, pharmacists, and study groups are now preparing further clinical research. They prefer to work with standardised medicinal cannabis that has a guaranteed quality, safety and availability.
In order to obtain permission for medical scientific research with humans, you need a detailed statement of the product that is studied. At the end of the study, the outcomes only say something about the specific plant, and its unique genetic composition, that was used in the study. Clinical research that is carried out with the existing Bediol variety, can only be carried out with that plant. Changing variety in the meantime is not possible from a substantive point of view, it is legally impossible, and certainly not desirable. If there were to be a change to a plant with only comparable THC and CBD levels, permission for the research would have to be applied for again. THC and CBD may well be comparable, but the chemical and genetic composition of the plant and the presence of other substances changes. So therefore, in essence the product used for the research changes too. It means the outcomes that were gathered up to that point are no longer usable, because they do not apply to this new, different plant.
4. MEDICINE DEVELOPERS
Constant availability of a standardised product is extremely important to developers of medication and medical devices
At the moment, medicinal cannabis only applies as a medical raw material, i.e. an API or Active Pharmaceutical Ingredient. Various companies around the world are working on developing medication or medical devices on the basis of this active pharmaceutical ingredient. One example is an extremely advanced inhaler, which was developed by using standardised products from the Netherlands from the beginning. This inhaler is so advanced that it detects even the slightest change in the form and composition of the product to be administered. For the device to work correctly, the same percentage of THC and CBD and exactly the same genetic and chemical composition of the product are important. Any change in plant will produce high modification costs and months, if not years, of delay in its further development.
Scientific research with standardised products; an overview
The importance of standardising the complete chemical composition of the plant is supported by various scientific studies. Below is a list of a number of studies into other substances in the cannabis plant and the entourage effect they cause:
- From Cultivar to Chemovar II—A Metabolomics Approach to Cannabis Classification
The study considered the ‘cultural’ designation of cannabis varieties, how to distinguish them in terms of effect and how they can be separated chemically and scientifically. The chemical difference is expressed in THC and CDB values, but also in other cannabinoids and terpenoids. This means that clinical research and anecdotal evidence could be used to study the various therapeutic effects of cannabis and/or certain varieties of cannabis could be prescribed to patients on the basis of the complete chemical profile.
- Taming THC: Potential Cannabis Synergy and Phytocannabinoid-Terpenoid Entourage Effects
This study introduces the ‘entourage effect’, which assumes interaction between cannabinoids and terpenes. This interaction may lead to positive effects regarding treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections. Unique therapeutic properties are ascribed to terpenes, the odour and flavour substances in cannabis.
- Terpenes and Derivatives as a New Perspective for Pain Treatment: A Patent Review
This study deals with the role of terpenes in pain relief and is particularly focused on the role those terpenes could play in developing new analgesics.
- Synergy Between Cannabidiol, Cannabidiolic Acid, and Δ⁹-Tetrahydrocannabinol in the Regulation of Emesis in the Suncus Murinus (House Musk Shrew)
This study demonstrated that a combination of THC, CBD, and CBDA (cannabidiolic acid) produced better control of vomiting and fewer side effects. This combination was administered to shrews. These effects are also expected to occur in humans.
- Beyond Cannabis: Plants and The Endocannabinoid System
Not just the substances in cannabis have an effect on the endocannabidoid system. This article deals with a number of other plants that could produce similar effects. It also deals more in-depth with the ‘entourage effect’.
- Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads
This article aims to answer the question as to the synergy between cannabinoids and terpenes in the therapeutic treatment of pain, psychiatric complaints, cancer and various other disorders. It also considers the therapeutic effects of substances in cannabis roots, leaves and seeds.
- Cannabis Constituent Synergy in a Mouse Neuropathic Pain Model
This animal study demonstrated that CBD strengthens the pain-killing power of THC during the treatment of neuropathic pain. The results suggest that a combined low dose of THC and CBD is the best option for dealing with neuropathic pain.
- Single and Combined Effects of Δ⁹-Tetrahydrocannabinol and Cannabidiol in a Mouse Model of Chemotherapy-Induced Neuropathic Pain
This study in mice demonstrated that really small doses of CBD or THC – administered separately – do not have an effect on reducing neuropathic pain caused by chemotherapy. However, when THC and CBD are administered in combination, these two substances have a synergetic effect and can be effective in dealing with pain.
- Appraising the “Entourage Effect”: Antitumor Action of a Pure Cannabinoid Versus a Botanical Drug Preparation in Preclinical Models of Breast Cancer
This animal study demonstrated that a full extract of cannabis has a better effect on treating tumours (breast cancer) than pure THC.
- The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain
This article proposes to stop categorising cannabis varieties by strains and to categorise them by chemical properties (‘chemovars’) instead. Furthermore, according to this article it is assumed that the combination of substances has a better therapeutic effect than the active substances alone – the ‘entourage effect’.
- An Experimental Randomized Study on the Analgesic Effects of Pharmaceutical-Grade Cannabis in Chronic Pain Patients With Fibromyalgia
This clinical study demonstrated that administering a combination of THC and CBD demonstrated a synergetic effect in patients, whereby the CBD increased the amount of THC in the bloodstream.