MEDICALCANNABIS PRODUCTS
Origin of Cannabis
Cannabis is probably one of the oldest cultivated plants in human history. Various historical sources prove that hemp is one of the most frequently cultivated crops worldwide. The term “hemp” has Indo-European origins and is derived from the Old German or Old English names “Hanaf” or “Hamp”. The first documentation of what cannabis looks like has been handed down from the year 512 AD. The so-called Anicia Codex, an ancient illustrated pharmaceutical manual, contains the first botanical drawing of the cannabis plant.
The origin of cannabis is often attributed in the literature to the East or West Asian region. From there, the cannabis plant was spread worldwide and its many uses became established in the advanced civilizations of the time.
Hash, a dried resin, is made from the glandular hairs of the female cannabis plant. Hash finds its origin in the Arab world, especially in Morocco. From there, its worldwide distribution took place. “Hash” is distinct from the term “marijuana.” The latter is made from the dried shoot tips of the plant. Historical sources indicate that marijuana has its origin in advanced Chinese civilizations.
History of the medical use of cannabis
Just as historical as the origin of cannabis itself is its importance in medicine. Thus, its use as a medicinal plant for therapeutic purposes is anchored early in history. Documented references to both psychotropic and therapeutic uses go back as far as 5000 years.
Сannabis Products
Hemp is one of the best researched plants in the history of mankind. As a result, several hundred biologically active substances of the plant are known today. The cannabis plant is an (economically) interesting crop in many respects. This is reflected in a wide range of cannabis products on the global market. From paper to pharmaceuticals – the hemp plant is considered a true multi-talent, as almost all components of this renewable raw material can be used and the research into new applications is flourishing.
Use in cosmetics and food industry
In the areas of the cosmetics and food industries, the so-called commercial hemp or industrial hemp is being increasingly used as a renewable source of raw materials. In Germany, the varieties approved as commercial hemp are strictly regulated by the Ministry of Agriculture and Food (BLE): only varieties containing a maximum of 0.2% THC (THC is the psychoactive component of the cannabis plant) may be cultivated.In the cosmetics industry, the oil extracted from the hemp seeds as well as extracts from the roots or even the leaves of the hemp plant are used. The product spectrum ranges from body and hair care products to bath additives. Products containing CBD in particular are becoming increasingly popular, as many functions valuable for the skin are attributed to this cannabinoid: According to the CosIng (Cosmetic Ingredients) database, CBD (CAS # 13956-29-1) has sebum-reducing, antioxidant, skin-conditioning and skin-protecting effects.
Hemp products are also becoming increasingly popular in the food industry. In particular, hemp seeds are used there because of their valuable substances. The hemp oil extracted from the seeds, or hemp seed oil, is an edible oil with numerous valuable ingredients: First and foremost are essential fatty acids, such as unsaturated omega-3 and omega-6 fatty acids. In addition, hemp oil contains a high concentration of important minerals such as zinc, iron, calcium and magnesium, as well as a large amount of vitamins, such as B1, B2 and E. In the course of the production of hemp cooking oil, the so-called hemp seed cake is produced as a by-product. This is highly rich in protein and is the main source of hemp protein. Hemp seeds and hemp protein are increasingly found in muesli bars, in shakes or in teas.
Use in the paper, textile and construction industries
Hemp is considered one of the most high-yielding fiber crops. The appearance of hemp fibers is similar to that of flax fibers. Especially the longitudinal fibers of the cannabis stalk are often used in the paper and textile industry. But hemp fibers are also being used more and more frequently in the economic sector of building and insulating materials, and research is constantly being carried out into new possible applications. As a renewable raw material, hemp is lucrative in many industries, especially because of its high yield. Some varieties reach a height of about 7 meters in a relatively short time. The fibers of the hemp plant are also longer compared to other plants. This gives them extreme durability and tensile strength. The fiber length is also particularly interesting with regard to recycling in paper production, as they remain usable over a higher number of recycling cycles.
Medical Use
Unlike the industrial use of commercial hemp, which involves both female and male hemp plants, only female cannabis plants are processed for medical purposes. In Germany, as of November 2022, cannabis products are only dispensed by prescription and distributed through pharmacies. A general distinction is made between two categories of prescription cannabis products: Finished medical products and prescription medicinal products.
According to Section 4(1) of the AMG, finished medical products are defined as “medical products that are prepared in advance and placed on the market in a package intended for delivery to the consumer, or other medical products intended for delivery to consumers, in the preparation of which an industrial process is otherwise used or which are manufactured commercially, except in pharmacies. Finished medical products are not intermediate products intended for further processing by a manufacturer.” Examples of cannabis-based finished medical products include Sativex®, Canemes®, or Epidyolex. Prescription medicinal drugs, on the other hand, are prepared on a patient-specific basis by a pharmacist in response to a physician’s prescription. Both cannabis flowers and cannabis extracts are considered prescription drugs.
The list of cannabis products that can be prescribed in Germany is growing steadily, and more and more manufacturers of medical cannabis products are entering the market. This contributes to a continuous expansion of legally available cannabis products in Germany.
LEGAL SITUATION
IN GERMANY
Prehistory
Although cannabis was used as a medicinal plant early in history, acceptance of cannabis-based medicines was lacking for a long time.
Since 2007, patients could submit an exemption permit to the Federal Opium Agency. However, this permit was only approved in exceptional cases and any treatment costs incurred had to be borne by the patients themselves.
Over the years, however, the open-mindedness towards the use of cannabis for medical purposes increased and the therapeutic potential became more and more the focus of new research approaches.
A corresponding draft law of the German government in 2016 paved the way for the legalization of cannabis as a therapeutic option.
Current legal situation
On January 19, 2017, the amendment to the law was passed and came into force on March 10, 2017. This amendment mainly affected both the German Narcotic Drugs Act, the Narcotic Drugs Prescription Ordinance, and Volume V of the German Social Insurance Code.
Specifically, this resulted in the following innovations:
- Cannabis flowers as well as extracts can be prescribed for therapeutic purposes. This means that the previously required application for an exemption at the Federal Opium Agency is no longer necessary.
- Every practicing physician, with the exception of dentists and veterinarians, can prescribe Cannabis-based medicinal products in pharmaceutical quality on a narcotic prescription.
- The treatment costs are covered by health insurance companies if certain requirements are met.
Thus, the legalization of medical cannabis for therapeutic purposes opens up new possibilities for health care in Germany.
CANNABIS VARIETIES
Botany of Cannabis sativa L.
The botanical genus Cannabis belongs to the hemp family (Cannabaceae). From a scientific point of view, the genus Cannabis includes only one species:
Cannabis sativa L. However, a division into three cannabis species is often found:
Cannabis sativa and Cannabis indica are used today in various hybrid breedings to generate different chemotypes. These have either a high THC and low CBD content, or vice versa, a high CBD and low THC content. The third chemotype is an intermediate form with balanced concentrations of THC and CBD.
Although these varieties differ in their THC and CBD content, their distinction is not based on this parameter alone. Rather, the overall composition of cannabinoids and terpenes and the resulting chemical profile serve to characterize them.
A further distinction is also made between (medicinal) cannabis and the so-called fiber hemp or industrial hemp (often referred to as commercial hemp). By definition, fiber hemp contains no more than 0.2% THC. As the name suggests, this form is used in particular for the extraction of hemp fibers. Its seeds are also used for food (e.g. hemp oil) and cosmetics.
In gerenal, there are both male and female cannabis plants. For medicinal purposes, mainly the flowers of the female plant are used due to the higher cannabinoids content.
ENDOCANNABINOIDSYSTEM
The endocannabinoid system (ECS) is a biological system of our body that can interact with endogenous cannabinoids to regulate vital processes. However, this interaction is not limited to endocannabinoids: plant cannabinoids, known as phytocannabinoids, can also interact with this system. The ECS is thus the biological basis for externally supplied cannabinoids to exert their effects in our bodies.
Essentially, the endocannabinoid system (ECS) consists of three components:
- endogenous cannabinoids such as anandamide (N- arachidonylethanolamide, AEA) and 2- arachidonylglycerol (2-AG).
- anabolic and catabolic enzymes for synthesis and degradation of cannabinoids
- specific cannabinoid receptors (CB1 and CB2 receptors).
The ECS mainly takes an essential role in the modulation of neuronal activities but also in the regulation of the functioning of various other organs. Numerous neurological dysfunctions are associated with dysregulation of this complex network, which is why the ECS is increasingly becoming the focus of medical treatment approaches.
Cannabis plant-derived phytocannabinoids, such as Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), can attach to CB1 and CB2 receptors in a analogous manner to endogenous cannabinoids thereby intercepting and counteracting potential dysregulation of the ECS.
CB1 receptors are particularly abundant in the central nervous system, where they are among the most common G-protein coupled receptors. In addition to the nervous system, the ECS is also associated with the immune system. Here, CB2 receptors in particular play an essential role, occurring on immune cells such as T and B lymphocytes and macrophages, as well as on hematopoietic cells.
The general mechanism of action of ECS in the neuronal context is to modulate neurotransmitter activity and reduce excessive responses. The inhibitory effect is based on the activation of cannabinoid receptors on neurons through binding of endocannabinoids. Endocannabinoids, unlike most other neurotransmitters, are not produced acutely by the upstream presynaptic neuron, but permanently by the downstream postsynaptic neuron.
If the concentration of other neurotransmitters in the synaptic cleft between two neurons is particularly high, endocannabinoids are increasingly produced at the postsynapse and released into the synaptic cleft. At the presynapse, they bind to the cannabinoid receptors expressed there, which are then activated and trigger a signaling cascade that reduces the excessive neurotransmitter activity on the presynaptic side (retrograde inhibition).
Recent scientific findings have proven that endocannabinoids also affect our digestive tract via the so-called gut-brain axis. This interaction leads to the fact that the ECS also exerts a decisive influence on the control of nausea and vomiting.
The complete elucidation of the exact functioning of the ECS is currently the subject of numerous research projects. However, ECS and thus the medical application of phytocannabinoids is already proving to be a promising concept of novel therapeutic approaches for various neuronal and chronic diseases.
Pharmacokinetics and bioavailability of cannabinoids
The term pharmacokinetics describes the entirety of processes in the body to which a drug is subjected to: starting with absorption, distribution throughout the body, metabolization and then finally excretion.
The root of administration of a drug has a decisive influence on its pharmacokinetics and thus ultimately on the availability of the active ingredients in the body (bioavailability).
INGREDIENTS AND ACTIVE SUBSTANCES
Cannabis sativa L. accumulates its characteristic constituents such as terpenes and cannabinoids not in intracellular vacuoles (cell organelles filled with cell sap) but in fine glandular hairs known as trichomes. These occur in particularly high density on the flowers of female cannabis plants. Among the best characterized cannabis active ingredients are the so-called terpenes and the phytocannabinoids, including the best-known active ingredient THC. The strain-specific composition of the cannabis ingredients ultimately determines the pharmacological effect of the plant.
Terpenes
Terpenes are volatile hydrocarbons and form the largest group of organic compounds in plants. They determine the characteristic smell and taste of a plant and are therefore the most important component in essential oils. More than 200 terpenes have now been described for cannabis.
The variety of different aromas but also of different pharmacological effects is consequently large. The individual composition of the terpenes, also called terpene profile, contributes to the characteristic chemotype of the respective cannabis strain.
Phytocannabinoide
“Over 100 cannabinoids are known to date for Cannabis sativa L.”
Cannabinoids form from their respective precursors, cannabinoid acids, which are found in high concentrations in freshly cut plant tissue. Decarboxylation produces the active cannabinoids from the cannabinoid acids. This metabolization is induced by factors such as UV light, heat (e.g. during smoking or vaporization), or prolonged storage.
THC
Δ9-THC (Δ9-tetrahydrocannabinol, THC) is probably the best known phytocannabinoid and is responsible for the psychotropic effect of Cannabis sativa L.. THC is highly lipophilic (fat soluble) and accumulates primarily in fatty tissue and the spleen. If THC is released again from the fatty tissue, it has a half-life of several days to several weeks.
From a scientific perspective, THC is probably the most extensively researched phytocannabinoid. It is known that THC is a partial agonist of both CB1 and CB2 receptors. This means that the binding of THC to these receptors, preferentially to the CB1 receptors, triggers an activating signal that is ultimately responsible for the psychoactive effects of this phytocannabinoid. In particular, its analgesic and anti-inflammatory properties are well documented in the context of numerous acute as well as chronic diseases.
For the medical use of the cannabis plant, an accurate declaration of the THC content is required. This requires that all pharmaceutically used THC products are tested for their THC content by means of specified standardized laboratory methods (in Germany according to the German Pharmacopoeia).
CBD
CBD (cannabidiol) is the best-known representative of the non-psychotropic phytocannabinoids of the cannabis plant. In contrast to THC, CBD is also predominantly found in commercial hemp (fiber hemp).
CBD acts as an antagonist of endogenous cannabinoid receptors. This means that CBD binds to CB1 and CB2 receptors, thereby blocking them. Even though this binding to the receptors occurs with comparatively low affinity, this inhibitory mechanism of action gives CBD the property to mitigate some undesirable side effects of THC. Pre-clinical studies particularly demonstrate the anti-inflammatory (anti-inflammatory) properties of this phytocannabinoid. Further studies complement these with possible immunosuppressive (immune response suppressing) and neuroprotective (nerve protecting) characteristics.
The CBD content as well as, if applicable, the THC/CBD ratio of cannabis products determines their medicinal effect. CBD, as already described for THC, must therefore be tested according to precise specifications in quality control laboratories before a product can be placed on the market.
CBG
CBG (cannabigerol) is another non-psychoactive cannabinoid that is found in larger amounts mainly in low-THC cannabis plants. It counts as a “precursor” cannabinoid for THC and CBD. As a partial agonist, it binds to binds CB1 and CB2 receptors with low affinity. In addition to its anti-inflammatory properties, CBG is thought to have anti-depressant effects. Promising data collected in animal models also suggest an antibacterial effect of CBG.
CBC
CBC (cannabichromene) also belongs to the non-psychoactive cannabinoids. In addition to its analgesic, sedative, and anti-inflammatory properties, CBC, like CBG, has promising anti-microbial potential. Initial studies also show promising results that CBC may have an inhibitory effect on tumor growth, which is why it is attracting increasing attention, especially in cancer research.
CBN
CBN (cannabinol) is present in fresh cannabis only in small amounts, as it is a product of THC oxidation. This reaction occurs mainly when THC is exposed to oxygen, heat or light over a long period of time. CBN is characterized not only by its general anti-inflammatory and pain-relieving properties, but also by its sedative effect.
Δ9-THCV
Δ9-THCV (Δ9-tetrahydrocannabivarin, THCV) is a propyl analog of THC. THCV can also bind to CB1 and CB2 receptors. For CB2 receptors, it has been described as a partial agonist with activating effects. However, at CB1 receptors, binding induces different signals depending on the concentration: at low concentrations, THCV acts as an antagonist and has a blocking effect. Higher concentrations, however, trigger activating signals. As a result, at higher concentrations THCV has a psychotropic effect similar to THC. In low amounts, however, it reduces the psychoactive effect of THC. Various studies suggest anti-inflammatory and anticonvulsant properties of THCV.
Various pre-clinical studies provide evidence that cannabinoids enhance each other’s biological activity, but also in combination with other herbal ingredients such as terpenes. This principle is referred to as the entourage or synergy effect.
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