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MEDICAL CANNABIS

History of the medicinal use of cannabis

Cannabis is probably one of the oldest cultivated plants of mankind. Thus, its use as a medicinal plant for therapeutic purposes is also anchored early in history. Documented evidence of both psychotropic and therapeutic uses goes back as far as 5000 years.

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 indica
Cannabis sativa
Cannabis ruderalis

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.

ENDOCANNABINOID SYSTEM

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.

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 called trichomes. These are found in particularly high density on the flowers of female cannabis plants.

Terpenes

Terpenes are volatile hydrocarbons that 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 been described in cannabis so far.

Accordingly, there is a huge variety of different aromas but also of different pharmacological effects. The individual composition of the terpenes, also called terpene profile, contributes to the characteristic chemotype of the respective cannabis variety.

Phytocannabinoids

Phytocannabinoids are bioactive plant substances found in various flowering plants, but also in fungi. Over 100 cannabinoids are known to date for the cannabis plant.

Cannabinoids are formed from their respective precursors, the cannabinoid acids, which occur in high concentrations in living as well as in fresh plant tissue. The neutral cannabinoids are formed from the cannabinoid acids by decarboxylation. This metabolization is induced by factors such as UV light, heat (e.g. during smoking or vaporization), or prolonged storage.

Δ9-THC

Δ9-THC (Δ9-tetrahydrocannabinol, THC) is probably the best known phytocannabinoid and is responsible for the psychotropic effects of Cannabis sativa L.. 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 effect of this phytocannabinoid. From a scientific point of view, THC is probably the most extensively studied phytocannabinoid. In particular, its analgesic and anti-inflammatory properties are well documented in the context of numerous acute and chronic diseases.

CBD

CBD (cannabidiol) is the best known representative of the non-psychotropic phytocannabinoids of the cannabis plant. CBD acts as an antagonist of endogenous cannabinoid receptors. This means that CBD attaches to CB1 and CB2 receptors and thereby blocks them. Even though this attaching 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 properties of this phytocannabinoid. Further studies complement these results with possible immunosuppressive and neuroprotective properties.

CBG

CBG (cannabigerol) is another non-psychoactive cannabinoid that is found in larger amounts mainly in low-THC cannabis plants. It is a partial agonist of CB1 and CB2 receptors and binds to them with low affinity. In addition to its anti-inflammatory properties, CBG has been recognized to have an anti-depressant effect. Promising data obtained in animal models also suggest an anti-bacterial effect of CBG.

CBC

CBC (cannabichromene) also belongs to the non-psychoactive cannabinoids. In addition to analgesic, sedative, and anti-inflammatory properties, CBC, like CBG, shows promising effects as an anti-microbial agent. Moreover, initial studies revealed first evidences that CBC may have an inhibitory effect on tumor growth, thus gaining increasing attention 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 for long periods 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 attach to CB1 and CB2 receptors. For CB2 receptors, it has been described as a partial agonist with activating effects. However, at CB1 receptors, attaching induces different signals depending on the concentration: at low concentrations, THCV acts as an antagonist and has a blocking effect. At higher concentrations, however, it triggers several signal cascades, resulting in a psychotropic effect similar to THC. In low amounts, however, it reduces the psychoactive effect of THC. Various studies also 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.

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).

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