Cannabidiol

Cannabidiol, also known by the abbreviation CBD, is a non-psychoactive ingredient of the female hemp plant (Cannabis sativa). It is found mainly in the flower, but also partially in the leaves of this plant. CBD belongs to the cannabinoids, a large, heterogeneous group of substances from the hemp plant, which includes more than 100 different in the form of resin. Cannabidiol is one of the best-known cannabinoids, along with the psychoactive ingredient tetrahydrocannabinol (THC).

Unlike THC, however, cannabidiol has no effect on the central nervous system and is therefore not intoxicating.
Medically, the anticonvulsant, anti-inflammatory and anti-anxiety properties of this active ingredient are increasingly exploited. Furthermore, it is effective against nausea. It is believed that there are other pharmacological effects in cannabidiol, which is why research is still ongoing to date.

Cannabidiol is contained in Sativex® together with THC in a 1:1 ratio as an oral spray and is used to relieve muscle spasms in multiple sclerosis.

As a monopreparation, cannabidiol is contained in Epidyolex® 100mg/ml as an oral solution. It is used to treat seizures associated with two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome in children at least 2 years of age and adults.

Likewise, it finds use in a genetic disorder called tuberous sclerosis (TSC).

It can be used alone or in combination with other antiepileptic medications.

Epidyolex® is a prescription medication that is to be used after close consultation with the doctor and following his/her instructions. The dose is determined by the doctor/pharmacist and depends individually on the patient's age, weight as well as the severity of the disease. The solution is taken twice a day, if possible always under the same circumstances (with or without a meal).

Cannabidiol is now also processed in all kinds of forms such as drops, oils, teas as well as cosmetic products and can exert calming, analgesic, anti-inflammatory, anti-anxiety and stress-relieving effects in the body, among others.

History

Cannabidiol was first discovered in 1940 by the American chemist Roger Adams. He isolated the cannabinoid from hemp extract and elucidated its chemical structure. In the following years, further research was conducted regarding the pharmacological properties of CBD.

In the 1960s, THC (tetrahydrocannabinol) was identified by Israeli scientists Yehiel Gaoni and Raphael Mechoulam, leading to a better understanding of the effects of these two cannabinoids on the human body.

Since then, numerous studies have been and continue to be conducted to gain new knowledge and exploit the potential of these active ingredients with each passing day.

Pharmacodynamics/mechanism of action

Like THC, cannabidiol is able to bind to the CB1 and CB2 receptors of the endocannabinoid system, thus triggering its effects. The CB1 receptors are predominantly located in the brain, while the CB2 receptors are distributed throughout the body, but are primarily found in the components of the immune system.

The natural ligands are endogenous substances such as anandamide, an arachidonic acid analogue whose structure is similar to those of THC and cannabidiol, triggering the same effects in the body at a certain equilibrium.

However, cannabidiol can not only bind to these receptors and trigger positive effects, but it can also block them through an unknown mechanism, preventing their effects from being exerted.

Cannabidiol inhibits the effects of the G protein-coupled receptor GPR55 by blocking the binding site without itself eliciting an effect. The physiological function of this receptor in the body is not yet fully understood.

There is likewise evidence that cannabidiol interacts with opioid receptors and may relieve stress by attenuating nerve signals.

Cannabidiol likewise interacts with vanilloid-1 receptors, causing an attenuation of pain in the body.

However, the exact mechanisms of action of cannabidiol are still being researched and are largely unresolved.

Pharmacokinetics

The pharmacokinetics of cannabidiol, the process from absorption to excretion from the body, is influenced by several factors such as dosage, route of administration, and the patient's age, gender, and health status.

Cannabidiol is best absorbed by the body after oral ingestion with a fatty meal. The bioavailability is approximately 6-20%, which means that only this portion actually reaches the bloodstream eventually due to the high first-pass effect, in which the active ingredient is partially metabolized in the liver.

Due to its lipophilic structure, cannabidiol, like THC, accumulates in fatty tissues such as the brain or liver.

Cannabidiol is metabolized primarily in the liver by CYP450, CYP3A4, and CYP2C19 enzymes, for example. Cannabidiol and its metabolites are then excreted mainly in the stool, to a lesser extent in the urine - the half-life is about 9 hours, which means that after these 9 hours, cannabidiol is half excreted from the body.

Interactions

Cannabidiol as an active ingredient may interact with the following drugs/groups of drugs:

• CYP3A4/ CYP2C19 inducers such as rifampicin, carbamazepine, enzulatamide, mitotane, and St. John's wort may decrease the effectiveness of cannabidiol.
• Antiepileptic drugs may result in increased effects and side effects with cannabidiol, so monitoring is required with concomitant use.
• UGT inhibitors may increase the efficacy of cannabidiol, so dose reduction may need to be ordered with concomitant use.
• Clobazam increases effects such as drowsiness when taken concomitantly with cannabidiol. In that case, the dose of clobazam should be decreased.
• Valproate increases transaminase enzyme levels when taken concomitantly with cannabidiol; it also increases the risk of diarrhea (diarrhea) and decreased appetite.
• Stiripentol may cause adverse side effects when combined with cannabidiol.
• Lamotrigine may have increased levels when used concomitantly with cannabidiol.
• Based on in vitro data, interactions may occur with concomitant use of CBD with CYP1A2 substrates (e.g., theophylline, caffeine, tizanidine), CYP2B6 substrates (e.g. Bupropion, efavirenz), CYP2C8 substrates (repaglinide), CYP2C9 (e.g., warfarin), UGT1A9 substrates (e.g., propofol, fenofibrate), and UGT2B7 substrates (e.g., gemfibrozil, morphine, lorazepam).
• In vitro data have likewise shown that cannabidiol inhibits CYP2C19 substrates, which may result in increased levels of drugs metabolized by this enzyme.

Contraindications & precautions

• Epidyolex should not be taken in case of hypersensitivity to the active ingredient cannabidiol or any other component of the formulation.
• Phenytoin has a narrow therapeutic range, therefore caution should be exercised when combined with cannabidiol.
• Epidyolex has been shown to cause elevated liver enzyme levels, which may subsequently result in liver injury. Increased transaminase levels are an indication of this and should therefore be monitored during treatment.
• Suicidal thoughts as well as risks of injury may occur during treatment with Epidyolex. In this case the doctor should be consulted immediately.

Side effects

The most common side effects of cannabidiol include:

• Somnolence
• decreased appetite
• diarrhea
• fever
• fatigue
• Vomiting

Other side effects that may be common include:

• Pneumonia
• Urinary tract infections
• irritability, aggression
• lethargy (listlessness), seizures
• Cough

Pregnancy and lactation

Due to insufficient studies and data, the exact effect of cannabidiol on pregnant women is unknown. Therefore, for safety reasons, use during pregnancy is not recommended. Likewise, it is not known whether cannabidiol and its metabolites can pass into breast milk or what effects it might have on the infant. Therefore, it is also not recommended to use cannabidiol during breastfeeding unless absolutely necessary and prescribed by a physician.