Delta-9-tetrahydrocannabinol (THC)

^{Δ9-Tetrahydrocannabinol}is one of the cannabinoids, the constituents of the Cannabis sativa (hemp plant). THC is often abused as an intoxicant due to its intoxicating effect, especially in the form of marijuana or hashish.

THC is naturally present in the plant as an acid and must be converted to the active form (THC) by heating. Therefore, THC is often introduced into the system through smoking, as this is the fastest way to release the effects of the substance. THC is similar to anandamide, which is an endocannabinoid in the body. Endocannabinoids are produced by the body itself and are therefore considered endogenous cannabinoids. For these, there are specific receptors in the body to which they dock in the endocannabinoid system and trigger their effects.

^{Δ9-Tetrahydrocannabinol}is pharmacologically known as dronabinol, a semi-synthetic derivative that has great therapeutic potential. It is processed mainly in the form of solutions or capsules and is used to treat pain or severe nausea, as well as loss of appetite in the context of chemotherapy. Thus, THC acts as a means of relief for people with severe illnesses. Other effects of dronabinol are still being studied.

Dronabinol preparations are usually magisterially, i.e. individually, prepared in pharmacies on the basis of a doctor's prescription. In Germany as well as Austria, two finished medicinal products are currently approved on the market, namely the mouth spray Sativex® for the relief of spasticity occurring in multiple sclerosis and Canemes® for the attenuation of nausea and vomiting in people suffering from cancer who are being treated by chemotherapy.

THC is not soluble in water due to its strong lipophilicity (fat solubility) and appears as a pale yellow, oily liquid or resin at room temperature. In addition, THC is sensitive to oxidation and light, so drug preparations should be prepared quickly.

Applications and indications

Dronabinol drops make up the majority of medical prescriptions and are taken orally, as the active ingredient is well absorbed by both the oral mucosa and the digestive tract.

Since every patient reacts differently to the active ingredient, the dose is adjusted individually by the doctor and can be adjusted again during the course of therapy. It is important to strictly adhere to the doctor's instructions!

It is recommended to take dronabinol in the morning and in the evening before meals.

Dronabinol capsules are an alternative to drops.

The finished drug Canemes® is a synthetic cannabinoid with the active ingredient nabilone.

Sativex® is the first and only cannabinoid-based finished drug containing THC and CBD (cannabidiol; also a cannabinoid).

Finished medicines are also based strictly on medical instructions.

History

THC was identified in the 1960s thanks to Israeli scientists Yehiel Gaoni and Raphael Mechoulam. It wasn't until 20 years later that Mechoulam and his team discovered the endocannabinoid system in humans, as well as the natural endogenous cannabinoid anandamide, which is structurally similar to THC. This was the beginning of research that continues to this day.

Pharmacodynamics/ Mechanism of action

THC's mode of action in the body is controlled by the endocannabinoid system, binding predominantly to CB1 receptors, which exert effects that predominantly affect the brain. CB2 receptors are distributed throughout the body, but are primarily found in components of the immune system.

The natural ligands of these receptors are endogenous substances called anandamides, which are formed from arachidonic acid in the body. Like THC, they are lipophilic and act similarly to THC in the body, among other things, in the regulation of pain and appetite. They also trigger a natural "euphoric" effect in the body and always try to establish a healthy balance.

An influence on this endocannabinoid system by e.g. THC can have considerable effects on these natural processes.

With THC as a ligand to the CB1 receptor, the processes originating from it can be significantly altered. In contrast to anandamide, which is broken down more quickly in the body, THC has a longer efficacy and thus leads to a lasting effect. However, it all depends on the dose, which is why THC can be abused as an intoxicant or exploited pharmacologically and cause positive effects.

With the binding of THC to the CB1 receptor, neurotransmitters are released that cause signal transmissions that mainly affect the nervous system and trigger effects such as feelings of happiness or pain relief.

However, the exact mechanism of action is not yet fully understood!

Pharmacokinetics

Dronabinol is medically administered either in the form of drops on the oral mucosa or orally as capsules. In this case, the bioavailability of the substance reaches in about 10-20% and the maximum concentration of the active substance is reached after about two hours.

Due to their high lipophilicity, they are able to lodge in fatty tissue, gradually detach from it, and thus re-enter the blood circulation. This is the reason for the prolonged half-life, i.e. the concentration of dronabinol in the blood decreases very slowly due to this.

The amount of the active ingredient that reaches the blood circulation after oral ingestion (bioavailability) is low due to the first-pass effect. As a result, it is first broken down in the liver before reaching the blood circulation.

Dronabinol is mainly degraded in the liver via CYP 450 enzymes and excreted mostly in the feces, with a smaller portion excreted in the urine. The metabolites formed in the course of degradation from the active ingredient are no longer psychoactive, but are equally capable of being deposited in fatty tissue, whereupon they are removed only very slowly. Thus, dronabinol and its degradation products are detectable in the blood, but how long depends on the amount of consumption.

Interactions

Since magistral preparations with dronabinol are used in seriously ill patients who are taking many medications anyway, the occurrence of interactions and dangers is quite possible.

The most common interactions that can occur are due to metabolism via CYP450 enzymes in the liver, as more than half of all drugs are broken down this way. The following interactions are not unique to dronabinol, but apply to all cannabinoids!

Substances that can increase the effect of dronabinol are:

• Antidepressants
• Opiode
• Antifungals
• Amiodarone
• Macrolides
• Isoniazid
• Antiviral agents
• Calcium antagonists
• Proton pump inhibitors such as omeprazole, pantoprazole

Substances that may reduce the effect of dronabinol include:

• St. John's wort
• Carbamazepine
• Phenytoin
• Phenobarbital
• Troglitazone
• Rifampicin
• Rifabutin

Dronabinol may alter the effects of the following agents by enzyme inhibition:

• Risperidone
• Omeprazole
• Warfarin
• Diclofenac

Contraindications & precautions

Extreme caution should be exercised when administering muscle relaxants, hypnotics, sedatives, and generally drugs that have a sedative effect such as tranquilizers, as they may potentiate each other's effects. This could lead to conditions such as severe drowsiness, dizziness and an increased risk of falls.

Alcohol and dronabinol can also potentiate each other's effects, which is why it is strongly advised not to consume alcohol when taking dronabinol.

If there are pre-existing conditions, especially heart disease, psychiatric disorders such as schizophrenia/depression or dependence (alcohol, drugs, medication), the doctor should be informed before therapy.

Side effects

The frequency and severity with which side effects may occur depends on the amount consumed as well as the length of time taken.

Common side effects that may occur include:

• Fatigue
• Dizziness
• Pulse acceleration
• mood swings
• increased sensory perception
• nausea
• diarrhea
• anxiety

Pregnancy and lactation

There are insufficient data to assess the effects of dronabinol on pregnant women, but it is not advised. Similarly, it is not known whether dronabinol can pass into breast milk or what effects it might have on the infant. Therefore, it is also not recommended to take dronabinol while breastfeeding unless prescribed by a doctor or absolutely necessary.