Cannabinoids in medicine

A dead end or a promising direction?

Viktor Lebedev, "Biomolecule"

In some countries, the use of cannabis and its derivatives for medical purposes is allowed. Perhaps in the future there will be more such countries, and at the same time the number of drugs based on cannabinoids will increase (inquisitr.com ).

Cannabis is surrounded by a "drug-addicted" halo, and the discussion of this plant from the standpoint of medicine is often perceived only as a reason to talk about the legalization of marijuana. The text you are reading is not related to the discussion on this topic. We will talk about what this plant can give to medicine.

Plants for ropes

The natural source of cannabinoids is Cannabis sativa (Fig. 1), a dioecious plant that has separate individuals with male and female flowers. Hemp is unpretentious enough to grow it on an industrial scale.

Drawing 1. Seed hemp (medieval botanical atlas).

Hemp has long been a source of material for fabrics and ropes: the famous hemp ropes were made from hemp fibers. Also, different parts of cannabis were used as cosmetics and allowed to feed cattle. The psychotropic effect of cannabis was also known to people, but in this capacity it was used relatively rarely.

The industrial use of cannabis was severely restricted in 1961 due to the entry into force of the "Single Convention on Narcotic Drugs". Despite this fact and the fact that many countries have adopted laws prohibiting the use of cannabis derivatives, today 130 to 230 million people use it as a drug worldwide [1].

The effect of cannabis on the psyche is caused by cannabinoids – a group of terpenphenolic compounds of plant origin. In total, several dozen cannabinoids are known, but the strongest psychotropic effect is provided by Δ9-tetrahydrocannabinol (THC) (Fig. 2). Other representatives of this family possess it to a lesser extent. In plants, cannabinoids are formed in two ways (Fig. 3). The polyketide pathway allows the synthesis of cannabinoids from olivetolic acid. The second mechanism is more complex: it is based on the production of geranyl diphosphate and the subsequent synthesis of monoterpenes [2].

Drawing 2. The tetrahydrocannabinol molecule (Wikipedia).

Drawing 3. Ways of biosynthesis of cannabinoids in seed hemp [2].

I wonder why cannabis needs this group of substances at all? Most likely, as in the case of nicotine, cannabinoids protect the plant from insect pests. It is not entirely clear whether they have a direct effect on the central nervous system of insects or act in some other way, but their effectiveness in this role is not disputed.

In search of a receptor

The possibility of exposure of a chemical substance to the human body implies the presence of a point of application (in other words, a target of action). This may be a specific receptor, as in the case of digoxin contained in digitalis. Another option is the global effect of the drug on a variety of processes and binding to a variety of receptors. Alcohol has a similar effect (but this is not accurate) [3].

Scientists have been trying for a long time to find the target of the action of cannabinoids in the human body. This was done in 1988, when type 1 cannabinoid receptors (CB1 receptors) were described [4]. In 1993, a second class of cannabinoid receptors (CB2 receptors) was also discovered [5]. CB1 receptors are located in the central nervous system. Activation and blocking of CB1 affect memory processes, neuroprotection, nociception. In addition to the brain, they can be found in the liver, myocardium, kidneys, gastrointestinal tract, lungs, as well as in the endothelial lining and muscle wall of blood vessels. CB2 is widely represented on immune and endothelial cells (Fig. 4) [6]. Synthetic cannabinoids, which are contained in smoking mixtures, mainly stimulate CB1 receptors - that's why these drugs so seriously change a person's mental state [7].

Drawing 4. Expression of cannabinoid receptors in human organs [6].

CB1 and CB2 receptors are 44% identical in their amino acid sequence [8]. Both types of receptors belong to the class of receptors associated with G-protein (on our website you can read a selection of articles about this type of cellular structures). Now scientists know with high accuracy the crystal structure of the cannabinoid receptor [9]. In addition, in recent years it has been possible to understand how receptors change when interacting with THC and another cannabinoid, hexahydrocannabinol [10]. Interestingly, with the help of pharmacological methods, it is possible to block CB1 and CB2 receptors separately, but at the same time it is not possible to stimulate them separately.

The question arises: why do we need receptors for the cannabis substance in our body? A year before the description of the second type of receptors, Science magazine published a paper describing anandamide, a representative of the endocannabinoid system of our body [11]. In other words, it is a molecule produced in the human body that acts on the same receptors as cannabinoids. In addition, endogenous cannabinoids include 2-arachidonoylglycerin. CB1 receptors are located in the neurons of the cerebral cortex, basal ganglia, cerebellum and hippocampus. The function of these receptors is to reduce the release of neurotransmitters – GABA or glutamate (Fig. 5) [12-14].

Drawing 5. The role of CB1 receptors in the nervous system. Stimulation of postsynaptic receptors leads to the production of 2-arachnoidylglycerin (2-AG), which, by binding to the presynaptic receptor, reduces the production of neurotransmitters by the feedback mechanism. In addition, 2-arachidonoylglycerin reduces the production of ATP in the mitochondria of astrocytes, reducing the intensity of metabolic processes. Symbols: mGluR5 – metabotropic glutamate receptor type 5; M1 – muscarinic receptor; CB1 – CB1-receptor; MAGL – monoacylglycerin lipase; NAPE -PLD – N-arachnoidylphosphatidylethanolamine phospholipase D; ATP – ATP; 2-AG – 2-arachnoidylglycerin; AA – anandamide; ABHD6 – protein 6, containing α/β-hydrolase domain; PIP2 – phosphatidylinositol bisphosphate; DAGLa – diacylglycerin lipase α; PLCß – fofsfolipase C β; COX-2 – cyclooxygenase-2; FAAH – hydrolase of fatty acid amides; PGE2-GE – glycerin ester of prostaglandin E2 [14].

Cannabis in a white coat

Despite the limitations in use, marijuana itself and isolated active substances of cannabis began to be used in medicine. The cultivation of cannabis for medical purposes and the subsequent production of medicines from it are strictly regulated by the state. It is unlikely that such activity of scientists can be considered as an argument in favor of the legalization of marijuana or its safety for humans. When it comes to cannabis and its medical use, another example of a "natural" medicine comes to mind – penicillin. The invention of penicillin was due to the fact that a certain type of mold suppressed the growth of bacteria in the laboratory. Nobel laureate Alexander Fleming, who made this discovery, later planned to isolate the active substance, synthesize it on an industrial scale and use it as a medicine [15].

With cannabis and cannabinoids, the situation is similar: why force people to smoke marijuana if you can simply identify the active substance, synthesize or isolate it from plants and use it in the treatment of diseases? The medical use of cannabinoids is reminiscent of how artemisinin from annual wormwood began to be used to treat malaria. Chinese researcher Yu Tu received the Nobel Prize in Physiology or Medicine for this discovery in 2015 [16].

Thanks to the song "In the supermarket" by the group "Casta", we know that under the influence of cannabinoids, a person's appetite increases. 

The why and how this happens is discussed in detail in the article "It broke through to the havchik" [17], and we will not dwell on this here. Now it is important to understand under what conditions this effect of cannabinoids can be used. As a rule, we are talking about the depletion of the body, which is observed in the advanced stages of HIV infection. A 2013 meta-analysis found that the use of THC and the use of marijuana itself can increase the appetite of patients in this group and contribute to weight gain [18]. In earlier work, dronabinol (a synthetic analogue of THC) was compared in effectiveness with megestrol acetate in terms of weight gain in patients with exhaustion on the background of cancer [19]. It turned out that megestrol acetate copes with this task better than its competitor.

Another direction of using cannabinoids is the treatment of nausea and vomiting during chemotherapy of oncological diseases [20]. The area of the brain responsible for the occurrence of vomiting (area postrema) is rich in type 1 cannabinoid receptors. These same receptors are present in large numbers in the nucleus of the solitary tract and the nuclei of the vagus nerve, which are also involved in the processes of nausea and vomiting. Stimulation of cannabinoid receptors on these nerve structures leads to a decrease in the feeling of nausea and the cessation of vomiting. Studies have shown that cannabinoids cope better with nausea and vomiting caused by chemotherapy than neuroleptics, but they lose out in this respect to ondansetron. Usually, cannabinoids are not first-line drugs and are used when other treatment methods are ineffective.

Interestingly, cannabinoids also have potential as anti-cancer drugs [21]. A large amount of laboratory data has been accumulated that stimulation of cannabinoid receptors can lead to the death of cancer cells. Similar studies have been conducted on breast, prostate, lung and pancreatic cancers. These types of tumors are widespread in the population and give high mortality rates, and existing treatment methods often do not give a satisfactory result. If we can find a way to stimulate the cannabinoid receptors of cancer cells and not involve the receptors in the central nervous system, then we will have a good remedy for cancer treatment in our hands.

The problem is similar to the one that faced the researchers when they were looking for the "ideal" opioid – a substance with a powerful analgesic effect, but without side effects in the form of addiction and respiratory depression. Apparently, after a long search, this problem was solved [22]. Now it is possible to use technologies for the digital construction of new molecules to search for the "ideal" cannabinoid that will work only on cancer cells.

Another approach is related to the peculiarities of cannabinoid receptors – they cannot be stimulated individually, but they can be blocked. In this case, the drug will be a mixture of a non-selective stimulant of cannabinoid receptors and their selective blocker. A similar principle is used in the treatment of Parkinson's disease with a combination of levodopa and carbidopa. Levodopa, as a precursor of dopamine, enters the central nervous system and improves the patient's motor function. Carbidopa "works" on the periphery, preventing the side effects of levodopa from manifesting.

In addition to use in oncopathology and For example, cannabinoids can be used in the treatment of multiple sclerosis [23]. They are better able than placebo to cope with spasticity in this disease (but the difference is not very great). In addition, cannabinoids help in the fight against neuropathic pain of various origins, which adds points to them (Fig. 6) [24].

Drawing 6. "Sativex" – a drug based on cannabinoids, 
which helps to fight spasms and pain syndrome
with multiple sclerosis (volteface.me ).

Noise source

Now let's talk about how cannabinoids and schizophrenia are related. Schizophrenia is a chronic mental disorder represented by three groups of symptoms. The first group (productive symptoms) includes delusions and hallucinations. The second group included negative symptoms: volitional decline, smoothness of emotional reactions. The third group (cognitive symptoms) – specific distortions in the processing of information by the patient's brain. You can read more about schizophrenia in the article "The Disease of lost connections" on our website [25].

The feeling of surveillance, constant internal tension and suspicion that a person experiences is a phenomenon often found in schizophrenia. For simplicity, it can be called paranoia. As the already mentioned "Caste" group informs us, when using marijuana, there may be a feeling of surveillance. Under the influence of cannabinoids, a person may feel that people around him are looking at him, discussing him or laughing at him. Experiencing such feelings, a person begins to be afraid and avoid crowded places, tries to behave secretly.

This similarity suggests that cannabinoids are able to change the work of the brain of a healthy person so that it becomes similar to the work of the brain of a patient with schizophrenia. Our neurons are constantly exchanging electrical signals, and in a healthy person this process is stable and without significant failures. In the case of schizophrenia, the signals become less stable, the amount of neural noise in them increases. The more noise, the higher the random component in the signal, the less stable the connection between neurons. This phenomenon is observed in schizophrenia, and it explains part of the symptoms of the disease. At the same time, an increased level of neural noise is observed during a period without pronounced productive symptoms [26]. The level of neural noise becomes significantly higher during the period of exacerbation of the disease [27].

Read about how stochastic processes in the brain are generally arranged in the article "Chaos in the brain" [28].

When using cannabinoids, healthy participants in the experiment showed an increase in the level of neural noise, and at the same time they experienced a number of symptoms characteristic of schizophrenia [29]. It is possible that the increase in the level of neural noise is caused by a malfunction of gabaergic interneurons, which stabilize the signal under normal conditions. Stimulation of this population of nerve cells by cannabinoids disrupts their function, and the signal becomes more chaotic. However, if we can find a cannabinoid that can act the other way around (that is, improve the work of interneurons), then we can get another drug for schizophrenia.

Cannabinoids, despite their The "narcotic" plume is just one of many classes of chemical compounds. They can be used for medical purposes, and this is already happening now. The range of their application is not very wide today, but it can be increased through further research. Will we get a new cannabis medicine? The question remains open. Open and interesting.

Preparations based on cannabinoids

There are three cannabinoid-based drugs on the world market that are already being used:
Nabiximols is a spray containing a mixture of two cannabinoids: THC and cannabidiol. It is used to treat spasticity and pain in multiple sclerosis. It is also used for the treatment of pain syndrome in oncological diseases.
Dronabinol is a synthetic THC that has an antiemetic effect and increases appetite. It is used by emaciated AIDS patients and patients with nausea and vomiting during chemotherapy.
Nabilone is a drug based on a cannabinoid structurally close to THC. It is used for nausea and vomiting caused by chemotherapy.

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Portal "Eternal youth" http://vechnayamolodost.ru  21.07.2017