Cannabis sativa is the natural source of cannabinoids. It is a dioecious plant that has separate specimens with male and female flowers. Cannabis is unpretentious enough to be grown on industrial scale. It 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 cosmetic products and as fodder. Psychoactive properties of cannabis were also known to people, but it was used rarely that way. Industrial exploitation of cannabis was seriously restricted in 1961 due to the coming into force of the "Single Convention on Narcotic Drugs". Despite the fact that a lot of countries have passed the laws prohibiting use of cannabis derivatives, nowadays, it is used as a drug by 130-230 million people.
Cannabis psychoactive effects are due to cannabinoids – a group of terpenphenolic compounds of plant origin. Dozens of cannabinoids are known, but Δ9-tetrahydrocannabiol is the most powerful one in terms of psychoactive effects. Other members of cannabinoid family have them to a lesser extent. Cannabinoids are formed in plants in two ways. The polyketide pathway involves their synthesis from olivetolic acid. The second pathway is more complex: it is based on the production of geranyl diphosphate followed by synthesis of monoterpenes. Wonder why cannabis needs this group of substances at all? Most likely, as in the case of nicotine, cannabinoids are a protective factor against insects. It is not quite clear, whether they have a direct effect on the central nervous system of insects or affect them in some other way, but their effectiveness in this role cannot be disputed.
In a recent study by the Institute of Molecular Medicine in Lisbon, together with researchers from the British Lancaster University, it was stated that long-term use of cannabis worsens memory. This conclusion was claimed to be true both in people who use it recreationally, and in people taking cannabis-containing medicine for treatment of some forms of epilepsy, chronic pain and multiple sclerosis. Lancaster University studied the effect of a specific drug called WIN-55,212 and found out serious memory disorders in that experimental animals. As a result of long-term use during ethological experiment, the mice could not distinguish between a familiar and a new object. Among other things, during functional studies of the animal brain, certain disorders were visualized in some areas involved in memory and learning. All of this, in fact, underlies negative effects of cannabis on the process of memorization.
Back in 2012, researchers led by Abush proved that long-term cannabis use had a statistically significant association with cognitive dysfunction and an increased risk of developing symptoms of mental disorders, including a spectrum of schizophrenic disorders. On animal models, it was revealed that the negative effects of cannabinoids on learning and memory were associated with dysfunction of long-term potentiation of synaptic transmission. Also, with a decreased modification of neural oscillations modeled by gabaergic interneurons and with a change in activity in the monoaminergic and cholinergic pathways of the hippocampal septum, which plays an important role in plasticity and other important processes.
Scientists had been trying to find the target of cannabinoid action for a long time. This was done in 1988, when the first type of cannabinoid receptors(CB1-receptors) were described. In 1993, the second type of receptors was also revealed (CB2-receptors). CB1 receptors are located in the central nervous system. Activation and blocking of CB1 affect memory processes, neuroprotection, nociception. Besides the brain, they can be found in the liver, myocardium, kidneys, gastrointestinal tract, lungs, as well as in the endothelial lining and the muscular wall of blood vessels. CB2 is widely represented in immune and endothelial cells. Synthetic cannabinoids, which are a part of smoking mixtures, mainly stimulate CB1-receptors, that is why this substances change person's mental state.
CB1 and CB2 receptors are 44% identical in their amino acid sequence. Both types of receptors belong to the class of G-protein-coupled receptors. Now scientists know the highly accurate crystal structure of cannabinoid receptor. Moreover, in the recent years it has become possible to understand how receptors change during interaction with THC and with other cannabinoid - hexahydrocannabiol. Interestingly, by using 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 have receptors to cannabis in our body at all? A year before the description of the second type of receptors, the journal Science published a paper where another part of endocannabinoid system – anandamide was a subject of consideration. In other words, it is a molecule produced in the human body that acts on the same receptors as cannabinoids do. Besides anandamide, endogenous cannabinoids include 2-arachidonoylglycerin. CB1-receptors are found 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.
Despite restriction in application, marijuana and isolated substances of cannabis found use in medicine. Growing cannabis for medical purposes and production of medicine from cannabis are strictly regulated by the government. It is unlikely that any scientific research at this point could be considered as an argument in favor of marijuana legalization and it's safety. When it comes to cannabis and its application in medicine, 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. The situation with cannabis and cannnabinoids is similar: why make people smoke marijuana, when you can determine the active substance, synthesize or isolate it from plants and use for treatment of diseases? Medical application of cannabinoids resembles how artemisinin isolated from annual wormwood began to be used to treat malaria. Chinese researcher Yu Tu received the Nobel Prize in Physiology or Medicine in 2015 for this discovery.
In the meta-analysis of 2013, it was found that the use of THC and marijuana itself increased appetite of patients in this group and contributed to weight gain. In earlier works, dronabinol (a synthetic analog of THC) was compared in effectiveness with megestrol acetate in terms of weight gain in patients with cancer cachexia. It turned out that megestrol surpasses its competitor in this task. Other direction of cannabinoid application is treatment of nausea and vomiting in patients undergoing chemotherapy for oncological diseases. The brain area responsible for the vomiting response (area postrema) is rich in CB1 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 in these nerve structures leads to a decrease in the feeling of nausea and the cessation of vomiting. Studies have shown that cannabinoids cope with nausea and vomiting caused by chemotherapy better than neuroleptics, but they are still a worse option than ondansetron. Usually, cannabinoids are not first-line medication and are used when other methods of treatment are ineffective.
Interestingly, cannabinoids have the potential to be anti-cancer drugs. A large amount of laboratory data has been accumulated on stimulation of cannabinoid receptors leading to the cancer cell's death. 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 without involvement of the receptors in the central nervous system, then we will have a good medication for cancer treatment in our hands. In addition to cannabinoid application in cancer and AIDS treatment, they can be used in the therapy of multiple sclerosis. They are able to cope with spasticity better than placebo (but the difference is not very great). In addition to this, they are quite useful against neuropathic pain of various origins, which is another one of their benefits.
Some medications based on cannabinoids:
Cannabis psychoactive effects are due to cannabinoids – a group of terpenphenolic compounds of plant origin. Dozens of cannabinoids are known, but Δ9-tetrahydrocannabiol is the most powerful one in terms of psychoactive effects. Other members of cannabinoid family have them to a lesser extent. Cannabinoids are formed in plants in two ways. The polyketide pathway involves their synthesis from olivetolic acid. The second pathway is more complex: it is based on the production of geranyl diphosphate followed by synthesis of monoterpenes. Wonder why cannabis needs this group of substances at all? Most likely, as in the case of nicotine, cannabinoids are a protective factor against insects. It is not quite clear, whether they have a direct effect on the central nervous system of insects or affect them in some other way, but their effectiveness in this role cannot be disputed.
In a recent study by the Institute of Molecular Medicine in Lisbon, together with researchers from the British Lancaster University, it was stated that long-term use of cannabis worsens memory. This conclusion was claimed to be true both in people who use it recreationally, and in people taking cannabis-containing medicine for treatment of some forms of epilepsy, chronic pain and multiple sclerosis. Lancaster University studied the effect of a specific drug called WIN-55,212 and found out serious memory disorders in that experimental animals. As a result of long-term use during ethological experiment, the mice could not distinguish between a familiar and a new object. Among other things, during functional studies of the animal brain, certain disorders were visualized in some areas involved in memory and learning. All of this, in fact, underlies negative effects of cannabis on the process of memorization.
Back in 2012, researchers led by Abush proved that long-term cannabis use had a statistically significant association with cognitive dysfunction and an increased risk of developing symptoms of mental disorders, including a spectrum of schizophrenic disorders. On animal models, it was revealed that the negative effects of cannabinoids on learning and memory were associated with dysfunction of long-term potentiation of synaptic transmission. Also, with a decreased modification of neural oscillations modeled by gabaergic interneurons and with a change in activity in the monoaminergic and cholinergic pathways of the hippocampal septum, which plays an important role in plasticity and other important processes.
Scientists had been trying to find the target of cannabinoid action for a long time. This was done in 1988, when the first type of cannabinoid receptors(CB1-receptors) were described. In 1993, the second type of receptors was also revealed (CB2-receptors). CB1 receptors are located in the central nervous system. Activation and blocking of CB1 affect memory processes, neuroprotection, nociception. Besides the brain, they can be found in the liver, myocardium, kidneys, gastrointestinal tract, lungs, as well as in the endothelial lining and the muscular wall of blood vessels. CB2 is widely represented in immune and endothelial cells. Synthetic cannabinoids, which are a part of smoking mixtures, mainly stimulate CB1-receptors, that is why this substances change person's mental state.
CB1 and CB2 receptors are 44% identical in their amino acid sequence. Both types of receptors belong to the class of G-protein-coupled receptors. Now scientists know the highly accurate crystal structure of cannabinoid receptor. Moreover, in the recent years it has become possible to understand how receptors change during interaction with THC and with other cannabinoid - hexahydrocannabiol. Interestingly, by using 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 have receptors to cannabis in our body at all? A year before the description of the second type of receptors, the journal Science published a paper where another part of endocannabinoid system – anandamide was a subject of consideration. In other words, it is a molecule produced in the human body that acts on the same receptors as cannabinoids do. Besides anandamide, endogenous cannabinoids include 2-arachidonoylglycerin. CB1-receptors are found 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.
Despite restriction in application, marijuana and isolated substances of cannabis found use in medicine. Growing cannabis for medical purposes and production of medicine from cannabis are strictly regulated by the government. It is unlikely that any scientific research at this point could be considered as an argument in favor of marijuana legalization and it's safety. When it comes to cannabis and its application in medicine, 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. The situation with cannabis and cannnabinoids is similar: why make people smoke marijuana, when you can determine the active substance, synthesize or isolate it from plants and use for treatment of diseases? Medical application of cannabinoids resembles how artemisinin isolated from annual wormwood began to be used to treat malaria. Chinese researcher Yu Tu received the Nobel Prize in Physiology or Medicine in 2015 for this discovery.
In the meta-analysis of 2013, it was found that the use of THC and marijuana itself increased appetite of patients in this group and contributed to weight gain. In earlier works, dronabinol (a synthetic analog of THC) was compared in effectiveness with megestrol acetate in terms of weight gain in patients with cancer cachexia. It turned out that megestrol surpasses its competitor in this task. Other direction of cannabinoid application is treatment of nausea and vomiting in patients undergoing chemotherapy for oncological diseases. The brain area responsible for the vomiting response (area postrema) is rich in CB1 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 in these nerve structures leads to a decrease in the feeling of nausea and the cessation of vomiting. Studies have shown that cannabinoids cope with nausea and vomiting caused by chemotherapy better than neuroleptics, but they are still a worse option than ondansetron. Usually, cannabinoids are not first-line medication and are used when other methods of treatment are ineffective.
Interestingly, cannabinoids have the potential to be anti-cancer drugs. A large amount of laboratory data has been accumulated on stimulation of cannabinoid receptors leading to the cancer cell's death. 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 without involvement of the receptors in the central nervous system, then we will have a good medication for cancer treatment in our hands. In addition to cannabinoid application in cancer and AIDS treatment, they can be used in the therapy of multiple sclerosis. They are able to cope with spasticity better than placebo (but the difference is not very great). In addition to this, they are quite useful against neuropathic pain of various origins, which is another one of their benefits.
Some medications based on cannabinoids:
- Nabiximol — spray, containing a mixture of 2 cannabinoids: THC and cannabidiol. Used for treatment of spasticity and pain as a symptom of multiple sclerosis. It is also used to treat pain syndrome in oncological diseases.
- Dronabinol — synthetic THC, which has antiemetic action and increases appetite. It is used to treat emaciated AIDS patients and patients with nausea and vomiting during chemotherapy.
- Nabilon — medication, which was based on a cannabinoid, structurally similar to THC. It is used to treat vomiting and nausea caused by chemotherapy.
When studying the brain of people who used cannabis for a long time (more than one year daily or at least 3 times a week) by functional magnetic resonance imaging, significant changes in the functional connections of brain structures related to "self-awareness" and certain types of memory were shown, as well as functional changes in the structures of the medial temporal lobe and prefrontal cortex. The Department of Biomedical and Biological Sciences at Lancaster University has done a lot of work to study the effect of chronic cannabis use on some metabolic processes of the brain, its functional connections and recognition memory. The results of the experiment demonstrated impaired cerebral metabolism and abnormal functional connections with the cortico-thalamo-hippocampal circuits underlying the processes of memorization.
At the same time, a deficiency of recognition memory was revealed without signs of altered motor abilities and anxious behavior. It is CB1-r in synapses that inhibit glutamatergic and GABAergic transmission with modeling of various forms of synaptic plasticity and neural oscillations that support various cognitive functions, including behavior and memory. Also, there was a disruption of the functional connections of the subiculum (the base of the hippocampus). It is a part of the recognition memory, and it receives direct axon connections from other parts of the brain responsible for long-term memory. Changes in the serotonin system function are confirmed by altered functional connections of the part of the brain called the habenula, the nuclei raphes with a change in the induction of serotonin levels in synapses and the density of serotonin receptors. All of this leads to the development of memory function deficiency. An interesting fact is that when using the CB1r antagonist (AM-251), the negative effect of cannabinoids on memory is leveled, and at high doses of cannabis and AM-251, there is no pronounced decrease in glucose uptake and mitochondrial respiration.
At the same time, a deficiency of recognition memory was revealed without signs of altered motor abilities and anxious behavior. It is CB1-r in synapses that inhibit glutamatergic and GABAergic transmission with modeling of various forms of synaptic plasticity and neural oscillations that support various cognitive functions, including behavior and memory. Also, there was a disruption of the functional connections of the subiculum (the base of the hippocampus). It is a part of the recognition memory, and it receives direct axon connections from other parts of the brain responsible for long-term memory. Changes in the serotonin system function are confirmed by altered functional connections of the part of the brain called the habenula, the nuclei raphes with a change in the induction of serotonin levels in synapses and the density of serotonin receptors. All of this leads to the development of memory function deficiency. An interesting fact is that when using the CB1r antagonist (AM-251), the negative effect of cannabinoids on memory is leveled, and at high doses of cannabis and AM-251, there is no pronounced decrease in glucose uptake and mitochondrial respiration.
Thus, it was proposed to determine a treatment strategy for the restoration of obvious memory deficits, correction of cognitive impairment in people who use cannabis for a long time. The following algorithm of therapeutic correction of cognitive disorders is recommended:
- Moderate intensity physical activity, intellectual exercise and a change of "habitual environment": daily swimming, physical therapy, board games (chess, etc.), changing hands when brushing teeth, reading aloud, learning foreign languages, compliance with the sleep-wake cycle.
- «Namenda» - 5 mg per day with meals for two weeks, then 5 mg once every three days for a month and a half.
- «Tebokan» (EGb 761) – one tablet once a day for one month (NB! Has no proven effectiveness).
- «Meldonium Olainfarm» - one tablet (250 mg) in the morning, with meals, for 1.5 months.
- Multivitamins - course.
- "Acetyl-L-carnitine" - 500 mg twice a day for 1.5 months.
- «Nicerbium» or «Sermion» - course for 14 days.
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