Cannabis is an annual plant genus belonging to the Cannabaceae family. Cannabis, which is used in yarn, weaving, and fabric production with its fibers in its stems, and the pulp part in making paper, is known as one of the oldest vegetable raw materials in human history, and marijuana, which is obtained from the flowers and seeds of the cannabis plant and has narcotic properties, is the most widely used illegal substance in the western world. Besides the health hazards of using cannabis as a drug, there is also evidence showing its benefits to health.
Cannabis treatment has been used for years as a painkiller and mode regulator. Nowadays, there are research examples supporting cannabis treatment for cancer and MS disease. Many scientists and healthcare organizations, including the American Cancer Society (ACS), for example, support the need for more scientific research into the use of cannabis and marijuana drugs to treat medical conditions. In this article, I’ll get into detail about cannabis treatment.
Use Of Cannabis for Treatment Purposes From Past to Present
The use of cannabis, which is thought to be the first cultivated plant, goes back thousands of years, and it is known that its flowers and resin are used in meditation and in various religious rituals in India and Tibet. In the first Chinese pharmacopeia (3200 BC) written by Emperor Chen Nung, it is written that cannabis was used in the treatment of fatigue, rheumatism, and malaria, and according to sources, hemp seeds were used in Chinese medicine as an anti-inflammatory agent in eczema and psoriasis due to their oil and protein content.
It is understood from the Ebers Papyrus and Assyrian tablets written about 3000 years ago that cannabis is widely used as a medicine. Cannabis is also a well-known plant used as a medicine in the Ancient Greek and Roman periods. When the data of this period are examined, it is observed that cannabis was used to relieve pain and improve mood.
Galen, a Roman physician, was one of the physicians prescribing medical cannabis, adding that Roman aristocrats ended their dinner with a cannabis-containing dessert. Ibn-i Sina wrote that the compress made with boiled cannabis root reduces fever.
The spread of cannabis use for medical purposes first to Arabia and then to the entire Middle East corresponds to the ninth century. At the end of the 13th century, when the famous traveler Marko Polo mentioned it in his travel book on his return to the west, the cannabis plant attracted the attention of Europe and began to be used extensively.
Leonhart Fuchs, a German botanist, and physician wrote in his book containing herbal treatments written in 1542 that cannabis root, which is boiled in water and wrapped in the relevant area, is good for gout. Portuguese physicians Garcia also Orta and Cristobal Acosta discussed the euphoric, sedative, appetizing, hallucinogenic, and aphrodisiac effects of cannabis.
At the end of the 18th century, the return of Napoleon’s army to Egypt introduced hemp to France. Irish Dr. O’Shaughnessy observed that the cannabis plant was used for analgesic, antispasmodic, antiemetic, and hypnotic purposes in India, and with this information obtained from India, the medical use of the cannabis plant was spread in the United Kingdom in the 1840s. It is stated that cannabis was also used for Queen Victoria’s menstrual cramps in the 1890s. In these years, cannabis has been used as a pain reliever, anti-inflammatory, antiemetic and anticonvulsant in England.
Cannabis Treatment After 19th Century
The cannabis plant was included in the American Pharmacopoeia between 1850 and 1942, while its use reached its peak in these periods, it has declined since the 1930s. In the United Kingdom, in 1928, the use of recreational cannabis was banned first, and then the name marijuana, which created a perception that it was very dangerous, was used instead of the name cannabis. In fact, in 1936, a propaganda movie called “Reefer Madness” was made to keep American youth away from using cannabis.
Among the reasons for these anti-propagandas, the presence of dangerous synthetic derivatives, variations in their effects due to the difficulty in standardizing herbal products, unreliable sources of supply, commercial pressures, and the abuse of euphoric effect, especially in countries such as Egypt, South Africa, and the USA, can be cited. In 1937, resulting in the US “Marihuana Tax Act” extended the scope of the ban and as a reflection of it many drugs in countries’ pharmaceutical codexes removed from the formulary, and prohibited from sale.
With the “Controlled Substances Act” enacted in 1970 in the USA, possession, use, sale, purchase, and cultivation of marijuana is prohibited. All these inspections and laws prevented the abuse of cannabis, but this also limited the supply of cannabis for scientific studies and its use in the clinic.
Scientific research on cannabis has continued despite all adverse conditions. Gaoni and Mechoulam revealed the chemical structure of tetrahydrocannabinol (tetrahydrocannabinol-THC), which is the main component responsible for the euphoric effect of cannabis in 1964. The CB1 receptor was found in 1988 and the CB2 receptor in 1993, and then endocannabinoids (anandamide, 2-arachidonic glycerol, et al.) and enzymes that synthesize and degrade endocannabinoids (FAAH and MGL) were discovered.
All these discoveries have increased the interest in the medical use of cannabis, and its use in the clinic has become popular again. The first state law was enacted in 1996 to free the use of medical cannabis in the USA. Today, cannabis use is legal in 29 states such as California, Nevada, Massachusetts, and Colorado in the USA. Recently, laws on the medical use of cannabis have been enacted in many European countries, and health professionals and scientific authorities also support the legalization process of medical cannabis.
Canada is one of the first countries to enact a law on the use of medical cannabis, and in 2001 it implemented the medical cannabis use law. In a study conducted in Canada in 2019, it was stated that doctors and pharmacists have positive views on the medical use of cannabis and even think it has fewer side effects than many existing medical treatments according to their personal experience.
Today, there are 4 cannabis-based drugs in total, 2 synthetic drugs in which the THC active substance in cannabis is used as a prototype, and 2 drugs using standardized extracts of cannabis. Dronabinol and nabilone are American Food and Drug Administration (FDA) approved synthetic cannabinoids used for nausea and vomiting accompanying cancer chemotherapy.
Nabiximols, on the other hand, is a standardized cannabis extract containing 2.7 mg THC and 2.5 mg cannabidiol (cannabidiol-CBD) in 100 microliters and used in the treatment of spasticity due to multiple sclerosis that does not respond to other available treatments in the form of a spray. Finally, in 2018, the cannabidiol-containing drug called Epidiolex was approved by the FDA to be used in the treatment of Lennox-Gastaut syndrome and Dravet syndrome, two severe and rare forms of epilepsy.
Therapeutic Use Of Cannabis on Treatment of Various Diseases
The idea that cannabis can be used in the treatment of many diseases has been around for a long time, as it contains phytocannabinoids, terpenes, and many different effective compounds that are not detailed here. Scientific studies on this subject have increased significantly, especially in the last 5 years. Below are data on the healing effect of cannabis on various diseases or symptoms.
The endocannabinoid system is thought to be one of the target mechanisms in age-related neurodegenerative diseases such as Alzheimer’s. In in vivo and in vitro preclinical experiments, cannabinoids have been shown to reduce β-amyloid toxicity and show a neuroprotective effect. In the study conducted by Suliman et al. in 2018, it was found that low-dose 9-THC significantly triggered neurogenesis in the hippocampus of elderly rats. It has been determined by in vitro experiments that THC regulates mitochondrial activities and therefore it has been stated that THC can slow the prognosis of Alzheimer’s disease.
It has also been found that 9-THC reduces intraneuronal β-amyloid accumulation and has an anti-inflammatory effect. Inflammation in the brain is one of the key mechanisms in the formation of neurodegenerative diseases such as Alzheimer’s. Therefore, it is predicted that besides both CB1 and CB2 receptor agonists such as 9-THC, selective CB2 agonists can also suppress neuroinflammation and oxidative stress damage and improve decreased memory functions.
Studies show that cannabis can be both anxiogenic and anxiolytic. It has been determined that low doses of 9-THC have anxiolytic effects, whereas high doses of 9-THC have an anxiogenic effect. In the same study, it was found that CBD exerts an anxiolytic effect by affecting the limbic and paralimbic regions in both animals and humans.
In a randomized clinical study in which a single dose of 600 mg cannabidiol was used, 24 participants with generalized social anxiety disorder were included, and compared with placebo, cannabidiol was shown to relieve these people’s anxiety due to public speaking. These data explain why so many people around the world are turning to cannabis to get rid of their anxiety complaints.
It is a known fact that people who use cannabis have an increased appetite. Likewise, THC and other CB1 agonists are also stated to have appetite-enhancing effects. In their experiments conducted by Scherma et al in 2017 in an anorexic rat model, they found that both natural 9-THC and its synthetic form reduced weight loss and increased activity in rats by increasing leptin signal and lowering plasma corticosterone levels.
Many studies suggest that CB1 stimulation can increase appetite and reduce weight loss in anorexic patients or severe anorexia due to cancer. Dronabinol, a synthetic THC derivative, has been used in the treatment of anorexia in AIDS patients since 1992.
In the diabetic rat model, it has been found that cannabidiol slows β-cell injury by decreasing IL-12 release from macrophages and plasma IFN-levels, and therefore studies on the importance of endocannabinoids in diabetes are increasing. However, the evidence for this main mechanism is not yet sufficient.
However, it has been found that glutathione reserves in the liver are significantly reduced and lipid peroxidation is increased in diabetes. In a study conducted on diabetic rats, it was found that CBD increases glutathione reserves in the liver and decreases lipid peroxidation accordingly. In this study, it was also determined that low NGF concentrations, one of the mechanisms responsible for diabetic neuropathy, can be increased with CBD treatment.
In another study, it has been proven that CBD and THC have higher levels of antioxidant activities than α-tocopherol and ascorbate. When all these data are evaluated, it is possible to say that cannabis is particularly promising in complications involving oxidative mechanisms such as diabetic neuropathy, but further research is needed on other mechanisms.
Many preclinical studies have shown that cannabinoids can be used in epilepsy. Although preclinical and clinical studies conducted with CBD and cannabidivarin, a propyl derivative of CBD, revealed its anticonvulsant effect, the mechanism of this effect has not been fully elucidated. In the study conducted by Szaflarski et al. with 72 children and 60 adults in 2018, it was observed that CBD treatment significantly relieved epileptic symptoms.
Following these studies, FDA approved the drug containing CBD named “Epidiolex” for use in the treatment of Lennox-Gastaut syndrome and Dravet syndrome, two severe and rare forms of epilepsy. Finally, Aran et al. stated in their retrospective study that CBD is a safe, tolerable, and effective treatment for persistent behavioral problems in children with ASD (atrial septal defect).
Considering all these data, it is seen that CBD, one of the phytocannabinoids, has a high therapeutic potential in various seizures, epilepsy, and other neurodegenerative disorders.
- Nausea-Vomiting Accompanying Chemotherapy
As is known, nausea and vomiting are among the most common side effects of drugs used in cancer chemotherapy. It is known that THC and cannabidiol prevent nausea and vomiting through CB1 receptors and some other mechanisms. Dronabinol and nabilone have been used in the clinic since the 1980s for the relief of nausea and vomiting due to chemotherapy, especially in cancer patients who cannot get results with conventional antiemetics.
- Chronic Pain
As it is known, one of the first effects of cannabis discovered on human health is its analgesic activity. Medical cannabis users also use cannabis mostly because of this effect. Although it is effective in many types of pain, including migraine, bone, and joint pain, menstrual cramps, etc., its effectiveness is much higher in difficult-to-treat pain types that do not respond to conventional treatments such as neuropathic pain and cancer pain. For this purpose, standardized hemp extract nabiximols containing THC and CBD has been used in the clinic since 2010.
Different preparations of cannabis can cause gastrointestinal pain, gastroenteritis, diarrhea, etc. It has been known to be used in many gastrointestinal diseases for a long time. Phytocannabinoids such as CBC, CBD, and CBG have been reported by various researchers to act as an anti-inflammatory in inflammatory bowel disorders in various experimental models. In the study of Nallathambi et al., it was determined that 9-THCA has anti-inflammatory properties in colon epithelial cells.
- Spasticity due to Multiple Sclerosis
Today, drugs used in the treatment of multiple sclerosis symptoms such as muscle spasticity, neuropathic pain, tremor, ataxia, and neurogenic bladder are not fully curative and their use may be limited due to side effects. This is the reason why cannabis is being tried increasingly by multiple sclerosis patients all over the world.
After 2010, Nabiximols started to be used in many countries, especially in Canada and most of Europe, in the treatment of spasticity and pain due to multiple sclerosis that does not respond to conventional treatments. Psychoactive side effects and resistance were reported at a very low level during these treatments, and the patients tolerated the treatment well.
- Schizophrenia and Other Psychosis
It has been shown that cannabidiol inhibits the psychoactive effects of THC and also has positive effects on metabolic, inflammatory, and stress-related symptoms in schizophrenia. In a randomized double-blind clinical study conducted by Leweke et al., 42 patients with schizophrenia were compared with cannabidiol and amisulpride after 4 weeks, and cannabidiol treatment was found to be superior because it both effectively reduced psychotic symptoms and had fewer side effects.
- Sleeping disorders
There are studies showing that short-term treatments with nabilone and dronabinol may be beneficial in obstructive sleep apnea. Studies have proven that nabilone also reduces nightmares due to post-traumatic stress disorder and improves sleep quality in patients with chronic pain.
- Tourette Syndrome
Tourette Syndrome (TS) is a neurodevelopmental disorder with a frequency of 0.4-0.6 in childhood, characterized by motor and vocal tics that last at least a year. It has been proven in some clinical studies that chronic cannabis or dronabinol therapy reduces tics in treatment-resistant Tourette syndrome.
Phytochemical Content and Treatment Effects of Cannabis
Cannabis is a plant rich in secondary metabolites. Today, 545 compounds from C. Sativa species have been isolated and it is predicted that this number will increase with new studies. More than 100 of them are phytocannabinoids that are more specific to cannabis strains and show cannabinoid activity. Phytocannabinoids are the most researched secondary metabolite group related to cannabis that is found in plants and binds to CB1 (cannabinoid receptor 1) and CB2 (cannabinoid receptor 2) receptors in the body and produces different pharmacological effects.
The main production sites in cannabis are the epidermal glandular hairs on the leaves, flowers, bracts, and stem of the plant. Resin is secreted from these glandular hairs, called trichomes, and this resin acts as a defense mechanism that protects the plant from pests and herbivores. It also has the function of protecting the plant from moisture and heat. The resin with psychoactive and medicinal effects is mainly found in the flowering branch tips and braces of the female plant. Resin secretion is low in the leaves of male plants.
Although cannabinoids are also found in the tepal, stamens, and pollen of male plants, they are not as dense as in female plants. THC in the resin secreted from trichomes is the main molecule responsible for the psychoactive effect and it is possible to obtain different products with different amounts of THC depending on which part of the plant is used. Examples of the most common narcotic uses are Bhang (obtained from the dried flowering ends and leaves of the male and female plants), Ganja (obtained by drying and crushing the non-pollinated female plants), and Charas (extracted with organic solvents from the raw resin collected at the plant tips. .) can be given.
The ratio of phytocannabinoids contained in cannabis also varies according to the environmental conditions in which it grows (eg radiation, temperature, humidity, soil composition, parasites, etc.). Less rain, low humidity, and an increased amount of sun lead to the increase of psychoactive substances synthesized by the plant. Again, in the studies, it was determined that the THC ratio in the structure of the plant increased as a result of UVB exposure.
The 104 phytocannabinoids isolated so far have been grouped into 10 chemical subgroups. These are 9-tetrahydrocannabinol, 8-tetrahydrocannabinol, cannabigerol, cannabichromene, cannabidiol, cannabinodiol, cannabielsoin, cannabicyclol, cannabinol, cannabitriol, and others. Terpenoids, flavonoids, steroids, phenanthrenes, fatty acids, nitrogen compounds, and other common plant molecules are other compounds identified in cannabis other than cannabinoids. Among these compounds, phytocannabinoids and terpenoids have been studied in detail because they are the major groups in cannabis.
Treatment With Cannabis Seed Oil
In addition to the content of cannabis rich in phytocannabinoids and terpenoids, it would be appropriate to mention hemp seed oil, which has been used as a food supplement and even as an aid to treatment in some diseases and has a very high nutritional value.
Judging by its composition, hemp seed oil consists of 25-35% fatty acids, 20-25% protein, 20-30% carbohydrate, 10-15% fiber, and many trace elements. It is very valuable because it contains all essential amino acids and essential fatty acids. The majority of its oil consists of polyunsaturated fatty acids linoleic acid (LA) and α-linolenic acid (ALA).
Moreover, the LA / ALA ratio is 3: 1 and this corresponds to the ideal omega6 / omega3 ratio. As it is known, omega3 fatty acids are anticancer, anti-inflammatory, antithrombotic, cardiovascular health-protective, antiosteoporotic, antiallergic, protecting nervous system health, and so on. In addition to these fatty acids, hemp seed oil also contains -linolenic acid, which further increases its nutritional value.
Apart from the unsaturated fatty acid content, just like hemp itself, its oil contains various terpenes. These terpenes in their structure also add anti-inflammatory, antiallergic, and cytoprotective properties to the oil. Apart from that, hemp seed oil also contains a phytosterol known as-sitosterol with antiviral, antifungal, anti-inflammatory, and antihyperlipidemic properties.
Hemp seed oil is also rich in vitamin E derivatives, also known as tocopherols. This increases the antioxidant capacity of the oil. Another component with pharmacological effects is methyl salicylate, which is structurally very similar to acetylsalicylic acid. Methyl salicylate is known to have anti-inflammatory, analgesic, and antipyretic effects. Apart from these, hemp seed oil may contain slightly higher amounts of 9-THC and CBD due to the fact that it is contaminated with the resin secreted from the trichomes of the plant during its production and mainly containing 9-THC and CBD.
However, no undesirable side effects related to hemp seed oil consumption have been reported so far. There are even opinions stating that CBD in oil will have positive effects on health due to its pharmacological effects. When all these data are evaluated, it is possible to say that the nutritive content of hemp seed oil is very high and at the same time, it can have extra contributions to health with the secondary metabolites it contains.
Although studies on parts of cannabis such as flowers, bracts, and leaves that contain phytocannabinoids come to the fore, it is possible to say that the root part of cannabis has many pharmacological effects and should be evaluated, considering its historical use and phytochemical content.
Unlike flowers, bracts, and leaves, the root of cannabis is not rich in cannabinoids. Instead, it contains triterpenes such as friedelin and epifriedelanol, alkaloids such as cannabisativin and anhydrocannabisativin, and various sterols. Studies have found that triterpenic compounds found in cannabis roots have anti-inflammatory, antipyretic, and analgesic effects, confirming their historical use.
Phytocannabinoids, Terpenoids, and Their Treatment Effects
Since cannabinoid-type compounds are responsible for most of the specific effects of cannabis, research is especially conducted on these compounds. Information on the properties and effects of certain compounds belonging to the phytocannabinoid class will be explained below.
- Cannabigerol-CBG: Cannabigerol is a heterogeneous compound that does not have psychoactive effects. In rat studies with CBG-rich extracts of C. Sativa, it was observed to stimulate the rats’ appetite. In addition, sedative, analgesic, and spasmolytic effects have also been detected. In a study conducted by Smeriglio et al in 2018, it was revealed that CBG and acid derivatives and CBD and acid derivatives can improve diabetic symptoms by inhibiting aldose reductase activity.
- Cannabichromene-CBC: CBC is among the most stable of the phytocannabinoids in hemp. It is more present in the vegetative phase of the plant and the amounts of CBC correlate with the amounts of 9-THC in the plant but do not act on CB1 receptors such as 9-THC. In a study conducted in 2013, it was found that it decreased nitric oxide, IL-10, and interferon- levels in peritoneal macrophages activated by lipopolysaccharide (LPS). These effects show that CBC has anti-inflammatory properties.
- Cannabidiol-CBD: Although the structure of cannabidiol is similar to 9-THC, it does not bind to strong CB1 receptors like it. In a study conducted, it was shown that tremors decreased by 20-50% in patients who were given 100-600 mg of CBD daily. Researches on CBD have proven to have anticonvulsant, antispasmodic, anxiolytic, antiemetic, antirheumatic, and neuroprotective properties.
In addition, studies are ongoing on Alzheimer’s, Parkinson’s, various types of cancer, and infertility. Due to its strong anticonvulsant activity without a psychoactive effect, clinical studies conducted with CBD in recent years have focused especially on epilepsy, and as a result of these studies, the FDA reported that the drug “Epidiolex” containing CBD, two severe and rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet Approved for use in the treatment of the syndrome.
- Tetrahydrocannabinol-THC: Although it has different derivatives such as 8-THC and cis-9-THC, which are included in this group, trans-9-THC is the main compound responsible for the psychoactive effect in cannabis. 9-THC has the ability to bind to both CB1 receptors, which reveal psychoactive effects, and CB2 receptors, which reveal immunological and anti-inflammatory effects.
Dronabinol and Nabilon, which are used in the treatment of nausea and vomiting accompanying cancer chemotherapy, contain synthetic derivatives of 9-THC. Clinical studies have shown that 9-THC has cancer pain, neuropathic pain, etc. It shows that its importance will increase in eliminating the types of pain that are difficult to treat.
Current research suggests that 9-THC may also be beneficial in Tourette syndrome. In the study conducted by Suliman et al. in 2018, it was found that low-dose 9-THC significantly triggered neurogenesis in the hippocampus of old rats. It has also been found that 9-THC reduces intraneuronal β-amyloid accumulation and has an anti-inflammatory effect.
- 9-Tetrahydrocannabivarin-9-THCV: 9-THCV is a THC derivative compound. While it antagonizes the effect of THC in low doses, it has been observed that it agonizes the effects of THC in high doses. 9-THCV also inhibits LPS-stimulated nitric oxide in macrophages via CB2 receptors.
Apart from phytocannabinoids, abundant terpene-derived compounds are synthesized in the flowers and leaves of cannabis, and also 10% of the resin secreted from trichomes is composed of terpenoids. It is thought that there are more than 200 terpene-derived compounds in cannabis, and terpenes are compounds that give the plant its characteristic odor. Limonene, myrcene, and pinene are the most common terpenes with high volatility. Just like phytocannabinoids, terpenoids also have the function of protecting the plant from insects and herbivores and show synergistic effects with the phytocannabinoids in the plant in performing this function.
- D-Limonene: Commonly found in citrus species, d-limonene is known for its powerful antioxidant properties. In mouse studies, it has been proven that d-limonene exerts an anxiolytic effect in the hippocampus and prefrontal cortex through serotonin and dopamine. In addition, perilic acid – a limonene metabolite synthesized in the liver – has been found to have an anti-stress effect in the rat brain. Subsequent studies have shown that it triggers apoptosis in breast cancer cells. It has also been proven effective in gastro-oesophageal reflux.
- β-Myrcene: β-myrcene is a terpene that is commonly found in cannabis and has various effects on the nervous system. Myrcene showed analgesic, sedative, anti-inflammatory effects, and spasmolytic effects in mouse models. These data show that the analgesic and anti-inflammatory effects of cannabis, along with phytocannabinoids, also contribute to the miraculous.
- D-Linalol: Linalol is monoterpene alcohol with anxiolytic and sedative effects. It also has a local anesthetic feature. Anticonvulsant, antiglutamatergic, and analgesic effects at high doses were revealed in mouse studies.
- β-Karyophylene: Karyophylene is a sesquiterpene with anti-inflammatory and antimalarial effects. Due to its anti-inflammatory effect, it has been used in the treatment of duodenal ulcers in the UK in the past. It selectively binds to CB2 receptors.
- Caryophyllene oxide: It is a sesquiterpenoxide with antifungal and insecticidal properties. It also showed blood thinning activity in in vitro experiments. It is the main compound responsible for the characteristic smell of cannabis that allows it to be sniffed and found by narcotic dogs.
- Pinene: A bicyclic monoterpene, which can be found in conifers and many other plants, pinene has a protective function for the plant thanks to its insect repellent effects. In many studies, pinene showed anti-inflammatory, a bronchodilator, and antibacterial effects. It also has the ability to inhibit the acetylcholinesterase enzyme.
- Phytol: Phytol, a diterpene that occurs with the degradation of chlorophyll and tocopherols in cannabis, is one of the compounds that cause the relaxing effect of cannabis.
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