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Humans have been using recreational drugs for centuries. But, up till now, the use of these drugs was associated mainly with recreational purposes, and many of these drugs were considered to be detrimental to human health. It was thought that the use of these drugs triggered dangerous psychiatric symptoms in the people, and the drugs were declared illegal by many countries around the world. No doubt, illicit drugs such as cocaine and morphine surely do have excessive detrimental effects on the health of the user, but there certainly are some advantages along with the use of these natural herbs. For example, morphine (the active part of heroin, obtained from the poppy plant) carries a very important use in relieving the post-surgical pain in the patients. Similarly, many other drugs which were considered dangerous are now finding uses in the field of pharmaceutical therapy all over the world.
Almost similar is the case for Cannabis sativa and Cannabis indica plants. These plants, commonly known as weed in layman terms, have been used by humans for smoking since the many centuries. The advancements in the field of medical research in recent years have proved the efficacy of using Cannabis for certain disorders. After decades of research, the physicians are now able to coin a new term for Cannabis, which is known as ‘medical cannabis’ or more commonly ‘medical marijuana’. At first, “Cannabinoid” was a collective term assigned to the set of naturally occurring aromatic hydrocarbon extracts obtained from the Cannabis plant. But, due to the increase in the acceptance of the medicinal use of marijuana, cannabinoids nowadays refer to a diverse set of therapeutic substances that have pharmacologic actions that closely resemble that of the plant-derived cannabinoids.
Cannabidiol (CBD) is a plant extract obtained from the Cannabis sativa plant, which is more commonly considered as an extremely common drug ‘marijuana’. The chemical compounds obtained from the extract of this plant are known as cannabinoids and include cannabigerol, cannabidiol, cannabichromene, and tetrahydrocannabinol (THC) along with some other chemicals. Among all the cannabinoids, tetrahydrocannabinol (THC) is the most known one and is psychoactive, and is used for addictive purposes. The next main constituent of the plant extract other than THC is cannabidiol (CBD), which constitutes about 40 percent of the total extract.
CBD in Action
The endocannabinoid system
The endogenous cannabinoid system, or more commonly known as the endocannabinoid system, serves to regulate a wide array of physiological and psychological processes and possesses considerable potential targets for the potential treatment of numerous disease states. The intrinsic location of the endocannabinoid system enables the potential for it to act as a binding site for several anxiolytic drugs and other pharmaceutical therapy agents. The endocannabinoid system is just another neurotransmitter system in our bodies just like the acetylcholine system or adrenaline system. The neurotransmitter systems of our body consist of apparatus such as synaptic junctions across which the nerve impulse is transferred, and specific chemicals called neurotransmitters that serve to pass on the nerve impulses to the next nerve in series. The neurotransmitters serve as a bridge between the electrical and chemical systems contributing to the travel of the nerve impulse throughout the nerve. There are various types of neurotransmitters known to science. Some of them are excitatory, some of them are inhibitory and some of them are mixed neurotransmitters that can either be excitatory or be inhibitory according to the required circumstances.
The endocannabinoid system is composed of neurotransmitters known as endocannabinoids. Endocannabinoids are one of the most widely known, potent, and versatile signaling molecules known up to now. The receptors which serve to bind these neurotransmitters and pass on information are called the cannabinoid receptors. Two types of cannabinoid receptors are naturally found in the human body. This is probably possible due to the two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands. Cannabidiol, CBD, binds to these receptors and then alters the function of these receptors and the resulting actions of the body on which these receptors and their ligands affect.
Just like most of the other chemicals, the cannabis extracts affect our brain by binding to a specific type of receptors present on the cells. When these cannabinoids bind to these receptors, they trigger some changes in the metabolic machinery of the cells. These receptors are present on the cells throughout the entirety of our central nervous system, and they are specifically called CB1 and CB2 receptors. Such receptors are found predominantly in the brain in the hippocampus and cerebellum. Because these receptors directly affect the function of the cell they are on, the psychic effects experienced after consuming marijuana have a rapid onset. The psychoactive cannabinoids such as THC result in euphoria, enhancement of sensory perception, increased heart rate, decreased pain stimuli, and difficulties in concentrating on specific tasks. These effects are due to the relative abundance of CB1 and CB2 receptors in the hippocampus. The effects may also include short term impairment of memory. These effects are largely due to the psychoactive agents found in cannabis such as tetrahydrocannabinol (THC).
We know that each type of neurotransmitter in our body has a particular effect. Some affect the sleep cycle, others serve to be of prime importance in passing on the motor nerve impulses to the muscles on the neuromuscular junctions. An example of such neurotransmitter is acetylcholine. Similarly, the cannabinoids serve to affect mood, anxiety, or may even grant muscle relaxant effects by interacting with the endocannabinoid system. The location of the cannabinoid receptors in our bodies is also very specific and is suited perfectly to their function. The cannabinoid receptors are found throughout the central nervous system. but to be more specific, CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in the inner brain areas such as the cerebral cortex and basal ganglia. Due to their location, these receptors interact with the ECB system to have sharp effects on the actions controlled by these areas of the brain that include thought processes, cognitive behaviors, focus, and other primitive senses such as pain perception and autoimmune responses. Due to these properties, the cannabinoids such as CBD can exert therapeutic properties in degenerative disorders that affect the central nervous system, particularly the brain. Due to this location, CBD also has some serious anxiolytic properties, that enable it to be used for stress disorders and anxiety after an intense psychological trauma or in diseases such as Alzheimer’s disease, Parkinson’s disease, and other disorders that affect the thought process of the subjects.
On the other hand, the other major type of receptors in the ECB system is called the CB2 receptors. CB2 receptors are most commonly are expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery. Additionally, CB2 receptors are also expressed on neurons, but to an extent that is almost as negligible as compared to the CB1 receptors. The abundant distribution of CB1 and CB2 receptors throughout the brain and periphery accounts for their ability to impact a diverse variety of physiological and psychological processes and other emotions such as memory, anxiety, and pain perception. Moreover, they are the prime targets for the pharmaceutical effect of CBD to combat inflammatory and autoimmune disorders such as fibromyalgia and multiple sclerosis.
Pharmaceutical Use of CBD and a Comprehensive Overview of its Specific Side Effects
Recent technological advancements in the field of science have enabled scientists to explore the previously hidden potential of cannabinoids in treating various brain disorders. The regulated use of CBD to treat these disorders has certainly brought a much-awaited drug into the regime of the very few drugs that can be used to combat the progression of brain disorders. But, when used improperly, just like some other drugs, CBD can surely inflict some side effects in the patients suffering from these disorders.
The side effects of CBD are feared because this substance has not been researched enough like other drugs by clinical studies. The route of administering CBD to non-human subjects in experimental studies is largely different from the route which is used in the human subjects. The most common route of administration of CBD in humans is through using oral administration of cannabidiol oil drops, or through inhalation of the vapors of the substance which is almost similar to smoking. The administration in non-human subjects such as rodents is carried out either via the quick absorption routes such as intraperitoneal injection or via the oral route using drops. Due to the difference in the routes of administration of CBD in human and non-human subjects, the effective plasma levels reached via oral administration in non-human subjects and through inhalation in humans can differ by a considerable margin. Both these observations can lead to differing active blood concentrations of CBD. These distinct levels of CBD change the effective dosage, so the experimental studies of CBD to stimulate its effects on the brain disorders using non-human sources is not known to the researchers and remains to be a field of widespread research all over the world.
A research paper published on PubMed comprehensively studied this phenomenon. All cannabinoids, including cannabidiol, penetrated the blood-brain barrier along with solutol much more easily than previously anticipated. This is due to some slight differences in the membrane structure of the human and non-human subjects. In mice, intraperitoneal administration of CBD always attained higher plasma and brain concentrations due to the direct absorption of CBD through diffusion into the blood of the subject. The numerical observations noted in the research proved that the route of administration of CBD does carry a significant impact on the rate of absorption of the substance from the source. Moreover, the rates of absorption of cannabinoids other than CBD also differ by a considerable margin. In rats, oral administration in measured doses offered significantly higher brain concentrations for cannabidiol amounting to 120 mg/kg and CBDV to an extent of at least60 mg/kg. this differed distinctly from the rate of absorption of THC in the rodent. The rate of absorption of THC was noted to be 30 mg/kg of the body weight. Similarly, cannabichromene also had considerably different rates of absorption in rodents as noted in the clinical studies to find the usefulness of CBD. Generally, it was found that the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behavior in a time-dependent manner matching its pharmacokinetic profile.
The difference of the targets to which CBD binds and exerts its effects on the body is also a point which increases doubt in the use of CBD as a pharmaceutical drug. In lab settings, controlled doses of the substance are administered to the non-human sources through carefully supervised techniques. The targets in the non-human sources are carefully studied first, before administering CBD to the subjects. That is why, the effects of CBD are not so properly studied in humans, which poses a possible threat as it may have some detrimental effects on the health of the user. CBD targets may differ between humans and animals. Therefore, the same blood concentration might still lead to different effects because of the difference in the basic body mechanisms in the human and non-human subjects. The targets to which CBD binds may even be the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.
CBD and Liver Metabolism – The Relation
Perhaps the most pronounced side effect of using CBD for the symptomatic treatment of various disorders in humans is the effect it has on the hepatic metabolism of various drugs. The liver is probably the only organ in the body that serves the function of detoxification of many toxic substances that are ingested with food regularly. It is also concerned with the breakdown of many drugs, thereby converting them into soluble metabolites that can then be excreted from the body through urine. From the plethora of the functions that are carried out by the liver in human bodies, these two functions are the pivotal ones that play a major role in maintaining the integrity of other organs against toxins and poisons. Any kind of substance that interferes with the liver function and its ability to metabolize the toxins and drugs can cause serious disorders not only in the liver but also to other organs of the body. Renal function is the most affected one in such cases. So, to protect other organs from this kind of fate, liver functions are of pivotal importance to our bodies.
The use of cannabis is linked to some particular problems that occur in the liver due to some properties of cannabis. The cannabinoids such as CBD and THC are found to disturb the metabolism of many important toxins such as morphine in the liver. A research study found that CBD was found to inhibit the demethylation of morphine in the liver, thereby inhibiting its detoxification and excretion from the body. The accumulation of morphine has adverse effects on the vital organs of the body such as the brain and heart functions. Interestingly, it was found that THC, another main constituent of cannabis, did not affect the inhibition of demethylation of morphine in the liver.
The adverse effects of cannabinoids such as CBD are intensified if the subject is already suffering from a liver disorder. For example, research has investigated the role of cannabis in patients who are suffering from hepatitis C. Hepatitis C is a viral disease that is caused by the Hep C virus. This virus infects mainly the liver, causing dangerous inflammation. In the case of Hep C, the body's immune system needs to work in full capacity to stop the replication of the virus, thereby preventing further liver damage in the patients. But, cannabidiol is effective in suppressing the immune function of the body, like suppressing the autoimmune responses that occur in central nervous system disorders such as fibromyalgia, and other inflammatory disorders such as rheumatoid arthritis. So, in the persons who are already affected by Hep C, administering CBD or smoking cannabis for recreational purposes can have drastic effects on the already weakened liver of the subject.
The influence of CBD in patients who are addicted to alcoholism or are suffering from fatty liver disease due to some reason is also very bad. Alcohol is detoxified in the liver, and the metabolites are then converted into soluble forms that can be then excreted from the body. Any accumulation of alcohol in the body has very drastic effects on the central nervous system. So, it is essential to remove alcohol from the body. Experimentally, it was found that the use of CBD in people addicted to alcoholism or suffering from liver disorders such as fatty liver disease promoted fibrosis in the liver of these patients. Fibrosis in the liver leads to the sudden death of the hepatic tissue so that the hepatocytes start dying and are unable to carry important liver functions in the body. The cannabinoid receptors such as CB1 and CB2 receptors played an important role in enhancing the fibrosis in liver disorder patients. Particularly, the CB2 receptor activation caused inflammation, which aggravated liver disease symptoms in the patients. It also led to insulin resistance, thereby increasing the risk of diabetes in patients of liver disease.
CBD Use in Immunocompromised Patients
Immunocompromised patients suffer from a degraded immune system and are unable to protect their bodies from infection. So, even a mild infection proves to be fatal for such patients. The degradation of the immune system can be attributed to certain diseases that interfere with the normal production and proliferation of immune cells such as B lymphocytes and T lymphocytes. These patients are so susceptible to infection that they can catch one even after eating something because there are thousands of foreign agents that are eradicated by an otherwise normal immune system every day. Research has shown that CBD acts to suppress the immune activity of a person after prolonged use. Particularly, CBD has an important role in suppressing the autoimmune responses in the body. Although this can be of great advantage in autoimmune disorders such as multiple sclerosis, the fact that CBD suppresses the immune system becomes a nuisance for those who are already suffering from an infection. These people need acute immune action in their bodies, while CBD acts to decline the immune functions of the body. There are also reports that smoking unsterilized cannabis is attributed to a rare lung disorder known as Aspergillus infection, which is a fungal infection that severely degrades the lung function of gaseous exchange. This not only causes respiratory problems for the victim but is also linked to an increased rate of cardiovascular disorders due to the incomplete oxygenation of the blood as it passes through the capillary bed surrounding the alveoli in the lungs.
CBD and Fertility
Along with a number of other side effects in the humans using CBD as a prolonged measure to combat brain disorder symptoms, one of the major concerns is the effect of this prolonged use on the reproductive system of the subject. Recent research has indicated that cannabinoids such as cannabidiol and THC have an impairing effect on the reproductive system. This was experimentally verified by studying the effects of CBD of fertilization in sea urchins. CBD is found to be detrimental for reproductive health in individuals who have a low sperm count in their semen. This is because, at very low sperm densities, CBD was found to inhibit active fertilization of the egg when used at a specific dosage. This meant that prolonged use of CBD is attributed to a decrease in the fertilization capacity of the sperm, thereby having a degenerative effect on the reproductive system of the individuals. Several cannabinoids such as THC and CBD were found to inhibit the much-needed acrosome reaction in the sperms, thereby showing another measure through which these substances can inhibit the fertilization of an egg by the sperm, and degrade the reproductive abilities of the individual.
The use of CBD was also found to be associated with a decrease in the testicular mass and testicular function in male individuals. For this purpose, a group of rhesus monkeys was studied in order to investigate the effects of CBD on the male reproductive systems, while remaining as identical to the human systems as possible. The study involved administering oral CBD to the monkeys for 30 days. Studies have also shown that CBD interferes with the process of normal sperm production and sperm differentiation (spermiogenesis) in the male rats when it is administered in high doses. A direct decrease in the rates of spermatogenesis and spermiogenesis was observed in Swiss male rats when they were administered CBD in doses greater than 30 milligrams per kilogram of their body weight. Moreover, the use of CBD caused the tail lengths of the sperms in the male mice to shorten, and this phenomenon was noted in most of the mice included in the study. There was an overall 28 percent reduction in spermatozoa tail, and more abnormalities were reported in the head region of the sperms. As a result, a significant decrease in the testicular weight was observed in the monkeys, indicating that CBD had a degenerative effect on the reproductive system of the male individuals.
CBD and Pregnancy
Just like CBD exerting detrimental effects on the anatomy of the male reproductive systems, it has been found that CBD also affects the female reproductive system to a considerable extent, if it is used for prolonged periods of time during pregnancies. CBD generally affects the pregnancies by interfering with the normal organ development in the fetus. The exact mechanism through which this happens is still not known to science. However, this has been experimentally verified by administering CBD to pregnant rats. It was noted that the administration of CBD let to developmental teratogenicity in almost all of the cases if the use of CBD was kept unregulated for long periods of time. The use of CBD in pregnant rats was also shown to cause a decreased rate of growth of the fetus, with delayed sexual maturity later on in life. This shows the potential side effects cannabidiol use might have if it is used for prolonged periods of time in the pregnant and/or lactating human mothers.
Prolonged Use of CBD for Anxiety
Anxiety, in its broadest perspective, can be defined as a natural reaction of the brain that is characterized by its responses to otherwise stressful and intensely occupying stimuli that shadow over the thoughts of the subject. Anxiety is usually found to be accompanying deranged feelings of tension along with worried thoughts and physical changes like increased blood pressure and heart rate. The physical changes in anxiety are attributed to the natural reflex response of the brain towards stressful conditions. The reflex response is responsible for altering the heart rate (most commonly accelerating the heart), causing gastrointestinal depression and other sympathetic responses such as hyperventilation. Acute accumulation of all these symptoms in the subject is known as an anxiety or panic attack. Anxiety is not always a medical condition requiring immediate attention, it is completely normal to have anxious feelings about something on a daily basis. It is very important to judge the situation when will a person having anxious feelings require medical attention before experiencing aggravated symptoms such as panic attacks due to increased anxiety. The anxiety is medically linked to the brain, or more specifically to the amygdala which controls the fear, thoughts, and emotions and serves as the hub of anxiety. The anti-anxiety drugs usually work by modifying the levels of certain chemicals in the central nervous system called neurotransmitters. These neurotransmitters are the chemicals which dictate our day to day mood and emotions. One of the most effective neurotransmitter systems in our body is the endocannabinoid system. The endocannabinoid system, consisting of some particular receptors called cannabinoid receptors, affect the overall mood, stress, anxiety, and metabolism of our bodies.
The ability of CBD to affect the endocannabinoid system, which in turn has supernumerary effects on mood, stress, anxiety, and state of mind of a person, has enabled it to become an effective drug to cure long term stress and anxiety that might reduce the quality of lifestyle of any person. Moreover, the quality of CBD oil that does not affect the psychological state of mind of the person who is using it, has granted it the ultimate sweet spot for having all the perks of marijuana without getting the ‘high’ sensation which is the characteristic of marijuana.
The anxiolytic properties of CBD are more pronounced in the persons that have very little or no history of any kind of association with marijuana. This is because of the fact that if marijuana is consumed in large amounts regularly, the receptors of the endocannabinoid system in the central nervous system can become desensitized to the use of cannabinoids, which include not only CBD but also THC. This leads to an increased rate of usage of CBD by the patients of anxiety who are already being administered CBD on a regular basis in measured amounts by their physicians. This increased amount of usage is particularly dangerous because, in this way, the person might develop desensitization, that can disturb the natural abilities of our body to harness the neuroprotective properties of the endocannabinoid system.
Nowadays, most of the states, about 47 out of 52 states in the US have legalized the use of medical cannabis for the pharmaceutical therapy of various diseases. The positive impacts of CBD on the patients suffering from debilitating brain disorders is surely gaining much attention from the physicians. There has been a marked increase in the CBD prescriptions by the physicians in the last decade or so, but the potential side effects that CBD might have on the patients suffering from compromised immune systems or liver disorders need to be considered carefully before therapy is started in such individuals.
- Schuel, Herbert et al. "Reduction Of The Fertilizing Capacity Of Sea Urchin Sperm By Cannabinoids Derived From Marihuana. I. Inhibition Of The Acrosome Reaction Induced By Egg Jelly". Molecular Reproduction And Development, vol 29, no. 1, 1991, pp. 51-59. Wiley, doi:10.1002/mrd.1080290109. Accessed 23 Sept 2020.
- Zhu, Julie, and Kevork M Peltekian. "Cannabis And The Liver: Things You Wanted To Know But Were Afraid To Ask". Canadian Liver Journal, vol 2, no. 3, 2019, pp. 51-57. University Of Toronto Press Inc. (Utpress), doi:10.3138/canlivj.2018-0023. Accessed 23 Sept 2020.
- Huestis, Marilyn A. et al. "Cannabidiol Adverse Effects And Toxicity". Current Neuropharmacology, vol 17, no. 10, 2019, pp. 974-989. Bentham Science Publishers Ltd., doi:10.2174/1570159x17666190603171901. Accessed 23 Sept 2020.