CBD for Multiple Sclerosis

Introduction

In recent years, Cannabis has found a drastic shift in its uses. Prior to modern research, it was considered that marijuana was no more than a street drug used for recreation by the street junkies. Almost no more than a decade ago, when modern research techniques coined the term ‘medical marijuana’, the concept of using the medical properties of marijuana as pharmaceutical drugs gained popularity. It was discovered that Cannabis contains two main agents which are responsible for the psychiatric effects of marijuana. These two main agents were tetrahydrocannabinol (THC) and cannabidiol (CBD). Among these two contents, the main agent responsible for the ‘high’ effect of marijuana is tetrahydrocannabinol (THC), which binds to and affects the cannabinoid receptors in the central nervous system, thereby manifesting psychiatric effects in the subject. For this reason, THC is considered to be a psychoactive substance. The other main constituent is cannabidiol (CBD). Cannabidiol (CBD) differs from other chemicals found in cannabis, as it has a different mechanism of action and a different effect on the body as compared to other chemicals such as the tetrahydrocannabinol (THC).

The Effect of Cannabinoids on Brain

The brain activity in humans is controlled through vast and intricate neuronal connections, the connections that not only influence the motor activity within the bodies, but also influences the cognitive effect of brain on the bodies. That is the very basis of marijuana acting to reduce anxiety and nervousness. Similar is the mechanism for other antidepressant drugs which serve to reduce anxiety.

Most of the pharmaceutical drugs exert their therapeutic effects by binding to certain receptors, the receptors which are used for normal functioning of the body. Whenever there is a disorder, most of the time, the reason lies in the disfunction of the receptor system or the second messenger system the receptors activate through binding to specific ligands. The effect of the ligand binding to a receptor may be positive or negative, depending upon the nature of the receptor.

Similar is the mechanism of action of various cannabinoids such as cannabidiol and tetrahydrocannabinol. These 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).

The blessing in disguise of using cannabidiol for brain disorders lies largely in the fact that cannabidiol (CBD) differs largely from THC in its psycho-activity. Apart from differing from THC in this respect, studies have also found the potential of CBD in granting neuroprotective properties to the central nervous system. This property of CBD is used to treat various brain disorders like multiple sclerosis, Alzheimer’s Disease, Parkinson’s Disease and many inflammatory disorders like arthritis and edemas.

CBD in Psychoactive Symptoms

According to some studies, it has been found that CBD may even act to counter the psychoactive effects of THC. Owing to its anti-psychotic effects, this compound has found itself being used for many pharmaceutical purposes.  These effects are possibly caused due to the opposite effects of THC and CBD on brain activity in regions such as the striatum, hippocampus, and prefrontal cortex. Many studies conducted by laboratories around the world, along with controlled clinical trials, have confirmed that CBD can be adopted as a well-tolerated, safe, and effective drug for antipsychotic purposes. The THC has an impairing effect on the body, while all the effects of CBD are non-impairing. But, CBD in cannabis has some effects on the body where it serves to release overall stress on the body. These effects are different from the euphoric or ‘high’ sensations induced in our bodies due to THC, and serve to alleviate the stress and anxiety. This makes CBD as the best alternate to marijuana to seek an escape from pain and anxiety.  23 states and the District of Columbia have legalized marijuana to be used for a variety of medical conditions. 15 other states have also formed laws that are intended to allow access to CBD oil and strains of marijuana containing high CBD to THC ratio.

What is Multiple Sclerosis?

Multiple sclerosis, in the simplest words, can be defined as an autoimmune disease that attacks the brain and the tissues that surround it. It is a potentially disabling disease, which can destroy the neural connections of the whole central nervous system, including the brain and the spinal cord. The whole central nervous system is covered with three layers of protective tissue, known as dura mater, pia mater and the arachnoid. These tissues not only provide nourishment to the central nervous system, but also has protective properties. 

Multiple sclerosis is also found to attack the myelin covering the central nervous system in the brain, spinal cord and the associated nerves around it. The myelin sheath secreted by the Swann cells in the central nervous system serves to enhance the impulse conduction of the whole nervous system. The myelin sheath is associated with specific nerve impulses called as the ‘saltatory impulse’, which is the nerve impulse that literally jumps through the gaps in the areas not covered by the myelin sheath. This property increases the speed of the nerve impulse that is being conducted through the nerves. However, on the other side, any pathological condition that affects the myelination of the nerve fibers, may also cause fatal interruption in the nerve impulse conduction.

Signs and Symptoms

The first symptom of multiple sclerosis is the clinically isolated syndrome. Clinically isolated syndrome (CIS) is the first sign of the neurological symptoms that are the manifestations of multiple sclerosis. This sign lasts usually for at least 24 hours. This sign might be recurring, or the people may never experience it again. Even if the patients of multiple sclerosis never experience the clinically isolated syndrome in the span of their disease, this is not suggestive of the fact that they might already be suffering from this disease even if they are not diagnosed or they do not know it. The symptoms result due to autoimmune degradation of the myelin sheath covering the neurons, and manifests symptoms such as optic neuritis, along with some other motor symptoms. The patient may also experience dizziness in their day, or there may be bladder problems associated with clinically isolated syndrome. The main symptom of clinically isolated syndrome is optic neuritis. Optic neuritis commonly causes blind spots or areas of poor vision. This is primarily due to the damage this disorder inflicts on the optic nerve, which carries the sense of vision from the eye to the brain to be interpreted by the areas of the brain concerned with vision. Damage to the optic nerve results in areas of poor vision, distorted focus and color inaccuracy surrounded by an area of normal vision. The color vision of the patient experiencing CIS can also be degraded and the patient may experience pain in the orbits during eye movement and while trying to focus on something. 

The peripheral symptoms of this disorder depend on area of the spinal cord which is damaged, because almost all the nerve tracts carrying information to and from the brain pass through the spinal cord. The damage to a particular nerve tract or multiple tracts will determine what symptoms the patient will experience and which peripheral limbs of the body will undergo distorted motor control. The most common signs include muscle weakness along with distorted movements, abnormal sensations in the peripheral parts of the limbs such as toes and feet, numbness or tingling, and bladder problems. Brainstem syndrome is also a part of CIS and is associated with sleep disorders. It occurs when multiple sclerosis affects the nerves in the brainstem which is the main area at the base of the brain where it connects to the spinal cord. 

The brainstem controls very primitive functions of the body such as breathing, heart rate and blood pressure. Symptoms of brainstem syndrome include dizziness or vertigo along with balancing problems, nausea, vomiting and double vision, but symptoms vary depending on the specific area affected.

Factors affecting the Symptoms of Disease

Signs and symptoms of multiple sclerosis depend on the area of the central nervous system that is affected by the disease. The symptoms vary widely, and in most of the cases, it is the myelination of the spinal and cranial main nerves that is affected. In some cases, people who are affected with severe degradation of the myelination of nerves may lose the ability to walk at all due to the nerve tracts not being able to conduct nerve impulses properly. However, the symptoms may not appear at all for some time, and the disease is not notable at all until the severity of the symptoms increase. In most of the cases, the motor ability to coordinate and initiate basic body movements is affected while the senses and cognitive ability is spared from the disease. The disease most commonly starts unilaterally, affected one side at a time.  The limbs may be affected both at the same time, or may be affected turn by turn. The motor disability starts usually very slightly, with some notable tremors in the affected side. The disease gradually progresses as the immunocytes attack the myelination of the nerves. Another sign that is very notable in the multiple sclerosis disorder is the Lhermitte sign. Lhermitte sign is probably caused by the spontaneous nerve impulse discharges in the nerves due to severely disrupted myelination. As a result of Lhermitte’s sign, the neck usually bends forward due to involuntary contractions in the neck muscles. It is usually a sudden sensation caused by a spontaneous nerve impulse that resembles an electric shock, passing through the whole body, down the back of the subject’s neck and travels into the spine. Spinal cord is the main center of nerve impulse and motor control, radiating out into the whole body through nerve tracts. Once the spontaneous impulse reaches the spine, the impulse can then radiate out into the whole body, often into the arms and legs of the person, which sometimes causes involuntary tremors and contractures.

Types of Multiple Sclerosis

There are several types of multiple sclerosis, which include benign MS, relapsing remitting MS, primary progressive and secondary progressive MS, and the type that does not progress. All of the types have slightly distinct symptoms that are not found in other types. 

The most common form of multiple sclerosis is relapsing remitting multiple sclerosis. It is the type of disorder in which the symptoms spontaneously appear in an aggravated state which is known as an ‘attack’ or a ‘relapse’. However, in this type of disorder, the symptoms automatically go away, which is called a remission. Hence the name, relapsing remitting multiple sclerosis. About 85 percent of the cases with multiple sclerosis consist of this type of disorder. In this disorder, every acute attack of multiple sclerosis is different in nature every time the attack occurs. The nature and frequency of the attacks cannot be predicted. The attacks can occur virtually at any time of the day with any severity and it isn't possible to predict when relapses will happen. The symptoms of this disorder become so much mixed with the day to day life that it soon becomes indistinguishable that what can be classified as the relapse and what is a remission.

Another form of multiple sclerosis is primary progressive multiple sclerosis, which is a comparatively rare but dangerous form of this disease. This disorder is comparatively rare, and is found in only 15 percent of the cases in multiple sclerosis. As is evident from the name of the disorder, the nature of the disorder is progressive from the beginning of the disease, and relapses do not occur in this disorder. The disability of the patient increases in progressive multiple sclerosis because of the gradual but progressive degradation of myelin sheath around the neurons. As the myelination degrades, the motor control also degrades to a large extent. However, like the relapsing remitting multiple sclerosis, this disorder also has an unpredictable nature. The rate at which the progression happens and the time which symptoms take to deteriorate to an appreciable extent varies from person to person and is largely dependent on the degradation of myelin sheath. The patient may feel well despite having a progressive multiple sclerosis, and there may be small periods in which the patient experiences improvement. But this improvement is temporary and the symptoms usually return with the passage of time and the progression of the disease in an aggravated state.

Another form of multiple sclerosis seen in the patients is the secondary progressive multiple sclerosis. This form of MS is a later stage disorder, where the subject who is already suffering from another form of the disease such as relapsing remitting multiple sclerosis experiences that his or her attacks and their frequency decreases with time. But, at the same time, their disability increases because of the worsening condition of the disease. The myelination gradually fades, and the conduction of the nerve impulse becomes more and more difficult as the saltatory impulse is unable to pass on from unmyelinated nerve fibers. As this type of MS appears at a later stage of the disease, some of the patients do not know but they are already experiencing the secondary progressive form of multiple sclerosis when they receive their diagnosis. This means that their relapsing remitting stage of the disease went undiagnosed, and their disease has aggravated. Studies have been conducted all over the world by neurologists monitor people having symptoms of multiple sclerosis over a long period of time. The research suggests that after passing through their teenage years, half of the patients who were found to be suffering from  relapsing remitting form of multiple sclerosis developed secondary progressive multiple sclerosis in some people, the secondary progressive form of the disorder is dominant eve before the onset of relapsing remitting form of the disorder, rather than having the secondary progressive form after having relapsing remitting multiple sclerosis. This further explains the stealth and unpredictable nature of this dangerous disease. The people who are suffering from the secondary progressive form of the disorder without going through the relapsing remitting form, may already have experienced relapses in the early stages of their disease. But the diagnosis of the remitting relapsing form of multiple sclerosis usually depends upon the severity of symptoms. It may also go unnoticed if the symptoms are very slight, or the patient may have mistakenly confused those symptoms with the symptoms of other disorders or fatigue.

A particularly sparing form of multiple sclerosis is known as benign multiple sclerosis. the disease is not so benign as is visible from the name of the disease itself. The disease is there, but it all depends on the severity of the symptoms. In this form of the disease, the patient experiences a form of relapsing remitting multiple sclerosis, but the frequency of the attacks is very less. The patient might experience long periods of wellness between the attacks in this type of multiple sclerosis.

The Usefulness of Cannabidiol (CBD) for Multiple Sclerosis

In this section of the article, we will discuss the various features of CBD that can prove effective in multiple sclerosis. 

Neuroprotective properties of endocannabinoid system and Cannabidiol (CBD)

Cannabidiol (CBD) acts by interacting with the endocannabinoid system of the body. For those who do not know about this system: it is just another neurotransmitter system in our bodies just like the acetylcholine system or adrenaline system. 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. These substances interact with a specific type of receptors which are called cannabinoid receptors which are found throughout the central nervous system (brain and spinal cord). The extracts of cannabis, or cannabinoids, are the main substances to interact with these receptors. When they bind to these receptors, they have a subsequent effect on a person’s mood and state of mind. All of the senses affected by the endocannabinoid system such as memory, nociception (pain perception), metabolism, appetite, stress, and anxiety, etc. are also affected to a considerable extent. 

The neuroprotective properties of the endocannabinoid system have been studied in great detail by various research papers. Research has shown that endocannabinoids are synthesized by postsynaptic dendrites at synaptic junctions during depolarization. These endocannabinoids include mainly 2-arachidonoylglycerol. This chemical synthesized by ECB system can act as retrograde ligands at type 1 cannabinoid receptors in the central nervous system located at presynaptic terminals at synaptic junctions. The binding of this chemical as a retrograde ligand serves to inhibit the release of excitatory or inhibitory neurotransmitters from the presynaptic neuron, thereby efficiently depressing or stimulating the nervous activity of the central nervous system as is needed by the body. 

On the other hand, endocannabinoids along with the cannabinoid receptors in the body also play a significant role in peripheral and brain immune function. The primary ways include discouraging the release of otherwise harmful substances such as inflammatory mediators which include factors such as interleukin-2, nitric oxide, and tumor necrosis factors. 

However, the endocannabinoids are particularly useful for autoimmune diseases such as multiple sclerosis because of their ability to inhibit the activation of cell-mediated immune responses. If the cell mediated immune responses are not controlled, they start causing reverse damage by attacking the useful tissues of the body. Similar is the case that happens in multiple sclerosis, where the immune cells attack the useful myelin sheath around the neurons. This causes an imbalance in the nerve impulses that are conducted through these nerves. Part from inhibiting these uncontrolled immune cell responses, the cannabinoids such as cannabidiol (CBD) also affect the proliferation and chemotaxis of the immune cells. By stopping the proliferation of these cells, cannabidiol stops the progression of multiple sclerosis. inhibiting the chemotaxis of the cells towards the myelin is also particularly helpful, as this prevents the myelin sheath from being attacked.

Calcium Channel Mechanism

Another mechanism through which the cannabinoids can help against autoimmune disorders is through inducing the closure of calcium ion channels. The calcium ion channels regulate the glutamate release from the central nervous system. Closure of these channels effectively prevents the glutamate release, thereby enhancing neuroprotection through the inhibition of glutamate release. This also prevents from potential brain damage through inhibiting the glutamate release thereby enhancing neuroprotection in a neonatal hypoxic-ischemic event, because the glutamate receptor blockers are considered to be dangerous in immature brains such as that of the neonates. Moreover, cannabinoids such as cannabidiol also serve to reduce direct N-methyl-D-aspartate neurotoxicity by direct inhibition of factors such as protein kinase A signaling and nitric oxide generation, which are potentially neurotoxic. All of these effects are induced naturally through the endocannabinoid system in the body. The ability of CBD to enhance the activity of endocannabinoid system by binding to the cannabinoid receptors thereby grants it the potential to be used in neurotoxic disorders such as multiple sclerosis and brain damage. Antiproliferative effects of endocannabinoids on cancer cells have been studied well, and their effect on stopping the inflammation is large. As inflammation particularly spreads vastly after a tissue injury due to contusion or other contact causes, so the rate of inflammation surrounding the brain injury can be particularly dangerous, as it causes necrotic cell death in the tissue on a large scale. This cell death proves fatal to certain brain areas that are hit directly by the injury. So, in the case, if traumatic brain injury, stopping the inflammation gains prime importance, as it reduces the chance of the damage spread. The microglia, or the macrophages that exist in the brain tissue, have a very important role in inflammation. Moreover, there are cells in the brain tissue called astrocytes. The astrocytes serve to nourish the brain tissue under normal circumstances, providing vital nutrients to the neurons thus playing an important role in tissue growth. However, under traumatic brain injury where the brain tissue becomes necrotic, the astrocytes have been found secreting certain cytokines along with other chemicals such as nitric oxide that mediate inflammation. 

Research based studies on the effects of CBD in Multiple Sclerosis

A comprehensive research to investigate the usefulness of cannabidiol for the treatment of multiple sclerosis was conducted by Department of Pathology in University of South Carolina. The research included inducing experimental autoimmune encephalomyelitis (EAE) in non-human subjects such as female mice using the bodily factors such as peptide MOG35-55 as an immunogen. These mice in which EAE was induced were then given either cannabidiol or a control substance as soon as the first EAE symptoms due to the immunogen were observed. The progression of disease induced was then noted through using properly assessed clinical scores, which were largely associated with different symptom expressions. The average score that was noted for each group of the subjects was calculated daily. The scores for the subjects which were treated with CBD (EAE-CBD) and the scores for the control group treated with a control substance (EAE-VEH) were then carefully compared in order to assess the efficacy of CBD for the treatment of symptoms in the mice.

The results were largely suggestive of using CBD for treating the symptoms. The mice treated with the control vehicle were found to be developing EAE at a continuous rate having a maximum mean clinical score of 4.1 during the whole course of the study. An average clinical score of 4 in this study meant that the subjects were progressing towards a state of tetra paralysis. The mice treated with CBD, on the other hand, experienced a distinctly slower onset of symptoms of EAE, and their peak mean clinical score of symptoms was 2.2. This score was smaller than the control group by a large margin, and these scores indicated which only the partial paralysis of the hind limbs in the mice treated with CBD.

The results suggested that CBD was clear in relieving the symptoms of multiple sclerosis. after the proper assessment of the results obtained from these trials, the researchers then use scientific techniques to investigate the role of CBD in human subjects using in vivo and in vitro techniques. The results obtained from the human studies also showed that CBD was efficient in treating the symptoms of the disease.

Another independent study was conducted by a group of biologists and the results were published on PubMed. This study relied on using an anonymous web-based survey which was hosted on an NGO known as the Michael J. Fox Foundation. The webpages of National Multiple Sclerosis Society also participated in the study which was conducted from 15 February to 15 October 2016. 

The research carried out in this study identified that CBD acted in two major ways in order to curb the symptoms of multiple sclerosis in the patients. These two mechanisms through which CBD can act to relieve the symptoms of MS and MS-like conditions were not known before this research. The first mechanism was through CBD inserting a direct positive influence on the levels of anti-inflammatory substances such as specific anti-inflammatory cytokines. This mechanism also included CBD exerting a direct negative influence on the levels of pro-inflammatory cytokines which were the main mediators of inflammation in the central nervous system. The second mechanism was based on the neuroprotective properties of CBD which protected the central nervous system tissue from autoimmune attacks. This effect was exerted through an indirect manipulation on the levels of anti-inflammatory MDSCs which inhibit the T cell induction that normally occurs in autoimmune disease. The uncontrolled response of the T cells is the main culprit in autoimmune diseases such as multiple sclerosis. as CBD served to increase the factors that inhibited the uncontrolled production of T cells, it directly helped the patients treat their symptoms. 

To this date, Sativex is the only drug approved by the FDA which includes a measured proportion of CBD, and is used for the treatment of symptoms in multiple sclerosis patients all over the world.

REFERENCES

1. Kindred, John H. et al. "Cannabis Use In People With Parkinson’s Disease And Multiple Sclerosis: A Web-Based Investigation". Complementary Therapies In Medicine, vol 33, 2017, pp. 99-104. Elsevier BV, doi:10.1016/j.ctim.2017.07.002. Accessed 20 Sept 2020.
2. Malcolm, Emily. "CBD And Multiple Sclerosis: What You Need To Know". Multiple Sclerosis News Today, 2020, https://multiplesclerosisnewstoday.com/news-posts/2019/09/20/cbd-oil-and-multiple-sclerosis/.
3. "Clinically Isolated Syndrome (CIS)". MS Trust, 2020, https://www.mstrust.org.uk/a-z/clinically-isolated-syndrome-cis.
4. https://commons.wikimedia.org/wiki/File:Types_of_multiple_scl%C3%A9rosis.png
5. https://commons.wikimedia.org/wiki/File:Cannabinoid_Receptors_With_THC-2.svg