Medical cannabinoids have been proposed by various medical research studies as a promising alternative to levodopa-containing agents used in the management of Parkinson's disease. The active component of cannabinoids known as tetrahydrocannabinol has been shown to have an effect of increasing the levels of dopamine in the body. On the other hand, Parkinsonism is associated with low levels of dopamine (Chevalier, 2017). Therefore, the relationship between the effects of cannabinoids and the pathophysiology of Parkinson's disease is explored in this paper based on the previous peer-reviewed research articles. Since there are no current conclusions on the efficacy of cannabinoids in managing movement disorders, the paper focuses on providing a preclinical platform where future researchers can base their studies towards the application of medical cannabinoids in managing Parkinson's disease.
In the United States, 29 states had legalized use of medical marijuana in conditions affecting the nervous system by November 2017. Additional 5 states have approved the use of medical marijuana also referred to as medical cannabinoids in the management of Parkinson's disease (Chevalier, 2017). The legal actions came up after various research studies concluded that cannabinoids have an effect on the motor function and muscle movement. According to psychology, motor function and muscle movement are coordinated by the nervous system through the motor neurons. Through motor control, people and animals are able to use their cognitive senses to activate their muscles and limbs for purposes of locomotion and movement ( Audrey, 2017 ). Even though children learn to walk and move muscles at an early age which later becomes an autonomous process, there are medical conditions that impede normal body movements such as Huntington’s disease, Tourette’s syndrome, Parkinson’s disease, Wilson’s disease, essential tremors, and tremors associated with multiple sclerosis.
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Cannabinoids are the phytochemicals derived from the marijuana drug which comprises of dried leaves of the hemp plant known as Cannabis sativa. In America, marijuana is an illegal drug and therefore people who use it have adopted various street names like “pot”, “smoke”, “Mary Jane”, “weed”, “herb”, etc. (Chevalier, 2017). Historically, marijuana was recognized as a medicinal herb with the ability to change mood, consciousness, and perception. In Jamaica, most people use cannabinoids to relieve stress at the end of a long working day. Ancient East Indians, Greeks, and Romans used cannabinoids as anesthetics and control of muscle spasms. Therefore, this is enough proof that cannabinoids have medicinal value that the current society is not exploiting ( More & Choi, 2015) . After having isolated the active ingredient as the delta tetrahydrocannabinol, it is upon the scientific institutions with the financial and legal support of the national and state governments to take advantage of the advancement in science and technology and derive useful compounds from marijuana.
The study on the use of marijuana in treating motor system conditions was motivated by the fact that some researchers discovered that people who abused cannabis and related substances had limb tremors before smoking the drug which was cooled after. However, the interests of researching into the agents took longer because tremors have been labeled by medical practitioners as a withdrawal symptom for drug addicts ( More & Choi, 2015) . Further research on the possibility of using cannabinoids in various medical conditions was influenced by the effect of marijuana in reducing post-traumatic stress disorder in soldiers after coming from the battlefield or training. However, animal models were used and the findings showed tremendous cooling and coordinated movement of muscles in the specimen after they were given cannabinoids ( Sexton et al., 2016 ).
Scientists have put a lot of interests in studying the relationship between Parkinson's disease and cannabinoids because the condition affects over one million people in the United States. Currently, Parkinson’s disease is the second most common neurological disorder in the country and it has been associated with a number of deaths ( More & Choi, 2015) . The claim that some cannabinoids have the potential of slowing the pathogenesis and helping patients manage the neurological symptoms of Parkinson’s disease has sparked interests among scientific researchers and clinicians to explore the components of marijuana.
Overview of Parkinson’s disease
According to Freedom Chevalier, Parkinson’s disease (PD) is "a progressive, neurodegenerative disorder of the central nervous system that mainly affects the motor system." The disease is caused by the gradual death of neurons that produce dopamine hence the reason why the onset of symptoms is usually slow over a period of time. Even though the cause of PD is unknown, clinicians believe that it is caused by environmental factors such as a history of head trauma, exposure to pesticides, and lack of caffeinated beverages ( More & Choi, 2015) . An interaction between environmental and genetic factors such as low urate concentrations in blood serum and family history of PD have been shown to increase the risk of developing Parkinson's disease.
The cure for PD has not yet been found. Clinicians primarily focus on managing the motor-related symptoms by replenishing the brain with dopamine. The most recognized symptoms of Parkinson’s disease that have been targeted using cannabinoids include tremors (shaking) while sitting, muscle stiffness (rigidity), slowness or difficulty with walking (akinesia) characterized by an abnormal gait. If untreated, sleep disorders, emotional problems, anxiety or depression, and dementia might develop (Loewy, 2017). The disease is common in older people above 50 years and it has been associated with accumulation of alpha-synuclein protein that affects dopaminergic neurons of the brains especially in the substantia nigra leading to depletion of dopamine in the nervous system. However, until today, none of the pathophysiological pathways proposed to cause the disease, lead to its complications, and death has been approved (Loewy, 2017). However, the pathways help in identifying the molecular targets of the disease.
Current management regimen target various pathways postulated to be the most probable causes of PD and they include neuroinflammation, oxidative stress, calcium dysregulation, mitochondrial dysfunction, kinase pathways, protein aggregation, etc. ( More & Choi, 2015). Due to the complexity of the pathophysiology of PD, the commonly used pharmacological regimen includes drugs containing levodopa which has a great effect in alleviating most of the symptoms. However, Parkinson’s disease requires long-term therapy yet the chronic use of levodopa causes levodopa-induced dyskinesia that has untoward effects on the patient. As a result, clinicians are forced to administer amantadine which has an antidyskinetic effect to maintain serum levels of dopamine at the physiological level (Loewy, 2017). But amantadine works by reducing the effect of drugs containing levodopa which has forced medical practitioners to embark on research and come up with non-dopaminergic agents. One of the agents that have been in research studies for the past 15 years medical cannabinoids.
Cannabinoids and Parkinson’s disease
Currently, investigations are ongoing trying to find out how cannabinoids can be manipulated to replace levodopa-containing agents in the symptomatic treatment of Parkinson's disease. Most studies target cannabinoids with least dependence effect but potent and specific for endogenous cannabinoid receptors (CB1 and CB2) and the Transient Receptor Potential cation channel subfamily V member 1 (TRPV1) receptors ( Sexton et al., 2016 ). Through physiological studies of the human body, it has been noted that the two most prominent nervous areas involved in controlling the motor system that coordinates body movements are substantia nigra and globus pallidus. The interest for targeting CB1 and CB2 in research for PD treatment is because the two regions contain the highest densities of cannabinoid receptors especially CB1and some endogenous cannabinoids like anandamide (AEA) and 2-arachidonyl glycerol (2-AG) ( Sexton et al., 2016 ). Researchers believed that the high concentration of cannabinoid receptors in the regions that control movement had some involvement in neuroprotection and alleviating factors that inhibit normal body function.
According to an anonymous scientist in the article, Parkinson’s Disease-Coming to Terms with the “New Me”, published by the editorial team in the American Psychiatry Journal, states that "cannabinoids in marijuana work in some of the same ways as those made by the body." He argues that plants and animals make cannabinoids which are referred to as endocannabinoid or natural cannabinoids ( Sexton et al., 2016 ). The function of this chemical in the body depends on its ability to bind to receptors such as dopaminergic receptors. And low dopamine levels have been associated with Parkinson’s disease. Therefore, the author argues that cannabinoids both exogenous cannabinoids from marijuana and endocannabinoids “may have antioxidant and anti-inflammatory effects that could be neuroprotective” ( Russo & Marcu, 2017 ). Even though marijuana has serious side effects to the user such as experiencing hallucinatory episodes, nausea, and dizziness, the author believes that exogenous cannabinoids can be exploited to replenish the body especially in Parkinson's patients who usually have very low levels of endocannabinoids. The role of cannabinoids in the progression of the disease is not yet known but the author believes that low levels of the chemical are associated with the PD ( Sexton et al., 2016 ). Therefore, future research should focus on finding the ways through which exogenous cannabinoids can be tolerated by reducing the side effects of medical marijuana and exploiting its substantial benefits.
In a research conducted by a medical research scientist Dr. Ethan Russo (2013) in his article, Full Spectrum Cannabis Hemp Oil with Cannabinoids: Treatment and Effects on Parkinson’s Disease, Russo concluded that “cannabis (hemp) could potentially slow the progression of Parkinson’s by acting upon the Endocannabinoid system and provide neuroprotective effects” ( Russo, 2013). In the research, a group of 20 patients with Parkinson’s was chosen and 10 of them were given daily doses of cannabinoids extracted from Hemp oil by Green Flower Botanicals, Inc. After one week, significant improvements in well-being were noticed in the patients who took the oil compared to those who never took it. Russo concluded that “cannabis in hemp is capable of suppressing oxidative injury, glial activation, and excitotoxicity that are known to cause degeneration of the dopamine-releasing neurons.” One of the complications in Parkinson’s patients is sleep behavior disorder and one of the patients who had the condition and was put on hemp oil for one week during the study showed tremendous improvements ( Russo, 2013) . Ethan Russo concluded that even though cannabinoids have not been proven to alleviate motor symptoms of PD, the chemical has the potential of improving overall neuron health by clearing cellular debris. And a ‘clean’ nervous system is important for patients recovering from Parkinson’s disease.
Audrey Joy (2017) conducted a literature-based study and summarized her findings in an article called The Use of Medical Marijuana on the Treatment of Nervous System Disorders, she postulated that “Although medical marijuana cannot cure Parkinson’s disease, it has been shown to decrease and alleviate symptoms such as tremors, motor disability, pain, sleep disorders, and bradykinesia” ( Audrey, 2017 ). She found out that researchers confirmed that PD is a cell/tissue degenerative disease and cannabinoids have the ability to promote cell health, therefore, reduce progression of Parkinson's disease. Other than relieving PD, she found out that smoking or ingesting marijuana relieves chronic pain and spasms caused by other nervous system illnesses such as Alzheimer's disease, Multiple Sclerosis, Fibromyalgia, etc. However, caution should be taken because marijuana reduces thinking capacity, balance, and coordination, and also reduces the ability to operate heavy machines ( Audrey, 2017 ). That is why people are advised not to drive under the influence of marijuana.
A team of scientists identified as ECHO led by Loewy conducted a research on the effect of cannabinoids on non-motor symptoms and published an article called Cannabinoids help treat Parkinson’s disease, Research Review Concludes . According to them, PD has both motor and non-motor related symptoms and previous studies concentrate on the effect of cannabinoids on motor symptoms (Loewy, 2017). Rather than concentrating on enhancing the amount of dopamine in circulation to manage the muscle rigidity, tremors, and bradykinesia, etc. associated with Parkinson’s disease, they focused in the therapeutic application of marijuana in non-motor symptoms. They found out that pain is a common symptom of PD and cannabinoids had analgesic effect hence it can be used to reduce pain. They also found out that cannabinoids possess anti-inflammatory properties that can reduce inflammation associated with neuronal damage (Loewy, 2017). They challenged future researchers to concentrate on other applications of cannabinoids rather than reducing motor symptoms. The natural compounds of marijuana have benefits to the treatment of Parkinson’s disease.
The idea ECHO of treating non-motor symptoms using cannabinoids was supported by a medical practitioner, Dr. Arielle Gerard, in his article Managing Parkinson’s Disease Symptoms with Medical Marijuana, who argued that “Descriptions of Parkinson’s Disease do not generally include the mention of pain” ( Sexton et al., 2016 ). He further stated that over 50% of patients with PD experience painful symptoms due to mental and physical discomfort. Other that dependence effects, Gerard argues that marijuana has a favorable safety profile and therefore, medical experts should take advantage of its medicinal functions in helping patients with severely debilitating symptoms of Parkinson’s disease (Loewy, 2017). The tetrahydrocannabinol component of marijuana has been shown to prevent free radicals from damaging neurons by inhibiting the free radicals oxidation process that is very destructive to nerve cells that lack the glucose-6-phosphate component.
An expert in science, Freedom Chevalier (2017) in his article Cannabis for the Treatment of Parkinson’s disease, tried to find the connection between the endocannabinoid system (ECS) and cannabis. He found out that, tetrahydrocannabinol (THC), the compound in marijuana that makes someone feel “high” can trigger various receptors of the ECS (Chevalier, 2017). The interaction was found to boost appetite, appetite, memory, immune system functionality, and promote sleep. Cannabinoids are able to achieve all these functions by stimulating the body to generate dopamine thus increasing dopamine levels which is useful in Parkinson’s disease because PD is associated with lower levels of dopamine (Chevalier, 2017). Other than increasing the levels of dopamine, Chevalier also found out that cannabis can aid in the elimination of toxins and other waste products from cells by stimulating mitochondria to increase energy production which is used in the detoxification process.
A research conducted by various scholars on the therapeutic role of cannabinoids in oxidative stress concluded that cannabinoids have a dual effect when it comes to reducing oxidative stress in PD patients. First, due to its antioxidant nature. And secondly, by replenishing cannabinoid receptors, especially CB1 ( Russo, 2013) . Their research was driven by the fact that Parkinson’s disease is associated with augmented oxidative stress. Reactive oxygen species are contained in the mitochondria and they weaken the process of energy production in PD patients ( Russo & Marcu, 2017 ). Even though the underlying cause is not known, the researchers found out that the membrane of the mitochondria in patients with PD has less CB1 receptors compared to a cell in a healthy person. They were able to relate Parkinson’s disease with an effect on the level of endocannabinoids evidenced by the reduction in the cannabinoid receptors ( Russo, 2013) . Therefore, they postulated an idea of providing the exogenous cannabinoids so that they increase the intracellular concentration and off-set a mechanism that lowers the CB1 receptors leading to oxidative stress depicted in PD patients.
However, their idea was criticized by a scholar who argued that there is no proven relationship between the level of oxidative stress and the concentration of cannabinoid receptors. However, he explained the process basing on the antioxidant nature of the cannabinoids which quench reactive oxygen radicals generated by the microglia. He backed his argument by stating that "The mechanism by which cannabinoids act to reduce oxidative stress in PD patients is not known, however, they act independently of CB1, CB2, or TRPV1 receptors” ( Baron, 2015). This is because, despite the low concentration of cannabinoid receptors, the antioxidant effect was largely felt in the animals tested.
With the advancement in technology, pharmacologists are taking advantage of the mechanized machines to exploit various plant components and extracts. One of the plants that have been extensively exploited is Cannabis sativa. Pharmacologists have been able to isolate various phytochemicals from the plant. They target the stems, buds, and leaves of the three main species of Cannabis namely sativa, indica, and ruderlaris ( Baron, 2015) . The major phytochemicals isolated with medicinal value were cannabinoids. Today, over 100 different cannabinoids have been extracted from the plant however only three have been found to have some activity, namely; tetrahydrocannabinol, cannabinol, and cannabidiol. The three phytochemicals have been tested to have an effect on the nervous system which eventually leads to a cooling effect on the mind.
The Direction for Future Research on Cannabinoids and Application in Parkinsonism
Currently, the usage of marijuana in any social setting or hospital facility is a controversial topic constantly debated by various stakeholders. Various state governments are reluctant to legalize the use of marijuana in medication despite proven medical benefits because of the dependence, tendency of abuse, and addiction associated with the drug ( Baron, 2015) . Currently, Canada, United Kingdom, and almost half of the states in America have legalized use of medical marijuana in health facilities giving medical practitioners the authority to use the substance appropriately. However, the federal government is still reluctant in accepting the use of cannabinoids thus leaving the drug in the same category with other illegal drugs like cocaine and methamphetamine.
According to the statistics, illegal drugs namely marijuana, cocaine, lysergic derivatives, and heroin account for only about 3,000 deaths annually ( Sexton et al., 2016 ). Out of those deaths, none is attributed to using of marijuana because studies have shown that it is rare for an overdose of cannabinoids to cause death. However, alcohols and cigarettes claim thousands of lives in America every year due to drunk driving, lung cancer, bronchitis, yet the government allows these two products to be advised even on family televisions and magazines.
The future of research depends on the role that the various state government will play in their countries ( Baron, 2015) . The government should act as an independent body and stop being misguided by well-financed pharmaceutical companies that argue that marijuana has more demerits than merits to the health of people. In countries like Canada and United Kingdom, reports indicate that cannabinoids are being used just like codeine as analgesics to relieve patients from post-operative pain, nausea, loss of appetite, and diarrhea. Also, the agent is under clinical trials for reduction of muscle spasms in movement disorders such as Huntington’s disease, Parkinson’s disease, and Tourette’s syndrome (Chevalier, 2017). The same story cannot be told in countries like the United States where most research studies are still at pilot stages because the efforts of researchers are dragged down by the reluctance of the federal government to legalize medical marijuana. It is evident that the first step in achieving any medical research lies in the legal action imposed on the project ( Audrey, 2017 ). Currently, scientific facilities are fighting with pharmaceutical companies to ensure the government legalizes the use of medical cannabinoids because the agents have a safe overall profile and their medical purposes outweigh the cons.
Conclusion
The use of marijuana for medicinal purposes is not a new concept to the world. In the past, various communities referred to it as a miracle plant, however, an era of ignorance has made the modern generation to label the product as an illegal drug. Even though the concept of using marijuana in Parkinson’s disease therapy is new, the cannabinoids obtained from this product have benefited many patients ailing from many other diseases. Marijuana has shown the potential of managing very many medical conditions both nervous (movement) conditions and lifestyle conditions such arthritis and cancer. Recently, cannabinoids have been shown to help patients with chronic diseases like cancer and HIV/AIDs deal with the stigma and intensive medication therapy that they undergo. Even though cannabis is not a drug for everybody, parents and adults should be given the liberty of choosing their medicines. It does not make any sense why people with Parkinsonism should be suffering when there is an alternative medication endowed with cannabinoids.
References
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Chevalier, F. (2017). Cannabis for the Treatment of Parkinson’s disease. Retrieved from https://news.lift.co/cannabis-for-the-treatment-of-parkinsons-disease/
Loewy, E. (2017). Cannabinoids help treat Parkinson’s disease, Research Review Concludes . Retrieved from https://echoconnection.org/cannabinoids-help-treat-parkinsons-disease-research-review-concludes/
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