i Medical Marijuana: A Policy and Perspective Scoping Review By Paige Burkhardt Tony Cuyler Ashley Gritten Michael Gulledge Chris Ireland Devon Noroski Chirag Patel Jake Power Jonathan Waltman Diana Wuelling A thesis submitted to the School of Radiologic Sciences in collaboration with a research agenda team In partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES (MSRS) WEBER STATE UNIVERSITY Ogden, Utah December 15, 2021 ii THE WEBER STATE UNIVERSITY GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Paige Burkhardt Bethony Cuyler Ashley Gritten Michael Gulledge Chris Ireland Devon Noroski Chirag Patel Jake Power Jonathan Waltman Diana Wuelling This thesis has been read by each member of the following supervisory committee and by majority vote found to be satisfactory. ______________________________ Robert Walker, PhD Chair, School of Radiologic Sciences ______________________________ Laurie Coburn, EdD Director of MSRS RA ______________________________ Tanya Nolan, EdD Director of MSRS ______________________________ Christopher Steelman, MS Director of MSRS Cardiac Specialist iii THE WEBER STATE UNIVERSITY GRADUATE SCHOOL RESEARCH AGENDA STUDENT APPROVAL of a thesis submitted by Paige Burkhardt Bethony Cuyler Ashley Gritten Michael Gulledge Chris Ireland Devon Noroski Chirag Patel Jake Power Jonathan Waltman Diana Wuelling This thesis has been read by each member of the student research agenda committee and by majority vote found to be satisfactory. Date ______________________ ____________________________________ Paige Burkhardt ______________________ ____________________________________ Bethony Cuyler ______________________ ____________________________________ Ashley Gritten ______________________ ____________________________________ Michael Gulledge ______________________ ____________________________________ Chris Ireland ______________________ ____________________________________ Devon Noroski ______________________ ____________________________________ Chirag Patel 12/15/2021 12/15/2021 12/15/2021 12/15/2021 12/15/2021 12/15/2021 12/15/2021 iv ______________________ ______________________ ______________________ ____________________________________ William Jake Power ____________________________________ Jonathan Waltman ____________________________________ Diana Wuelling 12/15/2021 12/15/2021 12/15/2021 v Abstract The medicinal use of marijuana has a long and complex history. One could argue that its vast array of potential health benefits has been underutilized in America. Federal and state regulations have undermined the effective scientific studying and research of medical marijuana. In addition, the Food and Drug Administration’s (FDA) process for pharmaceutical safety and purity has created insurmountable roadblocks to push marijuana through the Investigational New Drug application process. In the midst of the constantly evolving opioid crisis, this paper sought to review the current set of literature detailing medicinal uses of marijuana, in particular, as a potential alternative to opioid use for pain management. Ultimately, this scoping review study revealed that until regulations are lifted, some Americans will use marijuana medicinally, with or without their physician's advice, and its efficacy will continue to remain unaccounted for. Meanwhile, Americans will continue to battle the relentless opioid crisis. Ultimately, only the alteration of the Schedule 1 drug classification of medical marijuana would allow for appropriate large-scale research to take place, which in turn would allow physicians to obtain sufficient education on prescription and dosing recommendations. vi Table of Contents Chapter 1: Introduction ................................................................................................................. 8 Background ............................................................................................................................................ 9 Statement of the Problem ..................................................................................................................... 10 Purpose of the Study ............................................................................................................................. 11 Significance of the Study ...................................................................................................................... 13 Definition of Key Terms ....................................................................................................................... 13 Chapter 2: Literature Review ...................................................................................................... 15 Natural Receptors ................................................................................................................................ 17 Table 2 Cannabinoids and their Properties (Sharma, 2012) ............................................................ 19 Malignant Disease Processes ................................................................................................................ 19 Research Limitations ............................................................................................................................ 31 Physician Education ............................................................................................................................. 34 Legal Issues .......................................................................................................................................... 36 Documentation ..................................................................................................................................... 37 Chapter 3: Research Method ....................................................................................................... 39 Research Methods and Design(s) ........................................................................................................ 39 Population & Sample ............................................................................................................................ 39 Materials/Instruments .......................................................................................................................... 40 Data Collection, Processing, and Analysis .......................................................................................... 40 Assumptions ......................................................................................................................................... 40 Limitations ........................................................................................................................................... 41 Delimitations ........................................................................................................................................ 41 Chapter 4: Findings ..................................................................................................................... 43 Chapter 5: Implications, Recommendations, and Conclusions ................................................. 46 Implications .......................................................................................................................................... 46 Recommendations ................................................................................................................................ 48 Conclusions .......................................................................................................................................... 49 References ................................................................................................................................... 50 vii List of Tables Table 1 Cannabinoids and their Properties……………………...………....…………………...…….12 8 Chapter 1: Introduction Patients battling chronic diseases and illnesses continue to suffer from side effects caused by pain management medicine such as nausea, vomiting, gastrointestinal distress, and other potentially life-threatening effects. Medical cannabis has been referenced as a potential alternative means of medical management to greatly minimize or entirely exclude the need for many primary and secondary medications. Cannabis has been reported to have been in use for thousands of years for medicinal purposes. Cannabis was first reported to be used as a medicine in China to manage pain related to constipation and childbirth (Robson, 2018). Cannabis has even been linked to studies in a few states showing a lower overall mortality caused by Opioid overdose (Ishida, 2019). Many circumstances for the use of cannabis to aid in the management of chronic diseases have been proposed over the years. However, the pragmatic use of cannabis to manage disease symptoms and effects is lacking as a result of limited research and legal restrictions based on its drug classification. Part of this is thought to be associated with the restriction of federal money in conjunction with Schedule I drugs. The proposed benefits of cannabis range from symptom relief all the way to regression of disease effects. There is also limited data proposing an “anti-cancer” effect related to cannabis therapy (Pergam et al, 2017). As overdose and drug dependency have become more prevalent, alternatives such as the use of medical cannabis for disease and symptom management should be explored to identify the potential reduction in total opiate usage within the United States. In order to achieve these goals, more research into the potential uses of cannabis must be explored and physician education must be improved. Additionally, the legal issues surrounding cannabis need to be addressed in order for the widespread use of cannabis to be adopted for medicinal purposes. 9 The goal of this paper was to provide education on the extent of potential benefits via the utilization of medical cannabis, and to provide a framework for physicians and patients regarding the different ways to use cannabis while minimizing its potential adverse effects. Adverse effects of cannabis will be discussed along with the legal issues and history of cannabis in the United States. This paper should educate and inform readers of the practicality and safe medicinal use of cannabis/cannabidiol in place of using long-term pharmaceuticals for disease and symptom management, and ultimately to improve quality of life. The research completed on this subject is an illustration of the importance of finding an alternative to the use of synthetic opioids to manage pain associated with disease processes treatment. Background The significance of cannabis being used as a form of medical treatment comes at a time when the country is amidst an opioid crisis with an associated increasingly large number of opioid-related addictions and deaths. It has been identified that the use of synthetic opioids can lead to non-medical use, such as recreational abuse, which in turn can segue into the use of Heroin (Rose 2018). In prior years society, government, and the medical world have widely not been accepting of medical marijuana as a form of treatment. The classification of cannabis as a Schedule I drug by the federal government has limited the amount of research, funding, and potential indications for its use as a “medical” drug. The research that has been obtained regarding medical cannabis and its effects on certain comorbidities demonstrates that it indeed has beneficial qualities that may supersede that of synthetic opioids. Additional research will likely reveal new indications for access to medical cannabis and highlight its many benefits. 10 Statement of the Problem One of the current problems facing modern medicine is the ever-growing cases of opioid addiction and opioid-related tragedies. The controversial topic of cannabinoids in relation to the safety and effectiveness of their use as an alternative to opioids is a persistent tragedy of its own as its medical indications could change negative opioid use outcomes that could have otherwise been avoided. Currently, physicians are quick to prescribe long-term opioids and other medications to their patients without providing information on potential negative effects, including addictive properties. The struggle remains to identify proven alternative treatments that offer a better quality of life for the patient and present them in a manner that physicians feel comfortable prescribing those alternatives to patients. As such, the potential to at least partially replace opioids with medical cannabis brings forth the need for additional research on medical cannabis and cannabinoids. The problem the medical community is currently facing relative to this idea is the negative perception that comes with the idea of the widespread use of cannabis in medical management. In today’s society, there is a common thought that cannabis can be addictive or lead to the use of more addictive, “harder” drugs in patients who use it (Whitcomb, 2019). Since cannabis is considered a Scheduled I drug there is also an associated hesitance to prescribe it medicinally. Ultimately, the solution is multifactorial and will require funding and support for research, reevaluation of legal issues, and increasing availability of products for both research and treatment purposes. 11 Purpose of the Study The purpose of this scoping review study was to compile and explain research that has been done on medical cannabis and cannabinoids as well as identification of the potential benefits of its use. The research methodology used was a scoping review of published literature. A systematic review will be carried out to collect all possible studies related to cannabis and cannabinoids as an alternative form of medical treatment and pain management. This study reviewed and analyzed the research for an overview on the broad topic of cannabis and CBD oil being used in medicine. Prior research collection was performed primarily through the use of scholarly databases, such as PubMed, NCBI, MEDLINE, Google Scholar, and ScienceDirect. All publications being referenced were peer-reviewed, fact-checked, and published within the last ten years (2010 to present). Some publications included previous research that was conducted on patients that agreed to share their personal experiences and opinions. The goal of this scoping review was to provide information on how medical cannabis and cannabinoids can safely and effectively be used without addiction risk or wide-scale side effects, as well as how it can be used in place of previously prescribed pharmaceuticals to treat symptoms related to chronic diseases and cancer treatments. The hope was that with better understanding of this substance, physicians may become adequately educated in order to consider prescribing cannabis in place of long-term opioids, anxiolytic drugs, or other lifelong medications to treat chronic conditions. Research Questions Utilizing a scoping review approach to data collection allowed for discussion on the use of medical cannabis for the treatment of illness. The goal was to determine if cannabis can provide 12 long-term relief to patients as an alternative to the normally prescribed addictive opioids that may pose unnecessary and significant harm to patients. Additionally, an understanding of whether physician education on safety and effectiveness could play a substantial role in the future potential for replacement of opioids with medical cannabis was sought. Q1. Are there any severe adverse effects associated with medical cannabis use? Q2. Does Medical Cannabis have the potential to replace opioids in long-term pain and disease management? Q3. Is there existing research on how patients perceive the effectiveness of medical cannabis? Q4. Is there any education available for physicians on medical cannabis use? Nature of the Study This study was conducted with the intention of creating an awareness of the possibility of medical cannabis being used as an alternative for opioid use for pain management, control of symptoms, and relief of side effects of certain diseases. The information found in this research was helpful in determining that, in fact, medical cannabis could be used as a less addictive form of pain/symptom relief for suffering patients. Several different disease processes and the medications used to treat them were researched. By reviewing medical cannabis studies previously performed by other researchers, the answers to the outlined research questions can be expanded upon. Diseases such as cancer, post-traumatic stress disorder (PTSD), anxiety, chronic gastrointestinal disorders, and chronic pain syndromes, as well as the treatment of side effects such as nausea, vomiting, sleep deprivation, and pain were reviewed in this research. 13 Each specific disease was used as a starting point in the research of prior studies that have been conducted. Within these searches, various topics were explored. These topics included opioid dependence, adverse effects (opioids vs. cannabis), and cannabis as a form of symptom relief reduction. Lack of federal legalization, physician education, and prior research were discovered to be limitations and therefore prompted the need for more research and served as the core basis of this scoping review. The variation of topics researched helps this review provide a fair and all-encompassing overview of the current and future use of CBD and cannabis in medical treatments. Significance of the Study As stated, there is a growing problem with opioid dependence and abuse. This study shows importance in this field as a steppingstone to controlling the current opioid issue. Growing overdose percentages, up to 200% since 2000, are only showing to continue increasing (Rudd, 2016). Rudd also states that the increase in opioid overdose deaths could lead to a shortage of viable organs for organ donation cases. Attempting to correct this soon-to-be out-of-control problem has the potential for many lives saved, and lives improved. Patients who use medical cannabis for disease management have the potential for a life filled with fewer adverse effects from medications. Definition of Key Terms Term 1. Cannabis: Cannabis, (genus Cannabis), a genus of medicinal, recreational, and fibre plants belonging to the family Cannabaceae. By some classifications, the genus Cannabis comprises a single species, hemp (Cannabis sativa), a stout, aromatic, erect annual bulb that originated in Central Asia and is now cultivated worldwide. A tall canelike variety is raised for 14 the production of hemp fibre, while the female plants of a short branchier variety are prized as the more abundant source of the psychoactive substance tetrahydrocannabinol (THC), the active ingredient of marijuana. Encyclopædia Britannica, inc. (n.d.). Cannabis. Encyclopædia Britannica. Retrieved December 8, 2021, from https://www.britannica.com/plant/cannabis-plant. Term 2. CBD: A crystalline, non-intoxicating cannabinoid (C21H30O2) found in cannabis and hemp that is sometimes used medicinally. Merriam-Webster. (n.d.). Cannabidiol definition & meaning. Merriam-Webster. Retrieved December 8, 2021, from https://www.merriam-webster.com/dictionary/cannabidiol. Term 3. THC (tetrahydrocannabinol): Either of two physiologically active isomers from hemp plant resin, one that is the chief intoxicant in marijuana. Merriam-Webster. (n.d.). THC definition & meaning. Merriam-Webster. Retrieved December 8, 2021, from https://www.merriam-webster.com/dictionary/THC. 15 Chapter 2: Literature Review In researching the potential benefits of cannabis and cannabinoids, a number of themes were identified to strategically review the current literature. A brief history of marijuana use provides a background to the current state of affairs and ongoing research. During the literature review process, themes addressed were the physiological ways in which cannabis works, the malignant and chronic disease processes in which cannabis could be beneficial, the adverse effects of cannabis usage, research and legality limitations, growth and production limitations, and physician education. These themes are addressed in further detail in this chapter. Documentation This research project began with an initial interest in the medical benefits of cannabis and CBD as more and more states begin to decriminalize the use of recreational marijuana. The majority of these states began their cannabis evolution with medical marijuana. The research carried out for this paper progressed into a scoping review of the medical cannabis industry, rather than a systematic meta-analysis, as more questions than answers were revealed throughout the literature review process. Consequently, this research model was selected in order to identify the current body of knowledge and any existing gaps on the topic in the hopes that it may inspire future research to find its place within the medical community. The research was performed primarily through the use of scholarly databases, such as PubMed, NCBI, MEDLINE, Google Scholar, and ScienceDirect. All publications being referenced are peer-reviewed, fact-checked, and published within the last ten years. History Cannabis and cannabinoid (CBD) oil have been successfully used for a variety of therapeutic purposes across the world throughout history with many cultures taking advantage of 16 its benefits. China was among the first to use cannabis some 5000 years ago (Robson, 2019). Around 2737 BC, an ancient Chinese emperor discovered the medicinal effects of the cannabis plant for the management of malaria, constipation, childbirth, gout, and rheumatism-associated pain. The plant was believed to be one of the five sacred grains in ancient Chinese culture (Desjardins, 2018). The oldest cannabis plant is thought to have been used in Asia for medical, fibrous, recreational, and ritual purposes (Ren, 2019). The use of cannabis spread west and was used in burial rituals by the Scythians and smoked for religious reasons by the Hindu people. By 450BC to 1,000AD, the cannabis plant had made its way to western Europe and was used to ease labor pains for the elite women of Rome, as well as being used as a treatment for epilepsy in Arabic nations (Desjardins, 2018). After the Spanish conquest, the cannabis plant had spread across the entire world, however, not every country saw the plant as a benefit. In 1914 the United States passed the Harrison tax declaring marijuana a crime and in 1924 cannabis was taken out of the US Pharmacopeia. In 1937, the marijuana tax imposed a levy of $1 per ounce for medicinal use and $100 per ounce for recreational use. The AMA stood alone in the opposition of this act, but ultimately it passed. By 1970 the plant was classified as a Schedule I drug which resulted in hard limits on researching the benefits of marijuana as schedule I drugs are defined as having a high potential for abuse with no accepted medical use (Abrams, 2019). Regardless of the potential setbacks, the National Cancer Institute began supporting research trials for the use of THC to treat chemotherapy-induced nausea and vomiting (Abrams, 2019). Around 1985-1986, the first cannabinoids, Dronabinol and Nabilone, were approved for use in the management of chemotherapy-induced side effects. Despite the countless obstacles involving the utilization of marijuana for medicinal purposes, in the year 2000, the future of the plant started to change with 17 many states legalizing it first for medical consumption, and eventually some states even approving it for recreational consumption. Natural Receptors The chemical components of cannabis are complex and have unique properties. Cannabis plants contain over 400 chemicals with 61 being classified as cannabinoids. The first most utilized component is THC and the second most common is CBD. The means of pyrolysis while smoking cannabis produces more than 2000 compounds that are classified as one of the following chemicals: nitrogenous compounds, amino acids, sugars, simple fatty acids, hydrocarbons, and terpenes. These different compounds result in distinctive pharmacological and toxicological cannabis properties. Major cannabinoids are referenced in Table 1. Delta9-tetrahydrocannabinol (THC) is identified as the primary psychoactive component that relates to the behavioral factor of cannabis toxicity (Sharma, 2012). The mechanism and bioavailability of different cannabinoids result in interaction with different cannabinoid receptors and can result in a variety of effects. Additional research on these interactions and how they affect individuals is required to help close the gaps in current research. Medicinally, CBD contributes to pain relief and decreased inflammation without intoxicating or sedating effects (Russo, 2011). How cannabis affects the body was not discovered until 1964 by Dr. Yechiel Gaoni and Dr. Raphael Mechoulaml. Their purpose was to research the chemical makeup of the cannabis Sativa plant. Dr. Mechoulam, an organic chemist from Israel, was the first to discover Delta9-tetrahydrocannabinol (THC). Subsequently, he and his partner, Dr. Gaoni, were the first to isolate the THC molecule and discover the endocannabinoid system. The endocannabinoid system can be found throughout the body; brain, organs, connective tissues, glands, and immune 18 cells (Alger, 2013). According to Dr. Mechoulam, the system is “responsible for regulating everything from moods, sleep, and appetite to cognitive thought, energy metabolism, and ability to sense pain.” (Wilcox, 2016). Their research looked at the cell receptor of THC and how it binds to the body (Wilcox, 2016). Dr. Allyn Howlett initially isolated the receptor CB1 that binds to THC, but Dr. Mechoulam and his team found the body’s natural version, anandamide. The name anandamide originates from eastern philosophy, where Ananda in Sanskrit means supreme joy. The fatty acid neurotransmitter can be found in the central or peripheral nervous system and is broken down into CB1 receptors, primarily found in the central nervous system, and CB2 receptors, primarily found in the peripheral nervous system (Wilcox 2016). It is a relatively well-known fact that dopamine is a neurotransmitter produced by the body with effects that naturally provide a feeling of euphoria. When an increased amount of dopamine exists, people tend to have an overall feeling of positivity as Dopamine serves as a “reward booster” for the brain. Ferreira (2019) stated that CBD influences dopaminergic neurotransmission by inhibiting the dopamine uptake transporter, thus increasing the endogenous levels of dopamine. Due to the increase of dopamine created in the brain by cannabis, people that suffer from different medical conditions claim they sleep better and have an overall improved state of mental health with the use of CBD. Cannabis and CBD are not new science to our day and age. In fact, cannabis sativa L. was the original and most important source of cannabinoids, and it has been used as a herbal treatment for millennia. The first archaeological evidence of cannabis medical use dates back to ancient China's Han Dynasty, when it was prescribed for rheumatic pain, constipation, female reproductive system diseases, and malaria, among other ailments (Daris, 2019). 19 Studies show that plant-derived and synthetic cannabinoids' ability to control invasion, cell growth, and death has been shown and proven in numerous experimental studies using cancer cell lines and genetically engineered mouse models. Thus, different types of cannabinoids may have different modes of action. An example of this is Phyto cannabinoid THC which promotes apoptosis in a CB-receptor-dependent manner. At the same time, CBD exerts this effect independently of CB1/CB2 receptors and possibly includes the activation of the TRPV2 receptor in some cancer types (Daris, 2019). Table 1: Cannabinoids and their Properties (Sharma, 2012) Malignant Disease Processes Chronic disease management plays an integral role in many people's ability to function daily without pain. A review of the literature found cannabis, marijuana, and cannabinoids to be recognized by the National Cancer Institute Symptom Management and Quality of Life Steering Committee for relief of symptoms of cancer and its treatments. Studies have shown that cannabis, marijuana, and cannabinoids can help with cognitive impairment, cardiovascular 20 toxicity, neurotoxicity, and fatigue (Kleckner, 2019). Also, it can help with cancer-specific pain, bone health toxicity, sleep disorders, metabolic toxicity, and psychological distress. Next, the literature showed chemotherapy-induced nausea and vomiting, gastrointestinal distress, and loss of appetite/anorexia were improved due to the use of cannabis for these cancer treatment-related ailments (Kleckner, 2019). Furthermore, cannabis, marijuana, and cannabinoids are promising medications for symptom management in the context of cancer and its treatments because of their multiple-purpose use and availability. In the literature, factors were discussed with several common symptoms and side effects of cancer and its treatments, concluding preclinical and clinical studies of cannabis in cancer patients and other clinical populations (Kleckner, 2019). Cancer patients have countless disease symptoms and side effects of treatments that contribute to degradation of quality of life. Cannabis has been proposed as a potential alternative to many medications, as well as a possible means to reduce the severity of disease-related symptoms. Oce study concluded that up to 70% of patients reported improvements in pain control and general well-being, along with 60% stating improved appetite, 50% stating reduced nausea and vomiting, and 44% reducing anxiety. Most importantly, in the opinion of patients, 83% stated the overall efficacy of cannabis was overwhelmingly positive (Waissengrin et al, 2015) Many studies have been performed to test whether cannabis is effective in treating chemotherapy induced nausea and vomiting (CINV). This has led to mixed reviews on the efficacy of cannabis. Most research agrees that cannabis is effective when compared to placebo drugs for relieving CINV. Abrams (2019) explained in a study that the National Academies of Sciences, Engineering and Medicine (NSEM) concluded that oral cannabinoids can be effective antiemetics in patients with chemotherapy-induced nausea and vomiting. With progressively 21 rising preclinical evidence, a study done by Amber Klechner, advocate that the endocannabinoid system plays a large role in controlling nausea and vomiting. Cannabinoid receptors CB1 and CB2 are found within the GI tract and brain- stem. Within this study, the patient claims that cannabis relieves chemotherapy induced nausea and vomiting is widely recognized, and increasing clinical evidence supports this (Kleckner, 2019). In a study done by Mary Bridgeman and colleagues in 2017, of 23 randomized, controlled trials, patients experienced less nausea and vomiting when they received cannabis-based treatments. However, there has not been much research on newer, improved antiemetic drugs. There is currently insufficient evidence to draw conclusions on the efficacy of CBs compared to these new antiemetics due to a lack of sufficient RCTs comparing more recently approved drugs for CINV therapy such as 5HT3 antagonists or NK1-receptor antagonists. Even with evidence supporting the potential benefits in reducing nausea and vomiting, the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines do not recommend cannabinoids as first-line therapies (Bowles et al, 2011). Furthermore, Abrams (2019) states “the American Society of Clinical Oncology Expert Panel recommends that FDA-approved cannabinoids dronabinol and nabilone only be used to treat nausea and vomiting that are resistant to standard therapies.” Chronic pain is a common symptom facing cancer patients. Cannabis has been shown to aid in the management of chronic pain. Research has shown that it is more effective than placebo drugs in pain reduction. There is also evidence that cannabis works well when used in conjunction with opioids. Donald Abrams concluded in a study done in 2019, that there was strong evidence supporting the finding that patients who were treated with cannabis and cannabinoids for chronic pain were more likely to see a reduction in pain symptoms. He also concluded that cannabis appears to be able to synergistically work with opioids. Furthermore, 22 cannabis can be used when patients do not respond to opiates, as Schleider et al (2018) found in a study that THC and CBD induced pain reduction, both in an open-label study and in a placebo randomized trial. Another symptom paralleling chronic pain is Chemotherapy-induced peripheral neuropathy (CIPN). The symptoms of CIPN typically include abnormal sensory discrimination of vibration, touch, temperature variations, and pain. There were several placebo-controlled clinical trials that examined the effect of vaporized or smoked Cannabis for neuropathic pain for various reasons, though none yet for patients with cancer or CIPN (Kleckner, 2019). Patients suffering from chronic neuropathic pain for multiple reasons including, trauma/surgery, HIV, and diabetes, reported that smoked Cannabis significantly decreased central and peripheral neuropathic pain (Kleckner, 2019). However, CIPN is a complicated symptom to treat due to its elusive etiology and largely unpredictable presentation pattern. It is unclear if the seen effects of Cannabis are due to its impact on the peripheral nerves by decreasing damage, on the CNS by inhibiting or attenuating hypersensitization, or other mechanisms (Kleckner, 2019). There has been growing apprehension about the risks of opioids. One of them is opioid use disorder. Overdose-related deaths have prompted a greater focus on the more well-advised uses of these agents for managing pain, and the need to identify other agents to treat pain. (Ishida, 2019). Cannabis seems to present itself in today's society as a promising alternative to opioids and other drugs for cancer-related pain in the future, though more data are needed. In the studies reviewed, more than half of all cancer patients experience moderate to severe pain (Ishida, 2019). Controlling the pain management of a patient with cancer pain has improved dramatically by improving non-pharmaceutical practices such as cognitive behavioral therapy and exercise. However, insurance companies commonly don't like to reimburse these therapy's, leaving only opiates as patients' first-line treatment for cancer-associated pain. 23 That being said, there are alternatives for opiates. Patients look for other options because opiates do not always provide a sound effect for some patients, and some patients don't like how they make them feel and function. Some patients think that the opiate dose may lead to debilitating side effects such as vomiting, nausea, addiction, constipation. There is also a fear of the potential to overdose on these opiates (Ishida, 2019). Finding the individualized, suitable dose of opiates requires dose adjustments, which can take days or weeks to figure out. Further, the potential for dependence on opiates is exceptionally high, and patients with a high chance for survival from cancer may have a predisposition toward addiction should avoid constant and future opiate use (Ishida 2019). There is evidence that cannabis can affect both perception and sensation, and therefore, studies at the neurological, biochemical, and social levels psychologically are all critical. Indeed, there is physiologic and anatomic evidence of an interaction between opioid receptors and cannabinoids. Cannabinoids may directly and effectively target the opioid system and work with opioids to modulate cannabinoid and opioid pathways in tandem. In a retrospective study of 244 medicinal cannabis users with chronic pain, cannabis was associated with a 64% decrease in opiate use. There were fewer side effects of all drugs and improved quality of life (Kleckner, 2019). Opioid prescriptions used for controlling chronic pain and subsequent opioid-related complications have risen dramatically in the U.S. and have led to an epidemic in the United States. Recent data explained by Julie Ishida and colleagues suggest that medical marijuana laws have been associated with lower state-level opioid overdose mortality. Chronic pain affects approximately one-third of the U.S. population today, and opioid prescriptions have substantially increased steadily over the last twenty years. There has been an increase in opioid-related 24 complications, with opioid overdose deaths quadrupling between 1999 and 2015 (Ishida, 2019). The potential influence of marijuana substitution for all opioids is still unknown and further research and investigation are needed. In addition to chronic pain, cancer patients also have trouble maintaining body weight, either secondary to disease effects or as a result of treatments. Patients with decreased appetite and anorexia are among the most troublesome patients and suffer from the side effects of cancer treatments. More than half of patients with advanced cancer have suffered from this and lack appetite or have weight loss (Kleckner, 2019). Appetite-stimulating drugs currently used include: megestrol acetate (metoclopramide) which is a gut motility stimulator; steroids, including prednisone or dexamethasone; and dronabinol, which is a synthetic THC. All of these drugs except dronabinol are recommended for short-term use only, due to potential effects (Kleckner, 2019). Cannabis has a proven relationship with appetite increase. This has been studied in cancer patients to see if weight improvements could be noted in patients with cancer-associated anorexia-cachexia. A study completed by Holistere in 1971, showed that cancer patients who smoked Cannabis had an improvement in appetite, allowing them to maintain a little weight (Robson, 2001). Research is lacking in this area, and the research that has been done shows either inconclusive evidence or mixed reviews. One example being that the National Academies of Sciences, Engineering and Medicine found a lack of supporting evidence for the benefit of medical cannabis in treatment of cancer related anorexia (Pergam et el, 2017). It is seen however that despite the lack of supporting evidence, almost 50% of Oncologists would recommend its usage for treatment of the anorexia symptoms (Pergam et al, 2017). Another symptom that cancer patients struggle with is abnormalities in sleep and sleeping patterns. Mixed reviews are noted on this topic as well. Abrams (2019) found evidence that 25 cancer patients benefit from cannabis for sleep-related issues, but Birdsall et al. (2016) found low-quality evidence in a non-oncology population. Further research on this subject is required. Furthermore, cannabis offers many opportunities for palliative and supportive care in cancer. Recent changes in today’s social climate and legalization of cannabis will optimistically facilitate randomized studies to weigh in on the risks and benefits of cannabis use and find an optimized dose and administration methods. Currently, there is ever-growing clinical evidence amongst cancer patients that support the use of cannabis for treating chemotherapy-induced nausea and vomiting, loss of appetite, pain, and chemotherapy-induced peripheral neuropathy. Data from other populations suggest that cannabis could be used to alleviate gastrointestinal distress, anxiety, and sleep disorder potentially (Kleckner, 2019). Not only has cannabis been evaluated for symptom relief in oncology patients, but research has been performed to evaluate cannabis for the treatment of cancer. Limited studies on this subject matter exist and with very few clinical trials. Daris (2019) and colleagues researched the antitumor effects of synthetic cannabinoids and found that they are generally similar to the antitumor effects of plant-derived cannabinoids. These antitumor characteristics include cell growth inhibition, proliferation viability, enhanced apoptosis, invasion, and suppression of proinflammatory cytokines. This study came to the conclusion that synthetic cannabinoids have the potential to be even greater, more selective, and potent than their natural counterparts, and represent a promising therapeutic approach in the future of (Daris, 2019). Cannabinoids are a vast and important class of complex compounds that have a promising therapeutic potential for the treatment of a variety of diseases, including cancer. The anti-cancer effects have been shown in in-vitro studies. Once such study found that animal and in-vitro study data could suggest a potential for antitumor implications of cannabis and that, unfortunately, only two small studies 26 exist on this possible role of cannabis (Steele et al, 2019). Donald Abrams, MD, summarized things nicely in his 2015 review stating that there are not sufficient human studies showing cannabis as an effective anticancer agent that would warrant parents to use it over conventional cancer therapy, but also added the caveat that treating oncologists should not be discouraged from adding cannabinoid-based therapy in addition to traditional therapy. Suppression of proliferative cell signaling pathways, blockage of angiogenesis and cell migration, promotion of apoptosis, and/or induction of autophagy may all play a role in this anti-tumor action. (Bowles, 2012). The overall consensus is that there is limited evidence and not enough clinical trials to support this theory at this time. Chronic Disease Management Everyone in the world experiences anxiety to a certain degree. Anxiety is the body’s natural reaction to stress or fear of what is to come. According to an article by Kimberly Holland, symptoms of anxiety include increased heart rate, rapid breathing, trouble concentrating, fidgeting, and trouble sleeping (Holland, 2020). These symptoms can be triggered by many situations, including starting a new job, moving to a new place, taking a life-altering test, or even meeting new people. In general, the anxiety caused by these things can sometimes help push a person to work harder or be better. In these situations, anxiety may be considered as an adaptive response of the brain and body. When the anxiety response is constant in nature, it can become debilitating (Blessing, 2015). When the anxiety experienced by the person becomes debilitating and affects activities of daily living it is considered a disorder. Anxiety disorders are labeled and described based on their presentation. Some of these include panic disorder (experiencing recurrent panic attacks), social anxiety disorder (extreme fear of judgement), and 27 PTSD (anxiety following a traumatic event triggered by memories or similar situations) (Holland, 2020). Social anxiety disorder is one of the most common mental or anxiety disorders seen in the world today. It typically starts or manifests at a young age before adolescence. Neuroimaging functional studies have shown that increased activity in the amygdala and insula portions of the brain are linked to social anxiety disorder (Stein, 2008). Stein covers the DSM IV diagnostic criteria for diagnosing a patient with a social anxiety disorder (Stein, 2008). Included in Stein’s summary of the criteria is a notable and persistent fear of one or more social or performance situations with exposure to unfamiliar people or possible scrutiny by others, the person recognizes that the fear is excessive or unreasonable, and the feared social or performance situations are avoided or endured with intense anxiety or distress (Stein, 2008). Through these criteria, one can see that social anxiety could be devastating to a person’s life experiences. Studies have been conducted on the efficacy of cannabidiol in the treatment of social anxiety disorder. Nabuo Masataka (2019) performed a double-blind study on Japanese teenagers who presented with social anxiety disorder (SAD). He studied 40 teenagers, 20 of which were receiving the CBD and 20 that received a placebo. The results showed that the group receiving the CBD had a lower mean score on the post-intervention measurement. CBD was found to alleviate anticipatory anxiety in several studies. CBD was also found to have a substantial influence on increased brain activity in the right posterior cingulate cortex, which is known to be involved in emotional processing. In addition, this study notes that there are limitations due to the unknown amount of CBD found within the blood of the teens (Masataka, 2019). 28 In recent years it has been considered that cannabidiol can be used as a replacement for some pharmaceutical drugs. When administered acutely, preclinical evidence clearly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder (Blessing, 2015). Currently, there is an array of medications used to treat neuropsychological disorders. These range from serotonin reuptake inhibitors, benzodiazepines, serotonin nor-epinephrine reuptake inhibitors, antidepressant drugs, antipsychotics, and anticonvulsants. CBD is a phytocannabinoid found in Cannabis sativa that does not provide the same euphoric effects as THC (Blessing, 2015, para 5). Clinical studies have shown that CBD has many benefits including anticonvulsant, antipsychotic, analgesic, anti-inflammatory and antioxidant properties with minimal side effects. Of these benefits, many could be used to treat chronic disease without the worsening of negative effects experienced by patients. Research has shown CBD to be a good alternative to be used for anxiolytic purposes, due to the fact that it interacts with receptors in the brain that regulate fear behaviors (Blessing, 2015). Since anxiety disorders are thought to stem from fear, it is hypothesized that if a chemical can regulate the brain’s fear receptors, the anxiety can be calmed or treated. CBD has shown to have these beneficial effects, while also having an exceptionally good safety profile. No adverse effects were seen in the preclinical acute dosing trials. Cannabis and cannabinoids are widely used to cure and relieve symptoms or treat disease and non-cancer-related ailments. A systematic review of a randomized control trial was conducted, studying cannabinoids in treating chronic non-cancer pain, including smoked cannabis, extracts of cannabis-based medicine, dronabinol, nabilone, and a novel THC analog. Pain conditions included fibromyalgia, neuropathic pain, rheumatoid arthritis, and mixed chronic pain. Fifteen of the eighteen subjects within the trial showed an increasingly higher analgesic 29 effect from cannabinoids when compared to the subjects who received placebos. Cannabinoid use was well tolerated. The evidence from this study suggests that cannabinoids are safe and moderately effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis (Bridgeman, 2017). Despite having limited clinical evidence, a significant number of medical conditions and associated symptoms have been approved by quite a few state legislatures as qualifying conditions for medicinal cannabis use. The most common indications for medical marijuana are glaucoma, cancer, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and multiple sclerosis (MS) (Bridgeman, 2017). Adverse Effects Although Cannabis can have many beneficial therapeutic effects, potential ill effects do exist. Typically, side effects are mild and tolerable. One study found that thirty percent of patients reported at least one side effect at six months, however, side effects were relatively minor and easily overcome. The side effects experienced by patients using cannabis and cannabidiol have a range of appearances and vary by dose and administration route (Schleider, 2018). Birdsall et al. (2016) say the short-term side effects experienced approximately 30 minutes following consumption are anxiety, agitation, illusions, feelings of depersonalization, hallucinations, paranoid ideation, temporal slowing, impaired judgment/attention, red eyes, dryness of the mouth, tachycardia, and increased appetite. Whitcomb et al. (2019) reported an increased risk of mental illness in adolescent patients including anxiety, depression, and schizophrenia. Consumption in high doses may cause acute confusion, hypotension, hypothermia, and even psychosis. Another study found that with the use of nabiximols, the most common adverse events were dizziness, dry mouth, nausea/vomiting, somnolence (lethargy), and 30 confusion (Steele, 2019). Symptoms experienced by patients tend to be similar and are generally more intense with higher doses of cannabis/cannabidiol. Another consideration when smoking cannabis for treatment is the long-term effect on the lungs. This topic seems to have conflicting views. A study done by Bowles et al. (2011) states that there is little evidence that THC or other cannabinoids are carcinogenic. THC is not carcinogenic in skin tests on rodents, and THC and other cannabinoids are not mutagenic according to the Ames test. Interestingly, this study then went on to show that by contrast, cannabis smoke is carcinogenic in rodents and mutagenic in the Ames test. Cannabis smoke contains several of the same carcinogens as tobacco smoke at up to 50% higher concentrations and with three times the tar per cigarette (Bowles, 2011). One may potentially conclude that smoking cannabis is not worth the risk-to-benefit. Despite the side effects associated with cannabis use, one major benefit to it over some other drugs is that there have been no overdose deaths reported according to Abrams (2019). However, there is some disagreement about the potential addictive properties of cannabis. Abrams (2019) found that the addictive potential is low, but according to Whitcomb et al. (2019) cannabis carries an increased risk of addictive behaviors leading to addiction to other substances. Many of the side effects and addictive risks seem to be of less concern in certain patient populations. Many of the side effects are less severe than the symptoms related to the patient’s disease, or even the symptoms that the patient would experience using today’s pharmaceutical-grade treatments and medications. Additionally, many cancer patients are in the terminal phase of the disease and therefore, the addictive risk becomes less significant. 31 Research Limitations The great debate over the therapeutic benefits of medical marijuana is ongoing. While there have been studies performed in regard to the benefits of using medical cannabis as a form of treatment or symptom relief from certain disease processes and treatment regimens, they are very limited and most of them only employ small sample sizes. One such study notes that despite the fact that their study has a nationally representative sample, it has several limitations. The perceived efficacy of marijuana use for medical conditions was not directly addressed in this survey. It would be useful to know whether patients and their healthcare providers believe marijuana is helping them with their symptoms. In states where medical cannabis has not been legalized, many patients who used cannabis did not make their physician aware of it. This is possibly related to fear of repercussions (Azcarate, 2020). Regardless of the reason, large populations of cannabis users are not adequately represented. There are now many states in the U.S. that have active medical marijuana laws and a growing number that allow recreational usage. The federal government still classifies marijuana as a Schedule I controlled substance making it illegal to possess, which in turn limits medical studies that could investigate the potential benefits. With strong supporters weighing in on each side of this debate, arguments both for and against the legalization of marijuana remain highly controversial. There are many limitations regarding the legislative component of the treatment and therapeutic potential of cannabinoids. Even with the growing advances in medical cannabis usage today and the new ability to isolate THC from non-THC (or less potent THC compounds), there is still substantial controversy that clouds the use of medical cannabis for pain, especially in children and adolescents. The limited testing of data currently available does appear promising but does open up potential avenues for new research, especially with CBD. There will need to be 32 legislation that will consider the pediatric and adolescent patient population, as well as practitioners that are willing to professionally assess risks versus the benefits when prescribing to an already vulnerable population (Mayet, 2019). Additionally, there will need to be a change in the legislation on the use of cannabinoids for medical purposes and a list of all compounds of medicinal products requiring approval. A coordinated plan with proposed changes in labor law and workplace drug testing regulations would also be beneficial. Any change should be adopted in strict agreement with health, work and safety regulations and ensure a protective environment and workflow for the employees and patients (Daris, 2019). Another complicating factor arises from the Food and Drug Administration (FDA). The FDA has a strict Investigational New Drug application and approval process. Certain parameters must be addressed, including the proposed drug’s indications, contraindications, adverse effects, route of delivery, and dosing recommendations. Manufacturing specifications must also be divulged. This includes active and inert ingredients, reliable and predictable potency, lack of contamination, and lot-to-lot consistency (Bostwick, 2021). Because of these guidelines, complications arise due to the fact that cannabis, in raw plant form, contains dozens of cannabinoids and hundreds of other compounds. The raw forms in which states sell medicinal and recreational cannabis would never be able to meet the FDA standards. Interestingly, neither dronabinol nor nabilone are derived from cannabis plants. The only FDA-approved cannabinoid is epidiolex (a nearly 100% pure cannabidiol) and it was approved through an alternative pathway for botanical derivatives. Epidiolex is only one of three botanicals that have been approved through this pathway since its inception in 2004 (Bostwick, 2021). Finally, there needs to be additional studies providing further evidence that patients are self-reporting and feel they are improving by substituting their prescription medications with 33 marijuana. The impact of marijuana substitution for other drugs and its outcome on health is unknown and warrants further investigation. Additional research will only accelerate to meet the needs of patients and clinicians in this rapidly growing field (Ishida, 2019). Growth and Production Limitations Along with limitations associated with the laws and research that are currently circulating, there are also limitations on obtaining CBD (medical cannabis) for required research and patient needs. As stated previously, and per the federal government, cannabis is a Schedule I drug thus making it illegal to own, grow or distribute. Even in states that have a medical marijuana program, bypassing the illegality, limitations remain. Unfortunately, availability does not come with legalization. The production of CBD involves a detailed process with multiple means of production (Tylers, 2019). Carbon dioxide (CO2) is a common means of production and consists of growing the cannabis plant under very specific heat and humidity conditions, a process which takes weeks to months. Once the plant is grown it is placed into a chamber where CO2 is applied in liquid form. The liquid CO2 then picks up the oils and flavors from the plant and is pumped into a chamber where it is allowed to return to gas form, leaving behind the oils and flavors separated from the gas and plant (Tylers, 2019). The CBD process may not seem that complicated, but with only certain states legalizing the growth, use, and distribution, it is certainly a problem that needs solving with production only occurring in select states. That being said, medical cannabis dispensaries are growing and trending throughout the United States, though they do require special licensure. Additionally, if they reside in a state that has not legalized the use, the CBD and cannabis must be shipped from states that are legalized to grow and produce cannabis. This causes delays in distribution for patients needing medical cannabis for treatment as well as delays in the availability of cannabis for researchers engaged in larger 34 studies. It is thought that many recreational users grow their own plants illegally, but this does not support the medical and research shortage as there is no way to regulate the amount of THC or CBD in the finished product. With so many types and levels of involvement in growth and distribution, it makes regulation impossible. There is a need for additional state legalization in order to add regulated production sites and dispensaries throughout the US. Physician Education While cannabis has been around for thousands of years, physicians remain uncomfortable with their personal knowledge base in regard to its use. According to a recent poll of 400 US clinical oncologists, 80 percent of them discuss the use of medical cannabis with their patients, and while almost half of them suggest it, only about a third of them believe they are knowledgeable enough to make such recommendations (Abrams, 2019). Much of the lacking knowledge may result from the fact that cannabis is a Schedule I classification drug. The lack of knowledge and discomfort on the subject highlights the need for additional research on the subject to confidently prescribe cannabis for medical use. Research needs to be provided to physicians that potentially could offer medical cannabis as a treatment option for their patients. Not only do physicians feel they need more education, but patients also desire to learn more about cannabis from their physicians. In one survey of cancer patients almost all respondents wanted to receive information from their cancer team, with only 15 percent receiving it from their cancer physician or nurse. The majority of people got their information from friends and relatives, newspaper/magazine articles, websites/blogs, or another cancer patient. More than a third said they didn't get any (Pergam, 2017). 35 The literature outlined that the majority of physicians reported their lack of formal education on cannabis. In fact, much of physicians’ knowledge was based on their own personal opinions gathered through medical literature and personal experience. Some even reported their information was gathered from the media and conversations with other physicians. Patients of the surveyed physicians have requested to be prescribed cannabis, but only a small percentage of the physicians supported it. The results of one study confirm, “The majority of physicians felt that the literature supported the use of cannabis for nausea (87%), anxiety (60%), and pain (86%)” (Bega et al, 2017, p 92). However, they were not as strongly convinced that it helped with motor symptoms such as tremors and dyskinesia. The physicians in this survey confirmed the need for further attention and education in regard to medical cannabis and believe such information should be applied at the medical school level. Supportive education avenues need to be provided to physicians and more research needs to be performed to find the best dosing practices. There is an obvious gap between what physicians and patients would like to know, and what education they are in fact provided. Regardless of what physicians and patients may want, there are still underlying legal issues that arise in the realm of medical cannabis. The implications for physicians could be severe if the federal government follows its own policy. Individual states issue medical licenses, but the federal Drug Enforcement Administration issues controlled substance prescription licenses. Even if marijuana weren't on Schedule I, the states wouldn't be able to do what they're doing now. Furthermore, physicians can only "recommend" medical marijuana under their First Amendment free speech rights thanks to a loophole established in Conant v Walters, a 2002 Ninth Circuit Court of Appeals case. In other words, doctors who insist on recommending 36 medical cannabis risk losing their Drug Enforcement Administration credentials (Bostwick, 2021). Many states have devised an ad hoc workaround to safeguard physicians. In these scenarios, prospective medical marijuana patients must first obtain certification from their doctors that they suffer from a state-mandated medical condition. They next go to a medical marijuana pharmacy and hand over their paperwork to a state-licensed pharmacist, who determines which marijuana product to dispense and how to administer it to the customer. In this approach, pharmacists take over the prescription authority typically reserved for doctors (Bostwick, 2021). Legal Issues Steele et al. (2019) wrote that at the federal level, cannabis remains classified as a Schedule I substance under the Controlled Substances Act. Schedule I substances are not considered to have an accepted medical use and to possess a high potential for abuse and with the current classification of cannabis, making the distribution of cannabis a federal offense. At the state level, however, the legalization of cannabis use (for both medical and recreational use) has been gaining momentum over the past decade. With the passing of the Farm Bill in December 2018, industrial hemp became a legal agricultural commodity in all fifty states. While the Drug Enforcement Agency (DEA) still considers CBD to be a Schedule I controlled substance, it clarified in a memo that trace amounts of CBD found in hemp stalks or seeds were legal. However, the legality of hemp-derived CBD may vary from state to state (Steele, 2019). A number of websites attempt to clarify the legality of cannabis use, according to each state’s status. For example, the National Conference of State Legislatures provides a chart of 37 state legality regarding the use of both THC and/or CBD products within state boundaries. According to their current website, seven states have voted to keep both products completely illegal. Forty-three of the remaining states are CBD oil use only. This information is current as of November 2021; however, states may vote for legalization at the ballot with legislation (MAP OF MARIJUANA LEGALITY BY STATE, 2021). Refer to Appendix A. Documentation This research project began with an initial interest in the medical benefits of cannabis and CBD as more and more states begin to decriminalize the use of recreational marijuana. The majority of these states began their cannabis evolution with medical marijuana. The research carried out for this paper progressed into a scoping review of the medical cannabis industry, rather than a systematic meta-analysis, as more questions than answers were revealed throughout the literature review process. Consequently, this research model was selected in order to identify the current body of knowledge and any existing gaps on the topic in the hopes that it may inspire future research to find its place within the medical community. The research was performed primarily through the use of scholarly databases, such as PubMed, NCBI, MEDLINE, Google Scholar, and ScienceDirect. All publications being referenced are peer-reviewed, fact-checked, and published within the last ten years. Summary In conclusion, with the minimal amount of studies performed it has been determined that medical cannabis is in fact a suitable alternative to opioid use for ailments and diseases such as cancers, Crohn’s diseases, PTSD, anxiety, nausea, vomiting, sleep difficulties, and pain. Research has also shown that more studies should be conducted and elaborated on to further seek 38 out where medical cannabis can be used as an alternative. Currently, a majority of the studies are conducted on adolescents and the middle-age population. Not much research has been done with children or the elderly. Should cannabis be changed from a schedule I drug, more studies could be performed on its effectiveness and safety. Physicians are also in need of further education on this topic so that they can better inform and instruct their patients on the use of medical cannabis and to further understand the options that they have when prescribing long-term care. 39 Chapter 3: Research Method Research Methods and Design(s) Our research was first started by gathering a group with similar interests in mind. Within this group, individuals searched in multiple databases for prior research conducted on the topic involved in the research questions. The information was found using a scoping review method to collect studies related to cannabis and cannabinoids as an alternative form of medical treatment and pain management. This review was performed using prior peer reviewed literature found in multiple databases, as listed above. This study reviewed and analyzed the information that was collected and attempted to answer the question of whether cannabis is an effective alternative to long-term opioid or anxiolytic medications. During this process, further questions came about. Since the current research on cannabis and CBD is somewhat limited, the scoping review method was chosen over others, due to the fact that it allows the researchers to bring to light what has already been discovered and in turn create new questions and inspiration for future research to be conducted. Population & Sample This research was a review of published studies of medical cannabis, oftentimes, but not always, used in place of opioid medications for relief of pain and other symptoms associated with various conditions and diseases. The age range of the studied populations spanned from adolescent to elderly patients. The population included in this study was limited to the patient groups that were included in each of the publications reviewed. The samples used in the research and in this review ranged from small groups to groups of hundreds and of varying ages. 40 Materials/Instruments Research was performed primarily through the use of scholarly databases, such as PubMed, NCBI, MEDLINE, Google Scholar, and ScienceDirect. All publications being referenced are peer-reviewed, fact-checked, and published within the last ten years. Research was conducted for the purpose of evaluating if medical cannabis could be a potential alternative to opioid use in medically managing pain and other side effects of different disease processes. No materials/instruments were used as this was a scoping review research study. No interviews were conducted for this study. Data Collection, Processing, and Analysis The role of the researcher was to find information covering medical cannabis and cannabinoids ability to replace existing prescription opioids. A total of 28 peer reviewed, fact checked, scholarly articles were analyzed and used for the purposes of this scoping review. Over 100 articles were excluded from the research, primarily due to lack of supporting evidence of the information contained within the articles. Many of the excluded articles held potentially useful information yet did not have a strong foundation and contained potential biases and personal opinions. Additionally, there were also other specific diseases and associated symptoms that likely would benefit from medical cannabis, however, the disease-specific research on those was not viable for the purposes of this review. Assumptions It could be assumed that those who participated in the research studies could have contributed positive feedback to the research developers in favor of medical cannabis being used as an alternative form of treatment for specific diseases and ailments. It could also be assumed 41 that most data and feedback would be strongly in support of, or strongly opposed to the use of medical cannabis and therefore it was vital to review research and data that was balanced in regard to hearing both spectrums. Limitations One of the limitations is the small sample size with the use of medical cannabis in the form of CBD oils and the other forms of its use. There are positive results with the use of medical cannabis, particularly in certain disease processes. One of the ways to mitigate this is to increase the sample size with the cannabis form that provides the most results. CBD oils have become very popular especially with diseases such as Crohn’s disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson's disease, bipolar disorder, and schizophrenia. Another significant limitation is that to date there is not an abundant amount of research that has been conducted. The topic of the use of medical cannabis as a means to limit opioid use and dependency would significantly benefit from more extensive trials. Delimitations The scope of data used in this review was derived from prior research that had been conducted on CBD and Cannabis for medical use. Studies that covered CBD or cannabis use for certain diseases were prioritized over others. For example, in this scoping review, studies were chosen that contained information on diseases such as Crohn's disease, Alzheimer’s disease, cancer, chronic pain, social anxiety, and Post-traumatic Stress Disorder. The sample size of the study was not taken into account when selecting these articles. 42 Summary This research was completed using multiple scholarly databases such as PubMed, NCBI, MedLine, etc., using keywords such as medical cannabis, pain management, chronic disease management, cannabis, and anxiety, etc. Populations in this prior research ranged from adolescents to elderly adults. It is assumed that those who participated in the studies would have confirmed a positive notion that medical cannabis would be a good alternative to current long-term pharmaceutical medications. The major limitations of this study consisted of the fact that there was a very small sample size. Prior research is lacking in quantity and the trials that have been conducted were done so with small groups. The sample size was not taken into account when finding studies for this scoping review. Additional research will only accelerate to meet the needs of patients and clinicians in this rapidly growing field (Ishida, 2019). 43 Chapter 4: Findings Results The goal of this paper was to understand the feasibility of medical cannabis, and its derivatives, as a replacement for opioids in the management of long-term disease and pain. Additionally, it was hoped literature supported a strong support or opposition to use of medical cannabis for symptom relief. Research was collected to focus on the following: individual patient perceptions of symptom management by means of medical cannabis, education availability for physicians, the occurrence of any adverse effects associated with the use of medical cannabis, and legal issues associated with the research and use of medical cannabis. Evaluation of Findings During the process of evaluating the research and data, we discovered that there is an extremely limited amount of research on all aspects of this topic. Limited studies have shown that generally speaking, the adverse effects experienced by patients using medical cannabis were mild and short-lived in comparison to the adverse effects associated with chronic opioid use. Unfortunately, there is controversy on which derivatives of medical cannabis provide the most potential to individuals and more research is needed in this area to be able to isolate which derivatives pose the most potential benefit or risk to the individual. Additionally, there is also controversy on the potentially addictive properties of medical cannabis and potential associations with poor performance and depressive behavior. There is research suggesting medical cannabis may have negative behavioral and psychological effects. Euphoria, relaxation, alteration of time perception, impaired learning, concentration difficulty, and memory and mood changes were included in the list of potential behavioral effects of 44 medical cannabis. Potential negative physiologic effects include rapid deviation in blood pressure and heart rate, xerostomia (dry mouth and throat), appetite increase, bradypnea, and vasodilation. There is also research suggesting cannabinoids interact with the same reward systems as cocaine, opioids, and alcohol which raises concern for tolerance and dependence on cannabis. (Sharma, 2012). Another area of concern is dosing. The dose of cannabis to use was extremely circumstantial without guidelines clearly guiding practitioners as to how they should dose individual patients and conditions. Since cannabis is typically ingested gastrointestinally or via airways, it makes it very difficult to suggest dosing recommendations. Since the route of administration is considerably dependent on individual tolerance, physician This lack of standard creates hesitancy for the practitioner to recommend cannabis as a potential means of patient treatment and management. Lastly, legal issues associated with the availability of cannabis for medical research as well the classification of the drug in general have created difficulty in being able to carry out the extent of research that is required to fully evaluate this topic. Summary In conclusion, further research is required on prescribing dosages based on the clinical condition being treated, the effectiveness of symptom treatment/resolution, potential adverse effects, and legal issues associated with medical cannabis. To reiterate, the most significant limitation to this particular study was the overall lack of research conducted. This lack in research appears to be secondary to a multitude of reasons including but not limited to the scheduled class of the drug, predetermined mindset controversy, physician/provider education, lack of dosing guidelines, availability of cannabis for research, and legal issues. The most 45 beneficial contribution to future research would result from a large-scale, double-blind clinical trial. 46 Chapter 5: Implications, Recommendations, and Conclusions One of the main problems we face in today’s society is the growing opioid addiction. There is a potential for medical cannabis and cannabidiol to be used as alternatives for today’s pharmaceuticals. A major halt in this notion is that physicians and society as a whole are not well informed and hesitant to learn. The purpose of this review was to bring to light the research that has previously been performed on the subject. Multiple scholarly databases were used to scour published peer-reviewed research on the benefits and side effects of medical cannabis. Ethically, there is a fine line in this research as cannabis is currently classified as a Schedule 1 controlled substance. Thus, there is not a resounding amount of prior research performed. This chapter aims to discuss our research questions, outline our conclusions, and detail the limitations that were encountered. Implications The implications of this study are best outlined relative to our initial research questions. Review of the initial research questions and the implications of our findings are as follows. Q1. Are there any severe adverse effects associated with medical cannabis use? Throughout our review of prior literature, we discovered that medical cannabis is not a substance completely without side-effects. Typically, the side effects are mild and tolerable. Some of the common side effects experienced by patients using medical cannabis are anxiety, feelings of depersonalization, red eyes, dry mouth, and increased appetite. Symptoms tend to be worse at a higher dose. This is thought to parallel the current pharmaceuticals used. 30% of patients surveyed report mild side effects that were minor and easily overcome. Q2. Does medical cannabis have the potential to replace opioids in long term pain and disease management? 47 This question has proven difficult to provide a definitive answer. There is an astounding lack of prior research. Yet, from the research that was reviewed, it can be concluded that there is a potential for medical cannabis to be used as a replacement for opioids. However, further research and larger blind trials need to be performed for confirmation. This has proven difficult with the drug being a Schedule I class drug. The hope is that in the future, more research can be performed to help answer the question at large. Q3. Is there existing research on how patients perceive the effectiveness of medical cannabis? There is a limited amount of data on patient perceptions of effectiveness of medical cannabis. This could potentially stem from the lack of overall studies with cannabis due to various reasons, mainly due to the Schedule I classification. Knowledge of patient experience and perceptions on effectiveness would potentially provide a great deal of information to help answer prior research questions. Q4. Is there any education available for physicians on medical cannabis use? Currently there is a limited amount of information available to physicians. This is ultimately, again, due to the overwhelming lack of prior research done on this topic. Most of the knowledge that physicians have is based solely on prior experiences with dosing for patients, or trial and error. Due to this issue, patients are gathering their own information based on friends and family experiences and internet blogs. It would be highly beneficial for prescribing physicians to gain knowledge on the subject from further research. Only then, will physicians feel more comfortable using it in their treatment plans. In addition, physicians may only legally “recommend” the use of medical marijuana. In response, pharmacists have taken on the role of prescribing cannabis, making recommendations on dosing and route of administration. This legal 48 situation only compounds the role of the physician, further complicating an already sensitive medical scenario. Limitations to this scoping review consist mainly of the fact that prior research is very limited. Research that has been conducted also involved small sample sizes. Future research would benefit from larger sample clinical trials. These trials have the potential to show how beneficial medical cannabis can be as an alternative to current opioid treatments. Practical contributions from this research could be greatly beneficial. This specific scoping review could potentially prompt further research and trials. These further trials could contribute to an increase in patient and physician knowledge and ultimately prove that medical cannabis is a safe and effective alternative to current opioid therapies. Recommendations The ongoing classification of cannabis as a Schedule I controlled substance is inconsistent with scientific opinion, public/ political attitudes, and the overwhelming majority of state laws. There is now ample scientific and empirical evidence to rebut the federal government’s contention. As current research suggests, there are over 36,000 peer-reviewed papers in the scientific community referencing cannabis and cannabinoids, according to a keyword search on the search engine PubMed Central, the US government repository for peer-reviewed scientific research. While the vast majority of the overall research does not pertain to our particular scoping review, there is current research that is ongoing for the subject. Although cannabis is one of the most investigated therapeutically active substances in history it goes without controversy to classification as a controlled substance. The question remains as to whether or not it provides any medical value. Further, there is not enough data on safety or FDA-49 approved clinical trials. Based on the history and stigma with marijuana the continued struggle to get laws passed to enact the use of cannabinoids for medicinal purposes remains an obstacle. Conclusions There is a tremendous lack of published material and research about medical cannabis. Research is limited due to the scheduling class of cannabis, and physicians are not knowledgeable on the subject. Patients are potentially lacking treatment options other than opioids and current pharmaceuticals. New and extending research, as well as blind study clinical trials, need to be performed to broaden our knowledge and best help patients. 50 References Abrams, D.I. Should Oncologists Recommend Cannabis?. Curr. Treat. Options in Oncol. 20, 59 (2019).https://doi.org/10.1007/s11864-019-0659-9 Azcarate, P., Cohen, B., Ishida, J., Keyhani, S., Steigerwald, S., Zheng, A., (2020). Medical Reasons for Marijuana Use, Forms of Use, and Patient Perception of Physician Attitudes Among the US Population, 35(7) 1979-1986. https://doi.org/10.1007/s11606-020-05800-7 Bega, D., Simuni, T., Okun, M., Chen, X., Schmidt, P. (2017). Medical Cannabis for Parkinson’s Disease: Practices, Beliefs, and Attitudes Among Providers at National Parkinson Foundation Centers of Excellence 4(1) 90-95. https://doi.org.10.1002/mdc3.12359 Blessing, E., Steenkamp, M., Manzanares, J., & Marmar, C. Cannabidiol as a Potential Treatment for Anxiety Disorders. September 2015. Springer Series in Vision Research. DOI 10.1007/s13311-015-0387-1 Bridgeman, M. B., & Abazia, D. T. (2017). Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting. P & T : a peer-reviewed journal for formulary management, 42(3), 180–188. Bostwick, J. M. (2021). Medical Marijuana Regulations: You Can’t Make Sense of Nonsense. Mayo Clinic Proceedings, 96(10). https://doi.org/10.1016/j.mayocp.2021.08.015 Bowles, D. W., O’Bryant, C. L., Camidge, D. R., & Jimeno, A. (2012). The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology, 83, 1–10.https://doi.org/10.1016/j.critrevonc.2011.09.008 51 Daris, B., Tancer, M., Knew, V., & Ferk, P. (2019). Cannabinoids in cancer treatment: Therapeutic potential and legislation. Substitution Of marijuana for Opioids in a National Survey of US Adults., 14(10). doi:doi: 10.17305/bjbms.2018.3532 Desjardins, J. (2019, November 22). The 6,000-Year History of Medical Cannabis. Retrieved February 4, 2021, from https://www.visualcapitalist.com/history-medical-cannabis-shown-one-giant-map/ Ferreira, N., Santos-Pereria, M., Guimaraes, F., Del Bel, E., (2019). Cannabidiol and cannabinoid compounds as potential strategies for treating Parkinson’s Disease and L-DOPA-Induced Dyskinesia. Neurotoxicity Research, 37, 12-29. https://doi.org/10.1007/s12640-019-00109-8 Holland, K. (2020, September 03). Anxiety: Causes, symptoms, treatment, and more. Retrieved February 27, 2021, from https://www.healthline.com/health/anxiety Ishida, J. H., Wong, P. O., Cohen, B. E., Vali, M., Steigerwald, S., & Keyhani, S. (2019). Substitution of marijuana for opioids in a national survey of US adults. PLOS ONE, 14(10). https://doi.org/10.1371/journal.pone.0222577 Kleckner, A. S., Kleckner, I. R., Kamen, C. S., Tejani, M. A., Janelsins, M. C., Morrow, G. R., & Peppone, L. J. (2019). Opportunities for cannabis in supportive care in cancer. Therapeutic Advances in Medical Oncology, 11, 175883591986636. https://doi.org/10.1177/1758835919866362 MAP OF MARIJUANA LEGALITY BY STATE. (n.d.). DISA. Retrieved November 1, 2021, from https://disa.com/map-of-marijuana-legality-by-state 52 Masataka N. Anxiolytic Effects of Repeated Cannabidoil Treatment in TeenagersWith Social Anxiety Disorders. November 2019. Frontiers in Psychology. DOI 10.3389/fpsyg.2019.02466 Mayet, S. (2019). Clearing the Air: Medical Marijuana in Adolescents with Chronic Pain. South African Journal of Anaesthesia and Analgesia, 25(5), 23-26. Pergam, S. A., Woodfield, M. C., Lee, C. M., Cheng, G.-S., Baker, K. K., Marquis, S. R., & Fann, J. R. (2017). Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer, 123(22), 4488–4497. https://doi.org/10.1002/cncr.30879 Ren, M., Tang, Z., Wu, X., Spengler, R., Jiang, H., Yang, Y., & Boivin, N. (2019). The origins of cannabis smoking: Chemical residue evidence from the first millennium BCE in the Pamirs. Science Advances, 5(6). https://doi.org/10.1126/sciadv.aaw1391 Robson, P. (2001). Therapeutic aspects of cannabis and cannabinoids. British Journal of Psychiatry, 178(2), 107-115. doi:10.1192/bjp.178.2.107 Rose, M. (2017). Are prescription opioids driving the opioid crisis? assumptions vs facts. Pain Medicine, 19(4), 793–807. https://doi.org/10.1093/pm/pnx048 Rudd, R. A., Aleshire, N., Zibbell, J. E., & Matthew Gladden, R. (2016). Increases in drug and opioid Overdose Deaths-United STATES, 2000-2014. American Journal of Transplantation, 16(4), 1323–1327. https://doi.org/10.1111/ajt.13776 Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology, 163(7). https://doi.org/10.1111/j.1476-5381.2011.01238.x 53 Sharma, P., Murthy, P., & Bharath, M. M. (2012). Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iranian journal of psychiatry, 7(4), 149–156. Steele, G., Arneson, T., & Zylla, D. (2019). A Comprehensive Review of Cannabis in Patients with Cancer: Availability in the USA, General Efficacy, and Safety. Current Oncology Reports, 21, 10.https://doi.org/10.1007/s11912-019-0757-7 Stein, M. B., & Stein, D. J. (2008). Social anxiety disorder. The Lancet, 371(9618). https://doi.org/10.1016/S0140-6736(08)60488-2 Tafelski, S., Häuser, W., & Schäfer, M. (2016). Efficacy, tolerability, and safety of cannabinoids for chemotherapy-induced nausea and vomiting—a systematic review of systematic reviews. Der Schmerz, 30(1), 14–24. https://doi.org/10.1007/s00482-015-0092-3 Tylers. (2019, November 01). How is cbd oil made and extracted? The process outlined. Retrieved February 20, 2021, from https://americancannabisconsulting.com/how-cbd-oil-is-made-and-extracted/ Waissengrin, B., Urban, D., Leshem, Y., Garty, M., & Wolf, I. (2015). Patterns of Use of Medical Cannabis Among Israeli Cancer Patients: A Single Institution Experience. Journal of Pain and Symptom Management, 49(2), 223–230.https://doi.org/10.1016/j.jpainsymman.2014.05.018 Whitcomb, B., Lutman, C., Pearl, M., Medlin, E., Prendergast, E., Robison, K., & Burke, W. (2020). Use of cannabinoids in cancer patients: A Society of Gynecologic Oncology (SGO) clinical practice statement. Gynecologic Oncology, 157(2). https://doi.org/10.1016/j.ygyno.2019.12.013 54 Appendices Apendix A: Legalization of Cannabis By State State Legal Status Medicinal Decriminalized District of Columbia Fully Legal Yes Yes Alaska Fully Legal Yes Yes Arizona Fully Legal Yes Yes Arkansas Mixed Yes No California Fully Legal Yes Yes Colorado Fully Legal Yes Yes Connecticut Fully Legal Yes Yes Delaware Mixed Yes Yes Florida Mixed Yes No Georgia Mixed CBD Oil Only No Hawaii Mixed Yes Yes 55 Idaho Fully Illegal No No Illinois Fully Legal Yes Yes Indiana Mixed CBD Oil Only No Iowa Mixed CBD Oil Only No Kansas Fully Illegal No No Kentucky Mixed CBD Oil Only No Louisiana Mixed Yes Yes Maine Fully Legal Yes Yes Maryland Mixed Yes Yes Massachusetts Fully Legal Yes Yes Michigan Fully Legal Yes Yes Minnesota Mixed Yes Yes Mississippi Mixed Yes Yes Missouri Mixed Yes Yes 56 Montana Fully Legal Yes Yes Nebraska Fully Illegal No Yes Nevada Fully Legal Yes Yes New Hampshire Mixed Yes Yes New Jersey Fully Legal Yes Yes New Mexico Fully Legal Yes Yes New York Fully Legal Yes Yes North Carolina Fully Illegal No Yes North Dakota Mixed Yes Yes Ohio Mixed Yes Yes Oklahoma Mixed Yes No Oregon Fully Legal Yes Yes Pennsylvania Mixed Yes No Pennsylvania Mixed Yes No 57 Rhode Island Mixed Yes Yes South Carolina Fully Illegal No No South Dakota Mixed Yes No Tennessee Fully Illegal No No Texas Mixed CBD Oil Only No Utah Mixed Yes No Vermont Fully Legal Yes Yes Virginia Fully Legal Yes Yes Washington Fully Legal Yes Yes West Virginia Mixed Yes No Wisconsin Mixed CBD Oil Only No Wyoming Fully Illegal No No Note: This table determines the legalization status of each state in the United States in regard to cannabis use.