Cannabis as an Alternative Treatment for 11 Medical Conditions: a Literature Review

: Over the past years, the use of medical cannabis is becoming of interest in the medical world. It has been recognized as an alternative treatment and has been legalized in many countries for medical purposes. Although there have been numerous claims of what cannabis can do, conclusive findings regarding its properties remain elusive. While access to cannabis is high, information accessible to consumers is still limited. Countless past studies have been done on cannabis’ effect on health issues. Hence, the purpose of this literature review was to conclude and summarize the past findings on the therapeutic effect of cannabis, focusing on the Delta-9-Tetrahydrocannabinol (Δ 9 -THC) and Cannabidiol (CBD), on the following medical conditions; chronic pain, opioid use disorder (OUD), obesity, sleep disorders, cancer, post-traumatic stress disorder (PTSD), psychosis, epilepsy, traumatic brain injury (TBI), Parkinson’s disease (PD), and Alzheimer’s disease. The risks of cannabis consumption for these issues were also identified. The results suggested that cannabis has the ability to assist in chronic pain, OUD, sleeping disorders, and Alzheimer’s disease. Regarding PTSD, psychosis, and TBI, there have been findings only about CBD which showed a beneficial effect on the diseases. It could not be concluded that cannabis can be used to treat obesity, cancer, epilepsy, and Parkinson's disease due to limited evidence. The majority of the studies also demonstrated that high doses of CBD and low doses of THC should be used to maximize benefits. More clinical trials and research need to be conducted as there are research gaps and insufficient information in various subjects.


INTRODUCTION
Cannabis plant extracts are becoming of interest to scientists around the world to develop a way to use it for medical treatment, especially among patients who do not respond to conventional medications. Many countries around the world have already legalized and approved cannabis for medical purposes, increasing the availability and accessibility to cannabis. As a medicinal agent, the various biological effects of cannabinoids have been acknowledged as beneficial for a number of diseases [1]. However, basic information about cannabis consumption, such as route of administration, doses, and product formulations, is still lacking. There are numerous forms of cannabis products and wide varieties of administration routes, including inhalation, oral ingestion, topical application, and sublingual administration. Patients can have a hard time making a decision on choosing the forms of product, dosage, and route of administration that are appropriate for their purpose. Furthermore, there are rising concerns regarding how effective the product really is, the potential risks, and their side effects. These concerns will be attended to. The world market on these products is growing rapidly, especially on CBD products. The scientific community has made significant contributions to the development of the cannabis industry. This is evidenced by the increasing acceptance of the drug and its derivatives globally [1]. In 2020, it was estimated that the cannabis market size was valued at USD 20.5 billion globally. The market growth was projected to rise to USD 90.4 billion by 2026 [1]. With the expansion of the cannabis industry expected to increase continuously, more competition in business is definite. Lots of commercial claims regarding the therapeutic effect of cannabis have been made for marketing and profits. However, it is unclear if those claims are backed by empirical evidence.
The use of cannabis as an alternative treatment is still controversial. There are so many studies about cannabis, which could be difficult for patients to comprehend. It is crucial for patients to have the correct information before using cannabis and their concerns must be attended to. This review article determined what is known based on current evidence and what needs more research to be proven. Some of the most debatable issues are chronic pain, opioid use disorder (OUD), obesity, sleep disorders, cancer, post-There are many types of chronic pain, including headache, low back pain, cancer pain, arthritis pain, neurogenic pain, psychogenic pain, and postsurgical pain. The cause of chronic pain varies. It can result from surgery or repeated muscle injury, such as back sprain, broken bone or torn muscle. Chronic pain tends to develop when a damaged nerve happens to be in some particular area. Being damaged, the nerve is likely to create more intense and long-lasting pain than normal. However, in some cases the pain does not emerge from any prior reasons, but rather from an underlying disease, for instance, fibromyalgia, chronic fatigue syndrome, endometriosis, inflammatory bowel disease, and so on [15]. Moreover, there is a condition called "Central sensitization" which also involves the development and maintenance of chronic pain. By maintaining the nervous system in a persistent state of high reactivity, this condition heightens the sensitivity to pain of patients as well as their sensation of touch; it can turn a mildest bump into the most painful one for the patients [16].

Current Treatments:
Because of its complexity and unicity, chronic pain is a very challenging condition to be treated in patients. In order to alleviate the pain, health care providers will try to indicate the cause of the pain first. Then, they may recommend a variety of medications based on the root of the pain. The following treatments are the example of medications used to treat patients with chronic pain.
Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs are widely known to be very effective in alleviating mild to moderate pain or conditions associated with swelling and inflammation. Many NSAIDs, such as ibuprofen, naproxen, are not difficult to find and can be bought over the counter. The way NSAIDs work is by blocking an enzyme called "cyclooxygenase (COX)" which is released when the tissue is being damaged. By inhibiting this enzyme, the pain response is temporarily shut down; thus, the pain that an individual perceives is lessened [17]. The strength of NSAIDs varies depending on the dosage and the type of medication. If patients take more than the recommended doses, they may experience side effects, for example, nausea, stomach pain, ulcers. Studies have shown that there are unpleasant effects, adverse gastrointestinal and cardiovascular events, resulting from NSAIDs overdose. On top of that, the risks from NSAIDs overdose also increase with age and in the presence of other health conditions, including diabetes, a history of stomach ulcers, and kidney disease. There is a bottom line on this medication as well. Due to the ceiling effect in this medication, one can only take NSAIDs for a certain period of time. In other words, exceeding the recommended dosage will not only provide no additional benefits, but also increase the risk of experiencing the side effects [18].
Acetaminophen: as of today, acetaminophen is the most prevailingly used painkiller or analgesic worldwide. It is reported to be effective for mild to moderate pain suffered from osteoarthritis and back pain [17]. According to the World Health Organization (WHO), they recommended acetaminophen to be used as first-line treatment in all pain conditions. However, there are some conflicts of opinion related to this topic whether it is really potent in treating patients with chronic pain or not. Studies have claimed that there is little to no efficacy with skeptical clinical relevance. Further, only a few literatures cited the long-term use of acetaminophen in Prescribed medication: although obesity might be addressed by exercising or changes in diet, some cases cannot be resolved through the same means. If changing diet or other programs do not contribute to any improvement, doctors may recommend weight-loss medications, such as orlistat, phentermine, bupropion, liraglutide, etc. Patients need to be cautious when using these medications; because, not only does it help patients lose weight, but it also has harmful effects when being misused [35,36].
Surgery: in order to receive weight loss surgery or bariatric surgery, individuals need to have high-risk obesity or moderate-risk obesity with serious medical conditions related to weight. They also need to accept the fact that they have to adapt their lifestyles to receive the treatment. After the surgery, the amount of food they can consume and the ability to absorb nutrients and calories are limited [35]. Nevertheless, it is not guaranteed that after the incision patients will definitely lose all the excess weight or the result will remain forever. Besides, bariatric surgery bears some risks as well, dumping syndrome, low blood sugar, malnutrition, vomiting, ulcers, etc. Thus, patients need to be well informed of these risks before agreeing to receive the treatment [37].

Therapeutic Properties of Cannabis on Obesity:
The data was based on self-reported surveys of 41,654 respondents in the National Epidemiologic Study of Alcohol Related Conditions (NESARC) and 9,106 respondents in the National Comorbidity Survey Replication (NCS-R). Out of every participant, 4.0% and 7.3% of the participants in the NESARC and in the NCS-R, respectively, reported having used cannabis at least once in the past 12 months of the recording period. The accumulated data had shown that the pervasiveness of obesity was notably higher in non-cannabis users than in cannabis users. This study also cited other research that explicitly evaluated the association between cannabis and obesity. The results showed significant contrasts between these researches. The first study suggested that subjects with lower BMI tended to have a relation with cannabis use. The second one reported that cannabis use was associated with obesity in female adolescents. The last study showed that the use of cannabis was affiliated with the higher calorie intake, but did not seem to have a connection with a higher BMI [38].
There is not much research related to the specific use of CBD or THC on this topic. However, one study has reported that THCcontained drugs may contribute to weight loss and may have the capacity to be useful as a therapeutic for obesity's treatment and its complications [39].

D. Sleep Disorder
General Information: Sleep disorder is defined as conditions that alter the way an individual sleeps. It also affects the sleep quality, duration, and the behavior when being awake as well. Not only that sleep disorder can contribute to other medical conditions, but it can also be a sign of symptoms of other mental disorders [40]. Symptoms of sleep disorders include having trouble falling asleep or being awake, being disrupted while sleeping, experiencing an abnormal pattern of breathing while being asleep, having an irregular sleep pattern, etc. [40,41].
There are countless sleep disorders. Examples of sleep disorders are insomnia (difficulties in falling asleep), sleep apnea (breathing being interrupted while sleeping), circadian rhythm disorder (sleep-wake cycle is desynchronized and disrupts your everyday activities), restless leg syndrome (irresistible urge to move the legs during the attempts of falling asleep), narcolepsy (overwhelming daytime drowsiness).There are many causes that contribute to sleep disorders, and the cause varies from person to person. Despite varieties of causes, the common ground of these disorders is that they interfere with patients' natural sleep cycle and daytime wakefulness. The factors can be classified into medical conditions (cardiac, neurologic, endocrine, pulmonary, gastrointestinal and musculoskeletal), psychological conditions (depression, anxiety, phobias, panic attacks, psychotropic medications), and other factors (aging, trauma, and medications) [42].

Current Treatments:
Non-pharmacological: cognitive-behavioral therapy can be helpful for sleep disorders. The techniques employed include sleep restriction therapy, which limits the amount of time spent in bed to increase desire to sleep, and stimulus control therapy, which aids in changing sleeping habits. Relaxation techniques may be utilized when going to bed. Some hypnotherapists use hypnosis to make patients calm and fall asleep. Changing sleep hygiene can also make a difference. However, non-pharmacological may not be effective in severe sleep disorder Pharmacological: approved medications include histamine type 1 receptor blockers, benzodiazepines, non-benzodiazepine hypnotics, melatonin receptor agonists, and orexin receptor antagonists. These prescribed sleeping drugs can have negative side effects, such as drowsiness during the day and they can be habit-forming.
Other interventions: losing weight, using continuous positive airway pressure (CPAP), and, in certain cases, surgical treatment can help with sleep apnea. In patients with OSA who experience excessive sleepiness, the medication solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor, can be administered to promote wakefulness. Modafinil, a non-amphetamine stimulant that increases wakefulness, is considered first-line therapy for narcolepsy. Sleep difficulties caused by circadian rhythm anomalies can benefit from light-phase shift therapy. Restless leg syndrome is greatly improved with gabapentin enacarbil, and so sleep disturbance is reduced [42].

Therapeutic Properties of Cannabis on Sleep Disorders:
Sleep issues are frequently stated as a reason for medical cannabis use. ECS is engaged in the maintenance and promotion of sleep through regulating the circadian sleep-wake cycle. In the hamster, the endocannabinoid system had the ability to influence circadian rhythms, and should be examined for effects on circadian rhythm in humans [43]. CB1 receptor distribution in the brain supports a variety of theories about how the ECS could change the suprachiasmatic nucleus (SCN)'s responsiveness to light and affect the circadian rhythm [44]. Chagas et al. (2013) conducted a research on adult male Wistar rats to assess the effects on sleep of acute systemic administration of CBD. 28 rats were divided into 4 groups and received intraperitoneal injections of CBD 2.5 mg/kg, 10 mg/kg, 40 mg/kg or placebo. For four days, sleep recordings were taken during light and dark periods: two days for baseline recording, one day for drug administration, and one day after drug administration. When compared to the placebo group, the overall percentage of sleep increased significantly during the light time of the test day in the groups treated with 10 and 40 mg/kg of CBD. On the post-test day, rapid eye movement (REM) sleep latency increased in the CBD 40 mg/kg group, while it was dramatically reduced in the CBD 10 mg/kg group. Although there was a rise in the time of slow-wave sleep in the CBD 40 mg/kg group, this result did not achieve statistical significance. This study concluded that systemic acute CBD injection seems to increase total sleep time as well as sleep latency in the light period of administration day [45]. A study on sleep apnea was conducted by Carley et al. (2002). This study focused on the cannabinoids effect in respiratory stability during sleep by using 11 adult male Sprague-Dawley rats. Polysomnography was used to assess sleep architecture, respiratory pattern, and apnea expression. Animals were monitored after receiving intraperitoneal injections of THC, oleamide, and serotonin, either alone or in combination. Each animal was recorded on exactly 12 occasions in repeated measurements. THC and oleamide both stabilized breathing during all stages of sleep, according to the findings. In NREM and REM sleep, THC reduced apnea index by 42% and 58%, respectively. Oleamide suppressed apnea in a similar way. This finding implied that endocannabinoids play a significant role in autonomic stabilization during sleep. Serotonin-induced worsening of sleep apnea was prevented by oleamide and THC, suggesting that inhibitory coupling between cannabinoids and serotonin receptors may play a role in apnea expression. This study demonstrated that both exogenous and endogenous cannabis decreased sleep-related apnea [47]. Babson et al. (2017) reported that "Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain." [48].
In rabbits, cats, and people, acute THC treatment reduces REM sleep while increasing slow wave sleep in rabbits, humans, and rats. Chronic administration, on the other hand, has been shown to reduce slow-wave sleep while having variable effects on REM sleep in humans, cats, and squirrel monkeys. When THC was delivered persistently, these findings suggested that tolerance or some other sort of adaptation occurs [49]. However, it was demonstrated that treatment of cultured rat pineals with THC, cannabidiol or cannabinol significantly reduced melatonin biosynthesis [50].
Concluded based on the available evidence, cannabinoids assisted in maintaining and/or promoting sleep and decreasing sleep apnea. The activation of the CB1 receptor caused sleep to be induced [51]. Furthermore, initial work examining specific cannabinoids suggested a potential therapeutic effect of high-dose CBD combined with low-dose THC for sleep [48]. Long term effects of cannabinoids on sleep cannot yet be concluded.

E. Cancer
General Information: According to the National Cancer Institute, cancer is defined as a great array of related diseases which are characterized by the uncontrolled proliferation of our body's cells. Generally, human cells grow and divide, new cells are formed when the body needs them. Then, when the cells grow to a certain extent or when they are damaged, they die off through the process called apoptosis or cell suiside. After that, new cells come in and take their places. However, in some cases the cells do not die off instead they continue to expand [52]. These extra cells may form tumors, abnormal masses of tissue.  [54]. Third type of cancer is leukemia. Leukemia is cancer that originates in blood and bone marrow. It develops when healthy blood, specifically, white blood cells, build up and grow uncontrollably. The proliferation of these cells, eventually, inhibits the growth of other normal cells and prevents them from doing what they are supposed to do. There are four major types of leukemia including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia [55]. Lastly, lymphoma is a cancer that originates in the lymphatic system. There are many kinds of lymphoma. The two major types of lymphoma are Hodgkin's lymphoma and non-Hodgkin's lymphoma [56]. There are many factors that can contribute to cancer. Cancer patients may develop the mutation which can be caused by inheritance from their family, induction from the environment, or result of DNA replication errors (R). Study has suggested that R is responsible for two-third of the development of cancers in humans [57].

Current Treatments:
Chemotherapy: chemotherapy is a drug treatment that is used to treat cancer. By inhibiting the growth of them, cancer cells are, eventually, eliminated. Chemotherapy can be used to treat cancer alone or in combination with other cancer treatments. Although chemotherapy is very effective in treating patients with cancer, it also carries some side effects such as nausea, vomiting, diarrhea, hair loss, fatigue, pain, etc. [58].
Hormone Therapy: hormone therapy treats cancer by slowing the proliferation of cancer cells induced by the body' hormones. Cancers that can be treated by this approach include breast cancer and prostate cancer. The most common side effects of hormone therapy are hot flushes (sudden feeling of heat in the upper body), fatigue, weight gain, muscle loss, and hair loss [59].
Immunotherapy: immunotherapy is a kind of cancer therapy that enhances the body's immune system in order to fight cancer. After being boosted, the immune system may be able to detect and kill cancer cells which cannot be found before using this treatment. Then, cancer cells will tend to grow slower or stop growing. The side effects of treating cancer patients with immunotherapy are pain, swelling, soreness, redness, itchiness, rash and other flu-like symptoms [60].
Radiation Therapy: radiotherapy uses high-powered radiation to kill cancer cells and diminish tumors. Nevertheless, the cancer cells are not immediately eliminated, patients need to receive the treatment several times to damage the DNA of cancer cells enough for them to die. It takes days, or in some cases, weeks to eliminate cancers. The efficacy of radiotherapy also depends on the stage of cancer. Radiation from the treatment does not only kill cancer cells, sometimes it affects healthy cells as well. The side effects include soreness, fatigue, hair loss, loss of appetite, diarrhea, and so on [61]. Surgery: surgery for cancer patients is a procedure performed to remove cancer cells in the body. Induced immune system, increased cancer cells shedding, allowed healthy cells to survive, gathered the immune cells to capture cancer cells, caused the target cells and tissues to move to the target sites are all the effects of surgery [62].
Targeted therapy: targeted therapy is a cancer treatment in which medications are used to target particular genes and proteins associated with cancer cell growth and maintenance. Targeted therapy can alter the tissue milieu that aids a cancer's growth and maintenance, or it might target cancer-related cells such as blood vessel cells. Targeted therapy is often used in combination with chemotherapy. However, no matter how effective targeted therapy is, it does not always work. Unless the tumor has a target, the treatment will not work. Further, the presence of the target does not ensure that the tumor will respond to the treatment; even if it responds, the effect may not last indefinitely [63]. The side effects of targeted therapy include rash, dry skin, itching, red or sore cuticles, changes in hair or skin features, and photosensitivity [64].

Therapeutic Properties of Cannabis on Cancer:
Schleider et al. (2018) had evaluated the information compiled as a part of the clinical program involving 2970 cancer patients, who underwent cannabis-related treatment. Out of all participants, 26.7% had reported that they had used cannabis before. The most common types of cancer in this study were breast cancer, lung cancer, pancreatic cancer and colorectal cancer; over half of them were at stage 4. Six months of follow-up passed, and only 1211 participants responded. 95.9% claimed their condition had improved, while 45 patients (3.7 %) stated their condition had worsened [65]. Another research, S. Seltzer et al. (2020), was also conducted to determine the effects of CBD on cancer cells. The result suggested that CBD had potential to be a therapeutic option for cancer therapy in humans, either alone or in combination with other cannabinoids, chemotherapies, and radiation therapy [66]. Gurney et al. (2015) had found the association between chronic cannabis use and the incidence of non-seminoma-type testicular germ cell tumors. Nevertheless, Gurney et al. (2015) had a number of limitations in their review. It was self-reported data without any validation, and the interviewers of the case-control status of the participants could also be biased. Besides, the prevalence of cannabis use in participants could be biased as well. Due to the deficiency in the quality of the studies, there was not enough evidence to suggest that cannabis use could cause testicular cancer [67].
S. Seltzer et al. (2020) reported that, in both cultured cancer cell lines and mouse tumor studies, CBD had exhibited potent antiproliferative and pro-apoptotic effects on a great range of cancer types. Anti-tumor procedures, depending on the type of tumor, could differ from cell cycle arrest (stopping point in cell cycle where cell stops dividing) to autophagy (mechanism to remove dysfunctional components in the body) to cell death, or a mix of these. Not only that, CBD could also suppress the movement, invasion and neo-vascularization of tumors; however, the required doses of CBD to inhibit the growth of tumor were unknown. There was a risk that comes with CBD use. A study that had done clinical trials in mice and cats indicated that CBD did cause mild hepatotoxicity, thus more research is needed to be done in humans to prove the efficacy and side effects of CBD [66].

F. Post-Traumatic Stress Disorder (PTSD)
General Information: PTSD is a disorder that develops in some people who have experienced a shocking, scary, or dangerous event. It is natural to feel afraid during and after a traumatic situation. Fear triggers many split-second changes in the body to help defend against danger or to avoid it. This "fight-or-flight" response is a typical reaction meant to protect a person from harm. Nearly everyone will experience a range of reactions after trauma, yet most people recover from initial symptoms naturally. Those who continue to experience problems may be diagnosed with PTSD [68].
Re-experiencing symptoms: People with these symptoms may have bad dreams, frightening thoughts, or flashbacks about the trauma over and over. Physical symptoms, such as a racing heart or sweating, are also included [68].
Avoidance symptoms: People with avoidance symptoms may avoid objects, places, thoughts, and feelings that are reminders of the traumatic event. Arousal and reactivity symptoms: People with arousal and reactivity symptoms may be easily startled, feel tense, stressed or angry. Arousal symptoms are usually constant, instead of being triggered by things that remind one of the traumatic events.
Cognition and mood symptoms: People with cognition and mood symptoms may have negative thoughts or distorted feelings such as guilt or blame, and be unable to remember key features of the traumatic event. It is natural to have some of these symptoms for a few weeks after a dangerous event. When the symptoms last more than a month, seriously affect one's ability to function, and are not due to substance use, medical illness, or anything except the event itself, they might be PTSD. Some people with PTSD don't show any symptoms for weeks or months [68]. PTSD develops in about 1 in 3 people who experience severe trauma. It's not fully understood why some people develop the condition while others do not. But certain factors appear to make some people more likely to develop PTSD [69]. Types of events that can lead to PTSD include physical or sexual assault, domestic or childhood abuse, war and conflict.

Therapeutic Properties of Cannabis on PTSD:
Since ECS is known to have a crucial role in regulating anxiety, stress, and fear, which are related to PTSD symptoms, it is highly likely that influencing the endocannabinoid system could possibly have certain effects on PTSD symptoms. Despite a strong scientific rationale, clinical trials have been rare and all existing research in humans had medium to high risk of bias and significant flaws in methodology and design.
There was a double-blind crossover study of 10 Canadian military personnel who had PTSD and were facing treatment-resistant nightmares. It was found that subjects receiving nabilone, a synthetic form of cannabis that mimics the effects of THC, had a remarkable decrease in nightmares compared to the placebo group. Aside from that, they also had increased scores of general wellbeing and global improvement. Nonetheless, nabilone is not an extract from an actual plant, and the sample size was fairly small. However, this finding still pointed out that stimulation of cannabinoid receptors possibly has positive effects on some PTSD symptoms, such as nightmares [72].
According to Drnatmed Medical Marijuana Card Colorado (2021), CBD could help empower ECS and improve the quality of their lives. In contrast, there was not a lot of evidence showing that THC helped the symptoms of PTSD since many researchers used nabilone instead of the actual plant. Using the actual plant, therefore, has not been studied too widely just yet. PTSD patients have reported feeling more manic and potentially feeling worse. Using THC products could cause confusion, less bodily control, can trigger anxiety and other adverse effects [73].

G. Psychosis
General Information: People with psychosis will have certain conditions that affect their mind, where there has been some loss of contact with reality. During a psychotic episode, their thoughts and perceptions are distorted, and they possibly experience difficulty deciding what is real and what is not. Having false beliefs (delusion), disordered movements, odd or illogical thoughts, and hearing or seeing things that are not real (hallucinations) are also included in psychosis symptoms. During a period of psychosis, a person possibly faces positive symptoms or negative symptoms such as anxiety, depression, sleep problems, and social withdrawal [74].
There are many disorders included in psychosis, which are schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, Organic psychosis, Postpartum psychosis, substance-induced psychosis, psychotic depression, bipolar disorder, and dementia. There is no only reason why people develop psychosis. Psychosis may be a symptom of a mental disorder such as bipolar disorder or schizophrenia. Apart from that, sleep deprivation, certain prescription medication, and misuse of alcohol or other drugs can also cause psychosis. All psychiatric conditions also have a strong link to genetic factors. If a person has a relative with mood disorder, the rate of having disorders is 2-3 times higher, and severity of a relative's mood disorder is related to the greater risk of a person's mood disorder. relies on effectiveness and efficacy for the individual's seizure type. Nevertheless, other personal factors including gender, age, childbearing potential, and comorbidities also have to be considered [81]. Nevertheless, epilepsy cannot be controlled in 20-30% of patients, and patients with drug-resistant epilepsy often have serious comorbidity, including injury, depression, anxiety, and increased mortality [82].
Surgical treatment: when two well-chosen and tolerated medications do not work, a presurgical evaluation should be arranged [83,84]. Patients should be identified early in the evaluation and treatment in order to undergo surgery. This treatment is favorable for those who have medial temporal lobe epilepsy and partial seizures related to selected lesional pathology [83]. If the brain region, where the seizures arise, is identified, this region can be removed with a low risk of disabling neurological deficits [84]. Gaston et al. (2018) presented data from two trials, open-label expanded access programs (EAPs) and randomized placebocontrolled trials (RCTs), using highly purified oral preparation of CBD. According to the data from EAPs, a large number of patients with several types of treatment-refractory epilepsy had a significant improvement in seizure frequency. RCTs, which was recently approved by the FDA for treatment of epilepsy, showed significant reduction of seizure when compared to patients with Dravet syndrome and Lennox-Gastaut syndrome who received placebo [85]. Nevertheless, drug-drug interaction, which can cause adverse effects, can occur with highly purified CBD. Diarrhea and sedation are the most common side effects. Apart from that, patients also experience an increased incidence of aspartate aminotransferase and alanine aminotransferase whilst taking CBD [85].

Therapeutic Properties of Cannabis on Epilepsy:
Even though cannabis and THC are anticonvulsant in most animal models, there are some cases of healthy animals, where CBD and THC can be proconvulsant as well. The antiepileptic mechanisms of CBD are not totally understood, but effects on the equilibrative nucleoside transporter are possibly included. However, despite having anti-inflammatory and neuroprotective effects, studies of CBD in human epilepsy are still small and methodologically limited, hence being inconclusive. High-ratio CBD:THC medical cannabis is suggested to have claimed efficacy by recent studies, but these reports are not controlled. In other words, the efficacy of pure CBD in chronic patients and for epilepsy is not well understood because of the lack of data from well-powered, double-blind randomized, and controlled studies [86].

I. Traumatic Brain Injury (TBI)
General information: TBI is defined as a physical injury to the brain tissue that temporarily or permanently alters brain function. Various types of structural damage can be caused by head injuries. Mechanism and force play a role in determining whether structural changes will be gross or microscopic [87]. People with TBI possibly experience confusion, altered level of consciousness, seizure, coma, and focal sensory or motor neurologic deficit. Moreover, TBI is a common cause of death as well as a major cause of epilepsy.
Types of TBI can be classified by many criteria. One of them is physical mechanism classification, which considers whether the head strikes an object and the brain moves within the skull. The specific forces at specific magnitude and direction of each type are potentially able to predict patterns, types, and severity of the injuries [88]. There are 4 types of TBI, which are concussions (minor brain injury), brain contusions (a bruise of the brain tissue), penetrating brain injuries (when some type of object pierces through the skull), and anoxic brain injuries (when there is insufficient oxygen for the brain to operate properly). Causes of TBI depend on various factors, including age, geographic region, and socioeconomic factors. Road traffic injuries (RTI) also relate to the global incidence of TBI. In high-income countries (HICs), the most frequent causes of TBI are RTI and falls, which is the primary cause in the elderly. Nonetheless, younger people, whose age is between 28.8 and 33.1, in less wealthy countries have a higher rate of experiencing TBI [89]. Other incidents, such as violence, sport injuries, explosive blasts and other combat injuries, also can cause TBI.

Current treatments:
Immediate treatment after injury: in moderate and severe TBI patients, it is vital to ensure that they have sufficient oxygen and adequate blood supply. Maintaining blood pressure and preventing further head and neck injuries are also important. When patients arrive at the emergency room or intensive care unit, minimizing secondary damage from inflammation, inadequate oxygen supply, and bleeding. Some medications including diuretics, anti-seizure drugs, and coma-inducing drugs are sometimes needed. efficacy of cannabis in epilepsy patients is still not clear due to lack of data but there was evidence that diarrhea and sedation are the most common side effects. Results concerning TBI showed that CBD could possibly treat neurological dysfunctions brought on by trauma, but the empirical evidence is still sparse. Cannabis' remedial effect on PD is still undeterminable but it may have beneficial effects on mood, memory, and exhaustion in PD patients. Regarding AD, research showed evidence that cannabis may treat the disease by using a combination of THC and CBD. Nonetheless, the long-term impacts on this disease could not be addressed.
The topic about cannabis dosage is still debatable. Most studies suggested that there are no benefits from high doses of THC, since high doses of THC come with risks including cognitive impairment, psychosis risk, tolerance to cannabinoids, and endocannabinoid alteration. In contrast, high doses of CBD were required for the beneficial effects. CBD should be adjusted to greater concentration than THC in order to minimize THC's intoxicating effects. Cardiovascular illness, acute pancreatitis, cannabis hyperemesis syndrome, and industrial injuries can all be exacerbated by high THC levels. Anyhow, the standard dosage for each medical condition was not concluded.
It can also be seen that research on THC use for each disease is significantly lower than CBD. Most research and trials are focused on the use of CBD possibly due to the psychotic properties of THC. Although the majority might think THC consumption is for recreational purposes, many studies concluded that THC exhibits a therapeutic effect on certain medical conditions. While risks of THC use are great, the risks can be minimized by combining with CBD. Hence, more research on THC therapeutic properties should be conducted.
Many barriers still exist as an obstacle to research on cannabis. Most research on cannabis could not be done at a large scale due to many legal issues. To illustrate, the Controlled Substances Act (CSA) of 1970 in the USA categorized cannabis and THC as Schedule 1 drugs, which refers to a drug with no accepted medical use and a high potential for abuse. These legal barriers make it difficult to conduct research and clinical trials on humans. Findings from animal studies cannot conclude the effect of cannabis on humans. Should cannabis be completely legal for medical purposes, more studies would be permitted. So far, there are various gaps in the information we have, for example, the standard dosing and the long-term side effects. Much more research and clinical trials are essential to discover all of cannabis' therapeutic properties.

CONCLUSION
To summarize, there is substantial evidence that cannabis use positively affects the alleviation of chronic pain, OUD, sleeping disorders, and Alzheimer's disease. Favorable effects on PTSD, psychosis, and TBI have been found only in CBD. There is not enough evidence to conclude that cannabis use has beneficial effects on obesity, cancer, epilepsy, and Parkinson's disease. Nevertheless, absence of evidence does not necessarily imply no therapeutic effect. Risks of cannabis consumption for these conditions include cannabis use disorder, pregnancy complications, mild hepatotoxicity, cause of psychosis, drug-drug interaction, diarrhea, and sedation. Most studies recommended that using a combination of high portion CBD and low portion THC would maximize benefits and minimize the risks and no study suggested that high doses of THC is beneficial. Current information and empirical findings of cannabis are still insufficient, therefore, more research needs to be conducted to fully understand cannabis' properties. We hope this review will provide empirical data that can improve the understanding of medical cannabis.