Considerations for the Use of Medical Cannabis: An Overview of Benefits and Harms

plant extract): Epidiolex (can-nabidiol) and three synthetic cannabis-related products (synthetic isolates): Marinol (dronabinol), Syndros (dronabinol) and Cesamet (nabilone) under ABSTRACT Introduction: Cannabis use to treat various diseases or symptoms is not clearly defined. The purpose of this review is to explore the existing evidence regarding the harms and benefits of cannabis use across multiple illnesses. Material and Methods: Search for articles for this review was performed in PubMed, Google Scholar and PsycINFO. We summarize and discuss recent evidence regarding cannabis use in multiple neurological (including seizures, neurodegenerative disorders, multiple sclerosis), psychiatric (including depression, bipolar disorder, anxiety and psychotic illness) and other diseases (including chronic pain, cancer, vomiting, cardiovascular diseases, COVID-19). Results: The collated body of evidence shows that the benefit of its use (medicinal or recreational) mostly lacks adequate evidence warranting for further study. In pretext of already available better options (with better efficacy and safety), the consideration of this agent is seriously debatable. Conclusion: Harms or adverse effects of cannabis use clearly are evidence based and are at times serious (e.g. psychosis association), mainly from mental health perspective. Hence, its use should not be suggested and needs serious consideration before using it.

Changing dynamics in research at times demonstrate its usefulness for medical purpose due to anxiolytic, neuroprotective, antioxidant, anti-inflammatory, antidepressant, antipsychotic and hypnotic actions [10].
Cannabis is consumed mainly as: smoking cigarettes (joints) or inhaling from pipes, vaporizer, or resin burnt in a sawn-off plastic bottle. It can also be eaten by baking into cookies or cakes; edible form as bhang in Indian subcontinent and occasionally drunk as an extract [11]. The Global burden of disease estimates-2019 suggests cannabis use disorders resulting in 690,000 global years lost due to disability, 0.08% (0.05-0.1%) of total global YLDs [12].
Opponents of legalization view cannabis as a harmful substance due to its abuse potential, risk of aggravation of psychosis, road traffic accidents, low birth weight and respiratory diseases. Many studies are mostly inconclusive regarding cannabis use, with only a few studies showing some benefits in certain conditions (pain, nausea, vomiting, spasticity). These conclusions are also not properly interpreted, communicated and reported to policymakers, care providers and stakeholders, which has a huge impact on public health [8,13]. This narrative review intends to explore the existing evidence regarding harms and benefits of cannabis across multiple physical and mental problems.

Epilepsy and Refractory Seizures
CBD has been reported with anti-seizure properties, which are not direct action on cannabinoid receptors but are mediated through several other mechanisms, like agonist or antagonist effects on ionic channels, neurotransmitter transporters and multiple 7-transmembrane receptors [15]. A systematic review [four randomized trials involving 550 patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS)] showed greater reduction in seizure frequency with oral CBD [15].  [16]. A study from Nepal reports 4% of seizure psychiatry out-patients to abuse cannabis [17].

Neurodegenerative Disorders
CBD displays neuroprotective role via several mechanisms, i.e., through different signal transduction pathways mediated indirectly by cannabinoid receptors. It prevents glycogen synthase kinase 3β (GSK-3β) hyperphosphorylation caused by Aβ, making it a new therapeutic candidate for Alzheimer's disease [18]. A systematic review (twelve primary studies and one uncontrolled before-andafter prospective pilot study) suggests cannabis as effective for treating neuropsychiatric symptoms associated with dementia, e.g., agitation, disinhibition, irritability, nocturnal behavior disorders, aberrant motor behavior and aberrant vocalization [19]. Dementia is a qualifying condition for medical cannabis use in ten (41.7%) of the 24 states and localities in the US where medical marijuana is legal, primarily for agitation of Alzheimer's disease [20]. It warranted additional studies with larger samples and specific objectives to establish its benefit.
A double-blind, randomized, placebo-controlled, crossover pilot clinical trial with botanical extract of cannabis for the treatment of Huntington's disease, shows no differences on motor (p-value= 0.286), cognitive (p-value= 0.824), behavioral (p-value= 1.0) and functional (p-value= 0.581) scores as compared to placebo [22].

Multiple Sclerosis (MS) and spasticity
MS is characterized by auto-immune-mediated CNS myelin sheath destruction resulting in upper motor neuron lesion with features of muscle spasticity. Evidence supports baclofen, tizanidine, and gabapentin as first-line management of its spasticity [23]. whole-plant cannabis-based medicine containing Δ-9 THC and CBD active preparation as significantly superior to placebo (p-value= 0.048) [25]. A meta-analysis of five trials found cannabinoids with a greater average improvement on the Ashworth Scale for spasticity compared with placebo in patients with spasticity due to MS or paraplegia, although the difference was statistically not significant (−0.12; 95% CI: −0.24 to 0.01) [26].

Psychotic disorder and Schizophrenia
Cannabis use has been shown to alter the age of onset, course and presentation of psychotic disorder in vulnerable individuals [27]. A systematic review of 35 longitudinal population-based studies shows any cannabis use to associate with an increased risk of psychosis: adjusted odds ratio (AOR) of 1.41. There was significant dose-response relationship with twice the risk (RR: 2.09) for using cannabis more often [28]. Different factors increase the psychosis risk: type of cannabis (with high THC/CBD ratio), vulnerable subpopulation (adolescents), and familial and genetic factors (including the AKT1 rs2494732 polymorphism) [29]. After the onset of psychosis too, continued cannabis use is associated with more adverse outcomes, i.e., increased relapserate, prolonged hospital-stay, severe positive symptoms [30].  [36]. A three-year prospective study found conflicting results, where weekly to almost daily use resulted in increased chance of BPD (AOR: 2.47; 95% CI: 1.03-5.92), but not daily use (AOR: 0.52; 95% CI: 0.17-1.55) [37]. Cannabis use is also related to poor prognosis with higher chance of rapid cycling and mixed episodes in bipolar patients [38]. There are no studies regarding CBD use for BPD treatment.

Anxiety Disorder
A cohort study on 112,000 non-institutionalized general population of 10 countries showed a positive association between anxiety and cannabis use (OR= 1.24; 95% CI: 1.06-1.45; 15 studies).
The association with cannabis use disorder (OR= 1.68; 95% CI: 1.23-2.31; 13 studies) was even higher [39]. A systematic review and meta-analysis of 24 longitudinal studies on baseline cannabis use and anxiety outcomes found that cannabis use may increase the odds of developing any anxiety condition (OR: 1.25; 95% CI: 1.01-1.54). However, generalized anxiety disorder, panic disorder, or social anxiety disorder are not significantly associated with cannabis use [40]. A Nepali study reports panic disorder as the most common presentation among cannabis users [41] and other one reports 4% of OCD patients visiting a psychiatry clinic to abuse cannabis [42]. There is a low quality of evidence suggesting a single dose CBD 600mg given to individuals with social anxiety disorder showing improved scores on visual analog scale in simulated public speaking test in comparison to placebo [26]. More robust clinical trials are needed to validate its anti-anxiety effect.

Neuropsychological Effects
Harmful effect of cannabis on neurocognition is related to the preparation of cannabis with a higher THC:CBD ratio [43]. A systematic review and meta-analysis involving 69 studies found statistically significant negative effects in cognitive functioning with frequent or heavy cannabis use by adolescents and young adults, albeit the association was small. The abstinence for more than 72 hours decreased these cognitive deficits [44]. Other cohort study involving continued daily heavy cannabis use among adolescents to adults also showed a decline in executive functioning, learning, memory and verbal IQ at 38 years of age even after adjusting for multiple related covariates, and the neurocognitive functioning not improving in adolescent-onset cannabis use even after stopping cannabis [45].

Psychosocial Consequences
Adolescent cannabis use is associated with poorer psychosocial functioning resulting in lower educational attainment, risk of other drug use and higher levels of antisocial behavior during adulthood.
In adults using cannabis frequently and for a prolonged time; poorer psychosocial functioning was reported in many domains (academic performance, educational attainment, unemployment, occupational prestige/income, financial strain, alcohol and other drug use, antisocial behavior and interpersonal relationships likefamily and social relationship [46]) regardless of whether it was adolescent-onset or adult-onset. Association is not clear and causal mechanism is more likely to be social milieu factors [47].

Chronic Pain
Cannabis-based medicines (CBMs) are found to reduce chronic pain resulting from multiple causes. A systematic review and meta-analysis of 24 randomized controlled trials (a total of 1,334 patients) showed reduction in chronic pain (-0.61; 95% CI: -0.78 to -0.43), especially by inhalation (-0.93; 95% CI: -1.51 to -0.35) compared to placebo [48]. In other meta-analysis, cannabinoids had a greater average number of patients with a reduction in pain (37% vs 31%; OR: 1.41; 95% CI: 0.99-2.00; 8 trials), and a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference: -0.46; 95% CI: -0.80 to -0.11; 6 trials) compared to placebo [26]. This analgesic property has made them an option for control of cancer pain.

Cancer
Cannabinoids have some antineoplastic potential. A systematic review of experimental studies performed on animal colorectal cancer models has shown a reduction in the formation of preneoplastic lesions (aberrant crypt foci) and volume of neoplastic lesions [49]. CBD botanical substances were reported to achieve high aberrant crypt foci (ACF) reduction (86%) and tumor volume reduction via induction of apoptosis, interaction with cell survival, growth pathways and angiogenesis inhibition. Cannabis is also found to down-regulate immunologically generated free radical production by promoting a Th2 immune cytokine profile and hence, minimizes some carcinogenic pathways. THC inhibits the enzyme necessary to activate some of the carcinogens of smoke.
Due to lack of cannabinoids receptors in respiratory epithelial cells of lungs, DNA damage checkpoint mechanism is reported to remain intact even after prolonged cannabis smoking [50]. A pooled analysis of six case-control studies with a total of 2,159 cases and 2,985 controls failed to prove cannabis smoking as a risk factor for lung cancer and reported the overall pooled OR for habitual versus non-habitual cannabis users or never-users 0.96 (95% CI: 0.66-1.38) [51].

Cardiovascular System
Cannabis smoking can result in cardiovascular adverse effects via sympathetic nervous system stimulation, parasympathetic nervous system inhibition, inflammation of blood vessels, platelet activation and carboxyhemoglobin generation [53]. Although rare, it is associated with an increased risk of life-threatening cardiac dysrhythmia [54]. A systematic review of published cases of individuals with acute myocardial infarction following marijuana use has reported episodic marijuana use as a significant risk factor for acute myocardial infarction, particularly in individuals with no cardiac risk factors [55].

Reproductive System
The active components of cannabis activate the cannabinoid receptors of internal reproductive organs in both sexes, a part of endogenous endocannabinoid system [56]. A study among 1,215 Danish men aged 18-28 years showed regular marijuana smoking >once/week to associate with 29% (95% CI: -46 to -1) lower sperm count after adjusting for confounders. If the same frequency of cannabis smoking were combined with the use of other recreational drugs, sperm concentration would be reduced by 52% (95% CI: -68 to -27) and sperm count by 55% (95% CI: -71 to -31) [57]. This finding contradicted with other longitudinal study among 662
Cannabis is found to affect the fertility of women via either ovulatory delay or inhibition. A study done in 201 participants showed that women with occasional marijuana users (up to three times in the last 3 months) and infrequent users (more than three times in the last 3 months) had a longer follicular phase than nonusers (3.5 days and 2 days longer respectively) [59].
Cannabis also affects the pregnancy, its outcome, and physical plus providing the support for development of synthetic cannabinoids as new therapeutic agents to prevent and treat retinal diseases [62,63]. The endocannabinoid system (ECS) has also been found to play a role in lowering intraocular pressure, making cannabis a potential therapeutic agent in managing glaucoma. However, its side effects, i.e., tolerance and accompanying psycho-active influence have largely limited this use [64,65]. A mice study has shown topical application of cannabis extract to reduce corneal hyperalgesia and neutrophil infiltration resulting from superficial chemical injury of corneal epithelium [66]. However, long-term cannabis use is associated with significant decrease in corneal cellular density. A study among 28 patients with cannabis use disorder and 32 age-and sex-matched healthy individuals, has shown a significant decrease (p< 0.01) in corneal cell density (CD) in the cannabinoid group than control (mean CD was 2900±211 cells/mm 2 vs. 3097±214 cells/mm 2 ) [67].

Hyperemesis Syndrome
Cannabis acts both as pro-emetic and antiemetic agents. It exerts anti-emetic action at low doses and acts as pro-emetic at higher doses [15]. People with chronic cannabis use sometimes present with cyclic episodes of nausea and vomiting and get relief by frequent hot bathing. This syndrome is known as cannabis hyperemesis syndrome [68].

Road Traffic Accidents
Deterioration of specific cognitive functions and psychomotor abilities after cannabis use is responsible for impaired driving performance. The degree of impairment in performance observed in experimental studies with up to 300mcg/kg THC was equivalent to the impairing effect of an alcohol dose producing a blood alcohol concentration of more than or equal to 0.05g/dl, the legal limit for driving in most European countries. Blood THC levels do not correlate well with the level of cognitive impairment as it is quickly cleared from plasma and is widely distributed to tissues [69,70].
Use of both alcohol and cannabis has been shown to lead to greater odds of making an error than solo use of these substances [71].

Sleep Disorder
Although short-term THC use may show beneficial effects on reducing sleep latency, long-term use causes impaired sleep quality [72]. Sleep disruption and insomnia are associated with cannabis withdrawal, particularly in heavy cannabis use. In a study involving 30,000 teenagers in Fairfax County, Virginia with each hour of sleep lost, the chance of using marijuana increased by 23% suggesting the increasing use of marijuana after sleep deprivation [1,73].
Synthetic isolates like nabilone and dronabinol have shown some promise in obstructive sleep apnea (OSA) due to their modulatory effects on serotonin-mediated apneas in novel studies. For REMrelated sleep behavior disorder and excessive daytime sleepiness, CBD may be beneficial. Nabilone is useful in treating secondary insomnia conditions, e.g., PTSD and chronic pain. However, more robust evidence is needed to consolidate the findings [72].

COVID-19
People are attracted by its much talked off benefits, like: increased appetite, decreased pain and immunosuppresant action to overcome COVID-19. Like tobacco, chronic cannabis smoking can lead to increased sputum production, cough; reduced pulmonary function and respiratory tract diseases. Sharing of cannabis is common social practice in the form of waterpipes (bong, hookah, shisha) which during the pandemic can increase virustransmission risk [74]. Progression of COVID-19 is determined by two phase immune response: first phase related to eliminate the virus and progression to severe form and second phase related to virally induced cytokine storm syndrome. Cannabis compounds containing CBD, cannabigerol (CBG) and tetrahydrocannabivarin (THCV) may have clinical value (anti-inflammatory effect) by reducing cytokine secretion in lung epithelial cells. This is in contrast to fraction from Cannabis sativa Arbel strain (F CBD ) which also contains terpenes which is found to increase macrophage secreted IL-6 and IL-8 levels. It will ultimately result in worsening of cytokine storm causing more harm in COVID-19 patients [75].

Conclusions
Despite widespread belief of benefit from medicinal cannabis consumption, we are less aware of its negative consequences.
Changing global dynamics moving towards decriminalization and legalization of cannabis and our current understanding of cannabis use in any form (medicinal or recreational) are matter of concern.
Analysis of the literature shows more evidence for harms than therapeutic benefits of cannabis in majority of health conditions. This review shows that its benefit lacks adequate evidence warranting for further study. In pretext of already available better options (with better efficacy and safety profile), consideration of this agent cannot be favored. And, its harms and adverse effects are clearly evidence based, mainly from the perspective of mental health effects and serious condition (e.g., cardiac dysrhythmia).
Hence, the authors are of the firm opinion that its use should not be suggested and needs serious consideration before using it.