Review of Medicinal Use of Cannabis Derivatives and the Societal Impact of Legalization

Nausea and vomiting

Several studies have looked at the use of Cannabis to treat symptoms such as nausea and vomiting. It is hypothesized that inactivation of CB₁ receptors leads to vomiting. The antiemetic action of Cannabis is mediated via the activation of CB₁ receptors. In a meta-analysis looking at 28 studies where marijuana was used for nausea and vomiting,[15] marijuana showed benefits in their control in majority of the studies when compared with placebo as well as other alternatives. The comparator agents commonly used were prochlorperazine, chlorpromazine, and domperidone. The number of patients who showed complete resolution of symptoms with cannabinoid group was greater than the number of patients in the placebo group with an odds ratio of 3.82 (95% confidence interval [CI], 1.55–9.42). All these studies suggested that there was a benefit of cannabinoids compared with both active comparators and placebo, although the benefit was not statistically significant.[151617] However, when a review compared Cannabis against various other antiemetics, it was noted that Cannabis was associated with greater central nervous system side effects such as drowsiness, postural dizziness and hypotension, lightheadedness, and euphoria [Table 1].[18]

Appetite stimulation

Marijuana has also been used for appetite stimulation in patients suffering from anorexia nervosa, HIV, and cancer. Appetite stimulation is extremely important in these patients. Patients suffering from cancer and undergoing treatment have high nutritional requirements; however, delivering adequate nutrition may not always be possible due to the disease itself, any previous surgical intervention, or any ongoing treatment. The action of marijuana is exerted through the agonist action of CB1 receptors; it causes increased food craving and enjoyment, along with the promotion of deposition of energy as fat into adipose tissues.[1920]

A meta-analysis looked at the use of Cannabis for appetite stimulation as compared to a placebo or comparator agent such as Megastrol acetate among patients suffering from HIV/AIDS. Most of the studies included had a placebo as the comparative agent. The results showed evidence for increased appetite using marijuana as compared to placebo,[15] however, Megastrol acetate showed a significant advantage over patients using Cannabis both for appetite (75% vs. 49% [P = 0.0001]) and baseline weight gain (11% vs. 3% [P = 0.02]) [Table 1].[21]

Marijuana may be beneficial for appetite stimulation; however, further studies comparing it to known comparator agents are needed to conclusively determine its usefulness.

Chronic pain

Pain can be generally associated with several conditions, such as neuropathy, cancer pain, diabetic peripheral neuropathy, fibromyalgia, HIV-associated sensory neuropathy, refractory pain due to multiple sclerosis (MS), rheumatoid arthritis, musculoskeletal problems, and chemotherapy-induced pain. Most of these are chronic conditions and often, these patients are generally resistant to other pain medications. Marijuana has often been used for pain relief in such situations.

In a meta-analysis comparing Cannabis with a placebo for various painful conditions such as neuropathic pain, cancer-induced pain, diabetic peripheral neuropathy, and fibromyalgia, it was noted that the average number of patients who reported a reduction in pain of at least 30% was greater with an odds ratio of 1.41 (95% CI, 0.99–2.00). It is to be noted that 27 out of 28 studies had compared marijuana against a placebo agent.[15] In another study where Cannabis was compared with amitriptyline to manage insomnia due to chronic pain, it was seen that Cannabis was superior to amitriptyline (Insomnia Severity Index difference = 3.2; 95% CI, 1.2–5.3).[22] A randomized controlled trial (RCT) performed across three centers in the United Kingdom (96 patients) had two groups; one received marijuana followed by dihydrocodeine and vice versa was administered in the other group. The Visual Analog Scale was used to evaluate the pain relief in patients suffering from neuropathic pain. The authors found that dihydrocodeine was more effective when compared with Cannabis with a mean score of 6.0 mm longer for nabilone than for dihydrocodeine (95% CI, 1.4–10.5) in the available case analysis.[23] Few other reviews evaluated studies in which Cannabis has been compared to a placebo for the treatment of chronic pain and have shown promising results [Table 1].[1824] The evidence for use of marijuana as an analgesic, when compared with alternative drugs such as opioids, antiseizure medications, and nonsteroidal anti-inflammatory drugs, is still evolving.

Multiple sclerosis

MS is a potentially disabling disease of the brain and spinal cord (central nervous system). In MS, the immune system attacks the myelin sheath, leading to degeneration of nerves. An estimated 2.3 million people suffer from MS around the world.[25] A meta-analysis[15] included 11 studies comparing marijuana to a placebo. It showed that use of Cannabis can offer some benefit in reducing spasm in patients suffering from MS, however the results of these studies were not statistically significant (weighted mean difference, −0.12 [95% CI, −0.24–0.01]). A RCT with 37 patients showed that Cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (P < 0.0001).[26] Another randomized, double-blinded, placebo-controlled, crossover study with fifty patients concluded that a standardized C. sativa plant extract might lower spasm frequency and increase mobility with tolerable side effects in patients of MS with persistent spasticity [Table 1].[27] The current data for the use of marijuana for MS is limited by small sample size and placebo-controlled trials.

Epilepsy

Cannabis has been tried in patients suffering from rare epileptic disorders, such as Dravet syndrome and Lennox–Gastaut syndrome, which are often resistant to standard anti-epileptic medications. The exact incidence of these rare disorders has not been conclusively studied yet; however, few studies have shown an incidence of around 1:40,000 children. A systematic review on drug-resistant epilepsy found that Cannabis was more effective than placebo in reducing seizure frequency by over 50% (relative risk [RR] 1.74, 95% CI, 1.24–2.43, RCTs, 291 patients, low grade of recommendation), complete freedom from seizures (RR 6.17, 95% CI, 1.50–25.32, three RCTs, 306 patients, grade of recommendation), and improving quality of life (RR 1.73, 95% CI, 1.33–2.26).[28] A few other studies have also shown the efficacy of marijuana-related products in drug-resistant epilepsy (more so in rare forms and in pediatric population) though the definitive evidence to recommend its generalized use for this indication is lacking and requires further evaluation [Table 1].

Crohn's disease

Marijuana is known to have anti-inflammatory properties. Keeping this in mind, it has been used to treat inflammatory bowel conditions such as Crohn's disease. A RCT on twenty patients suffering from Crohn's disease, demonstrated that a complete remission (Crohn's Disease Activity Index [CDAI] score, <150) was achieved by 5 of the 11 patients in the Cannabis group (45%) and 1 of 10 in the placebo group (10%; P = 0.43) (Naftali et al.). A clinical response (decrease in CDAI score of >100) was observed in 10 of the 11 patients in the Cannabis group (90%; from 330 to 105-152-109) and 4 of 10 in the placebo group (40%; from 373 to 94-306-143; P = 028)[29] Further long-term studies against standard treatment regimen are required to evaluate the utility of marijuana in such cases [Table 1].

Anti-cancer

There is some evidence in literature that Cannabis has antitumor properties and prolongs life. Studies have shown its exact mechanism, which may involve suppression of proliferative cell signaling pathways, inhibition of angiogenesis and cell migration, stimulation of apoptosis, and/or induction of autophagy.[3031] Few investigational studies have been conducted on various tumors such as gliomas, lymphomas, prostate cancer, breast cancer, lung cancer, skin cancer, and pancreatic cancer.[32] A Phase 1 study was done on nine patients suffering from glioblastoma multiforme to assess the antitumoral effects of Cannabis. It showed that Cannabis may be administered safely without significant adverse effects. The study further showed that Cannabis inhibited tumor cell proliferation in vitro and decreased tumor cell Ki67 immunostaining when administered to two patients.[33] Cannabis has been shown to be effective when used in combination with other anticancer drugs. This has particularly been seen in pancreatic cancers and gliomas.[34] Thus, the evidence for the anticancer effect of Cannabis does exist, but it is exploratory and evolving. Addiction potential, risk of developing other malignancies, and various other side effects have precluded the use of Cannabis for antitumor effects. Majority of the existing studies have been conducted ex vivo, and further studies are required to confirm or refute such effects.

Glaucoma

Cannabis has neuroprotective properties and effectively reduces the intraocular pressure (IOP). A randomized, double-masked, placebo-controlled, four-way, crossover study on six patients showed that a single 5-mg sublingual dose of Delta-9-THC reduced the IOP temporarily for a duration of 4 h and was well tolerated by most patients; hence, this may form a future pathway for the management of glaucoma.[35] This was a single study which evaluated the use of marijuana for this purpose and moreover, the sample size was small, hence there is a requirement of gathering further evidence [Table 1].

Sleep disorder

There is some evidence that Cannabis may be beneficial in patients suffering from sleep disorders due to chronic pain or any other obstructive disorders. A meta-analysis evaluated two studies where marijuana was used for the management of sleep disorders. One study compared Cannabis versus placebo and showed a greater benefit on sleep apnea/hypopnea index (mean difference from baseline, −19.64; P = 0.02). Another study compared Cannabis to a comparator drug (amitriptyline) and showed improvements in insomnia (mean difference from baseline, −3.25 [95% CI, −5.26–−1.24]) and with greater sleep restfulness (mean difference from baseline, 0.48 [95% CI, 0.01–0.95]). Their long-term efficacy and efficacy at higher doses needs to be compared.[15]

Tourette syndrome

Tourette syndrome is a chronic, childhood-onset, neuropsychiatric disorder characterized by waxing and waning motor and vocal tics that persist for more than 1 year. The estimated incidence of this syndrome is around 5 in 10,000. Patients suffering from Tourette syndrome have shown improvement in tic severity when these patients were administered Cannabis. Two RCTs, with small sample sizes, have evaluated Cannabis versus placebo and found that there was statistically significant improvement with Cannabis [Table 1].[15] It needs to be reiterated that such patients actually requiring Cannabis are too few in numbers, and that this is a very specific indication of the drug.

Effect on development of brain

The effect of marijuana on the development of brain has been seen particularly in addicted adolescents, with weekly usage impact on their learning abilities and memory can last even up to 28 days post last usage.[36] When compared with people who do not use marijuana, adults who smoke marijuana regularly show impaired neural connectivity. This has been assessed using diffusion-weighted imaging, a magnetic resonance imaging modality capable of elucidating axonal directionality and microstructure in vivo performed in 59 Cannabis users with a history of long-standing, heavy use and 33 nonusers.[37] The areas of brain which are affected are the precuneus node, which is involved in functions which need high degree of integration, and the hippocampus, which is involved in learning and memory functions.[38]

Addiction

The International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders designate Cannabis as an addictive substance, with recognized Cannabis-related dependence disorders.[39] Around 9% of the users, more significantly teenagers who try Cannabis, ultimately become addicts.[38] Cannabis withdrawal syndrome is a known condition with symptoms such as irritability, sleeping difficulties, and dysphoria.[38] A study showed that the relapse rates for marijuana addicts were as high as 71% at 6 months.[40] There has been an increased incidence of motor vehicle accidents in patients who may be either short-term or long-term users of marijuana. In a study which retrospectively analyzed the Fatality Analysis Reporting System for 1999–2010, marijuana was the second most common cause after alcohol for the increased number of road traffic accidents in young adult victims.[41] Patients who are under the influence of marijuana have been shown to have longer response times and slower driving speeds in a dose–response fashion. The combined effect of alcohol with marijuana increases impairment, and the risk of road traffic accidents is more than using either substance alone.[4243] For less-than-weekly users of marijuana, 10 mg or more of THC[44] or a blood THC level of 2–5 ng/ml causes significant impairment[42] and should wait for 6–8 h for the impairment to resolve.[45]

Risk of cancer

Marijuana smoking leads to exposure to a number of harmful by-products. Some of the carcinogens present in tobacco are present in Marijuana smoke as well. These include polycyclic hydrocarbons and benopyrenes.[47] Animal studies have shown the carcinogenic effect of Marijuana both in vitro and in vivo.[48] A few studies also show that at a lower dose, Cannabis may stimulate the growth of cancer cells.[49] Various studies have hypothesized an increased risk of cancers of the upper aerodigestive tract and the lungs in Marijuana smokers.[50] Few others have shown a positive association between Marijuana smoking and cancers of the lung, showing a twofold increase in its incidence (hazard ratio 2.12, 95% CI, 1.08–4.14). In contrast, few studies found no positive association between cancer and Marijuana use on adjusting for confounders such as cigarette smoking.[51] Another review opined that its association with lung cancer may not be appreciated so clearly because of smaller quantities being smoked compared to tobacco.[52] Studies have also noted an increased risk of developing other cancers such as nonseminoma testicular germ cell cancer, prostate cancer, and cervical cancer.[5354]

As can be understood from these studies, some association between Marijuana use and subsequent cancer development does exist; although to clarify it further, research on this aspect is required.

Pulmonary disease

The exposure of the upper aerodigestive tract to a number of harmful by-products of Marijuana smoking often leads to various complications. These by-products affect the functioning of the immune system and also alter the expression of inflammatory cytokines. Cannabis smoking is associated with smaller butt length of the joint, deeper and prolonged inhalation, and higher combustion temperature as compared to tobacco smoking. This increases the concentration of harmful chemicals in the airway, thereby increasing their absorption.[55] A review of literature noted that Marijuana smoking affected the bronchial dynamics and the lung volumes. Thus, its use is associated with an increased risk of bronchitis, pneumonia, respiratory distress, and emphysema.[56] In individuals <40 years, daily or near-daily marijuana use may be associated with bullous lung disease complicating to pneumothorax.[57] Changing over from marijuana smoking to vaporizing may have fewer respiratory symptoms and improved pulmonary function.[58]

Cannabis hyperemesis syndrome

Few case reports have described a condition which is known as Cannabis hyperemesis syndrome and is specifically seen in Marijuana addicts. A study showed that there was a higher incidence of this syndrome in young adults with a history of long-term use of Marijuana.[59] These patients with chronic Cannabis use show a triad of symptoms such as cyclic vomiting, abdominal pain, and compulsive hot water bathing.[60] Though the pathophysiology of the condition is not well understood, it has been proposed that central effects of long-term Cannabis use on the hypothalamic–pituitary–adrenal axis might play a major role in the development of cannabinoid hyperemesis syndrome.[59] However, as only a few cases have been reported, a detailed description of this condition is, therefore, elusive.

Vascular conditions

Patients smoking Marijuana are at an increased risk of suffering from transient ischemic attacks, stroke, myocardial infarctions, and Cannabis arteritis. A recent 5-year observational study presented at the 11^th Stroke Congress showed that among 2.3 million hospitalizations for patients who had used marijuana recreationally, 32,231 (1.4%) had a stroke. Of these, 19,452 patients presented with acute ischemic stroke.[61] There have been several studies which have demonstrated that Marijuana use is associated with higher chances of having angina and myocardial infarction. It has also been found to be associated with peripheral vascular diseases and cerebrovascular accidents.[62]