Medical Marijuana: Is it a blessing in disguise or a curse for humanity?

The influx of companies, the launch of pipeline therapies, and the legalization of marijuana/ cannabis are the major drivers of the medical marijuana market.

Cannabis, popularly known as Marijuana, is the most commonly used illicit drug after alcohol. More than 150 Million people regularly smoke marijuana. Approximately 11.8 Million young-adult American population consumed marijuana in 2017 according to the results of a survey by the National Survey on Drug Use and Health. Moreover, the percent of the middle and high schoolers consuming marijuana has remained the same; however, the year 2018 witnessed an increase in the number of 8^th and 10^th graders using marijuana in different forms daily, demonstrated the analysis from ‘Monitoring the Future’ survey. 

Marijuana has several nicknames. Weed, pot, dope, grass. All for the same drug, extracted from the same plant i.e., Cannabis. It is smoked, drunk, eaten, and vaped. Most people use it for recreational purposes. It is believed that inhalation or smoking of marijuana readily produces the effect that wears off in a few hours, and if ingested orally, the onset of euphoria is delayed, however, the duration of pharmacokinetic effects are also extended. However, the catch is to use the same drug legally to address medical ailments. 

Where does it come from?

Cannabis or marijuana belongs to the Cannabaceae family of flowering plants. The family comprises a total of 170 species groups in 11 genera. Cannabis, itself is a phenomenally diverse plant that can be categorized among thousands of strains and subspecies. The exact number of sub-species within the genus Cannabis remains unclear, however, three species are the most recognized namely Cannabis sativa, Cannabis indica, and Cannabis ruderalis. However, despite hailing from the same species, the effects, appearance, and characteristics of each one vary greatly. 

Known for their pain-relieving properties, soothing aches and pains, Indicas remain the preferable choice for medical use. Sativas, on the other hand, although can rouse euphoric feeling when consumed, are an ideal choice for recreational purposes. The poor performers, Ruderalis strains, have rather lower levels of THC, thus are not used for recreational purposes. However, their use in clothing, or textiles is pretty much common due to their fibrous stems. 

The Science of Marijuana 

Although humankind has cultivated cannabis for the past 5000 years, a little is known when it comes to the biochemistry of the plant. Cannabis is a complex plant comprising over more than 400 chemical entities with at least 60 being cannabinoids such as Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Nabiximols (CBN), Cannabichromene (CBC), Cannabigerol (CBG) to name a few. Even though the chemical structure of all the four compounds is somewhat similar, their pharmacological effects vary dramatically. The two best understood and researched cannabinoids are Tetrahydrocannabinol and Cannabidiol. 

During the pyrolysis of marijuana, more than 200 compounds are released that alter the functioning of the brain, which are marijuana’s main sites of action. The cannabinoid d-9-TH binds to two types of G-protein-coupled cannabinoid receptors, CB1 and CB2 predominantly expressed in the brain (Pertwee 1997). THC is lipophilic and readily crosses the blood-brain barrier. Moreover, due to its lipophilicity, THC gets stockpiled in fat and has a longer duration of half-life lasting from several days to a week. Although the cannabinoids act the same way, however, major differences lie in the generation of “high” sensation. Tetrahydrocannabinol, the main psychoactive compound gives a ‘high-sensation’ when consumed whereas Cannabidiol does not produce any such euphoric effects rather dampens the effects of THC by acting as an antagonist at cannabinoid receptors. 

Let’s rewind to the times when Marijuana was a Panacea

Marijuana has been in use for five million years for diverse purposes including medical, recreational, and spiritual. There were times when marijuana was considered the elixir of life that could cure pains without worrying about any potential side effects. Several studies documented the use of hemp at different locations in Central Asia. Hemp is the variety of cannabis that is referred to as “non-intoxicating” and contains 0.3% or less THC content (by dry weight). The oldest record of the use of hemp comes from China’s mainland. Documented evidence from 1500-1200 B.C exists that acknowledges the existence of cannabis plants among Chinese people. China has used hemp since the dawn of time in medicine, oil, rope, food, paper, and clothing. Moreover, the ancient papers were produced out of hemp. In India, the use of hemp dates back to 1000 B.C as a remedy. 

In 1100AD, al-Mayusi heralded the use of cannabis in treating Epilepsy in first-ever written proof. As another proof came into light a written text from Avicenna, the most influential medical writer and physician of the Middle Ages. “Avicenna’s Canon of Medicine” emphasizes the use of cannabis in alleviating severe headaches, gout, and edema. By the mid-twelfth century, Cannabis had transcended from Central Asia to western regions to Persia and Egypt due to early trade relations between Indians and Arabs. Some texts even pinpoint the recreational use of cannabis to release heat and feel euphoric. Cannabis was introduced to European regions such as France by Napoleon, who encountered it during his Egypt expedition. Finally, in the mid-1800s, Dr. W. B. O’Shaughnessy, a physician working in British India officially reported the therapeutic use of cannabis to the western world. From this time to the 1930s, physicians prescribed cannabis for a plethora of indications. However, the use of cannabis as therapeutics was cut short upon the implementation of the Harrison Narcotics Tax Act in the US the import, use, and possession of cannabis was regulated. With the passage of the Marihuana Tax Act of 1937, anything that was associated with the use of cannabis had become less economical and by 1970 stricter laws came into force to regulate its use. 

Once a fiber crop to the agriculturist, and a remedy of pain to physicians, now Cannabis was akin to an object of a criminal offense. 

Back to the times where it is not less than a Pariah

Medical Marijuana is a hot topic, a term with never-ending debate. Every time the topic broils, several questions arise. Is it safe to use? Is it ethical to prescribe? Is it even effective? What about legality? It is addictive? Why use it when there are plenty of other drugs in the armamentarium? However, the most intriguing of all the questions is Why is marijuana illegal? 

It is because of the unclear aftermath of the consumption of the plant. It is because of the lack of therapeutic evidence and poor understanding of the pharmacokinetics of the compounds that the plant produces. It is because of the fear that its consumption will lead a person into believing in fallacies, getting trapped into hallucinations, and eventually leading to the vicious cycle of addiction.

The legality of marijuana either for medicinal purposes or recreational has always been debatable. Several states and jurisdictions have from time to time detested the use of marijuana on their land. 

Some have quasi-legalized the use of cannabis. Others appear to be unwavering such as Afghanistan, Albania, Algeria, Andorra, Armenia, Azerbaijan, Bahamas, Bahrain, Barbados, Belarus, Benin, Bhutan, Japan, and others. Some countries such as Argentina, Australia, Barbados, Chile, Colombia, Cyprus, Israel, Italy, Jamaica, Lithuania, Luxembourg, North Macedonia, Norway, New Zealand, Peru, Portugal, Poland, Switzerland, Thailand, and Zambia have legalized the medical use of cannabis. 

Take the case of China for instance, the country has produced and consumed marijuana for thousands of years, yet today its possession and consumption are strictly prohibited and marijuana is considered dangerously a narcotic substance. However, the case is not the same for everyone out there. 

Following the footsteps of Uruguay, Canada now is the second country to fully legalize the use of marijuana. Similarly, in the United States, 33 states and the District of Columbia have green-lighted the medical use of marijuana; however, at the federal level, its use for any purpose remains prohibited.

Cannabis laws in Europe vary significantly from country to country. In some countries such as Spain, Portugal, Italy, Ireland, Slovenia, Croatia, Bulgaria, Latvia, Belgium, and the Czech Republic minor possession of marijuana is acceptable whereas in other countries including Greece, Cyprus, Hungary, Sweden, and Finland mere possession can land a person in jail. However, the grass appears to be greener in the Netherlands than other countries as there although not fully legalized, marijuana use is decriminalized. Spain is quite ok with the private use of marijuana. Germany tolerates the use of medical cannabis, and France is learning to loosen up a bit in the field. 

What does the US FDA say? 

To date, the FDA has not affirmed the use or approved marketing application of any of the cannabis products. Moreover, cannabis falls under the Scheduled substance I and is controlled under the Controlled Substances Act (CSA) attributed to the risk of high abuse. However, the agency was lenient when it came to cannabis-related/ derived products. 

The FDA, in June 2018, approved the use of Epidiolex (GW Pharmaceuticals), a purified form of the drug substance CBD for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in patients two years of age and older. The European Commission (EC) approved the marketing authorization for Epidiolex recently in September 2019, for adjunctive therapy of seizures associated with Lennox–Gastautsyndrome (LGS) or Dravet syndrome (DS), in conjunction with clobazam, for patients two years of age and older. GW Pharmaceuticals already has Sativex approved for multiple sclerosis (MS) symptoms and the treatment of severe neuropathic-related cancer pain. 

Moreover, Marinol (AbbVie) and Syndros (Insys Therapeutics) having an active ingredient dronabinol, have also been approved for treating anorexia associated with weight loss in AIDS patients. In addition to this, Cesamet (Valeant Pharmaceuticals) is another approved drug that contains nabilone, another active ingredient in cannabis.

Marijuana, Therapeutics and the Future 

Cannabis is widely used to alleviate pain such as neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Apart from pain relief, marijuana is used to treat a number of different conditions like glaucoma, hiv/aids symptoms, multiple sclerosis, muscle spasms, and Dravet syndrome. Medical marijuana is also helpful in treating nausea and vomiting associated with cancer chemotherapy, certain forms of epilepsy and Lennox-Gastaut syndrome.

Despite limited clinical evidence, a higher inclination of patients towards marijuana has caused several pharma companies and regulatory authorities to look at the medical use of marijuana in a new light. At present, there are approximately 400 either active or completed clinical trials worldwide investigating the potency and tolerability of cannabidiol (CBD) in different indications such as Agitation related to dementia, Hidradenitis suppurativa, Cancer pain, Neuropathic pain, Dermatomyositis, Systemic sclerosis, Cystic fibrosis, Systemic lupus erythematosus, Drug-resistant epilepsy, Glioblastoma, Psoriasis, Spasticity in patients with multiple sclerosis, Obstructive sleep apnea (OSA), and Tourette syndrome. 

Several pharmaceutical companies are involved in exploring the potential that the medical marijuna market offers. Companies including MedReleaf, Tetra Bio-Pharma, TO Pharmaceuticals, Corbus Pharmaceuticals, Therapix Biosciences, Arena Pharmaceuticals, Canbex Therapeutics, Daisy Pharma Opioid Venture, Tilray, One World Cannabis Ltd, One World Cannabis Ltd., Centrexion Therapeutics and several others are proactively testing different strains of marijuana for different indications. The pipeline therapies in different phases of clinical trials are Caumz (Tetra Bio-Pharma), Lenabasum (Corbus Pharmaceuticals), BX-1 (Bionorica SE), Cannabis oil (TO Pharmaceuticals), THX-110 (Therapix Biosciences), Olorinab (Arena Pharmaceuticals), VSN16R (Canbex Therapeutics), Dronabinol (Daisy Pharma Opioid Venture), TN-TC11G (Tilray), OWCP and OWC MGC cream (One World Cannabis), CNTX-6016 (Centrexion Therapeutics) and others. 

Many companies are collaborating and partnering with other companies to dominate the familiar waters of the medical marijuana market. 

Canopy Growth, one of the largest and diversified cannabis, hemp, and cannabis device companies with operations in over 12 countries, had reported a major acquisition of 72% of the stake in BioSteel Sports Nutrition, a leading producer of CBD-based sports nutrition products. The investment offered Canopy a step up to lay its base in the production, distribution, and marketing of cannabidiol (CBD) and enter the marijuana market. Last year, Canopy Growth completed the acquisition of cannabinoid-based research company Beckley Canopy Therapeutics as a part of its strategy to leverage the ever-expanding opportunity in the medical marijuana market. Spectrum Biomedical UK, which is also a biopharmaceutical arm of Canopy Growth, has hauled a new real-world evidence deal with Emerald, a real-world evidence company to take leaps in regulatory recommendations and commercialization of its medicinal cannabis products. Moreover, now BioSteel has signed Kansas City Chiefs quarterback Patrick Mahomes as the endorser of the brand. 

A frontrunner in the marijuana market, Aurora Cannabis has been on an acquisition spree to expand its business internationally. A few months back Aurora announced the acquisition of Reliva, a leader in the sale of hemp-derived CBD products in the United States for approximately USD 40 million of Aurora common shares. Although the company is under major debt due to its expansion, nevertheless 2020 might be a bright year as the company reported positive EBITDA in the past four quarters. Apharia, another heavyweight in the medical marijuana market, which entered into a Strategic Supply Agreement with Canndoc, a subsidiary of one of the largest medical cannabis producers, InterCure, also had plans to merge with Aurora, however, the deal did not prove to be materialized enough for both the companies. 

Since cannabis is illicit in several countries and is consumed widely recreationally, pharma companies have also started to file for the patents. Even then, the medical marijuana market is a bumpy ride. However, this has not deterred big pharma giants such as Teva, J&J, Merck, and Pfizer to try their luck in the ever-expanding yet risky market. To restore its title of an industry leader and an innovative pharma player, J&J’s R&D arm, JLABS Toronto accepted the first medical cannabis company, Avicanna. To maintain the legacy of investing in the cannabis market, Novartis inked a global supply and distribution agreement for medical marijuana with Tilray. Teva’s subsidiary Salomon, Levin, Elstein (S.L.E.) had signed a distribution agreement with Israeli therapeutic company Canndoc last year. This led other giants to follow the lead, however, they went for something beyond specific deals. Surprisingly, a few big pharma leaders have also registered for the cannabinoid-related clinical trials in the U.S. and Canada. AbbVie emerged to be occupying the front spot in the cannabis battlefront with a maximum number of registered patents in its name and several others under trials with Merck, Sanofi, BMS, Pfizer, and a few others following behind. 

What Lies Ahead?

The legalization of the cultivation and possession of marijuana has opened doors for pharma companies to exploit the opportunities previously untapped in the medical marijuana market. Although the evidence that cannabis is efficient and less risky than other drugs remains anecdotal, the inclination of patients towards its use and positive reviews regarding its effect is abounding. Due to this, the medical marijuana market is gaining momentum globally. Rich pipeline and the influx of companies are further accelerating the growth of the cannabis industry.  Several emerging therapies in the medical marijuana pipeline are under evaluation for different indications at the different stages of clinical trials. 

A few days back, a series of World Health Organization (WHO) recommendations on cannabis and its derivatives, the Commission on Narcotic Drugs (CND) unanimously decided to remove cannabis from Schedule IV of the 1961 Single Convention on Narcotic Drugs, which comprises a list of deadly, addictive opioids, including heroin that have little to no therapeutic benefits. The decision can be heralded as long-anticipated yet delayed. This decision might persuade some countries to change their negative stance about the medical use of cannabis, however, separated jurisdictions will still have authority to classify the use of the plant. Overall, it is clear that the move by the International organizations will help fortify the Medical marijuana market size growth.

However, The U.N. still deems cannabis a controlled substance. In its recommendation to the U.N. Commission on Narcotic Drugs, the WHO committee remarked that marijuana can have adverse effects. It can be denied that prolonged cannabis use can impair cognitive development, psychomotor performance, exacerbate schizophrenia and cause dependence. But the drug’s benefits continuously on display by numerous clinical research trials ongoing in reducing pain and nausea, as well as providing symptomatic relief in medical conditions such as anorexia, epilepsy and multiple sclerosis cannot be overlooked. Further, unlike opioids such as fentanyl, cannabis is not associated with a significant risk of death.

The decision that may appear rewarding to several pharma companies in the Medical Marijuana market, however, there exists evidences that vote against the use of cannabis as therapeutic in any form. People who smoke marijuana on regular basis can experience an epithelial injury of the trachea and major bronchi. Hallucinations, panic, increased risk of stroke, impaired pulmonary defense against infections, short-term memory problems are some of the other negative impacts of marijuana intake. If the consumption of marijuana is long-term, it can hamper the overall development of the brain, learning, and can result in the decline of the verbal ability of an individual. Moreover, there is a possibility that cannabis might have carcinogenic hydrocarbons. 

There exist snags that can act as speed breakers in the way of accelerating the marijuana market. Although cannabis might appear as a way to fight the opioid epidemic, however, its high abuse potential dampens the spirits. There is always a risk of developing marijuana use disorders. Where people are screaming about its benefits, concomitantly some studies have come up listing negative associations between marijuana use and health.

Moreover, the regulatory agencies are always keeping a watchful eye when it comes to cannabis. Stricter laws and varying ethical stances among different communities deter are some of the other market restraints. So, it becomes indispensable to take a look before the leap while investing in the medical marijuana market.