The word cannabinoid refers to every chemical substance, regardless of structure or origin, that joins the cannabinoid receptors of the body and brain and that have similar effects to those produced by the Cannabis Sativa plant.
Cannabinoids are compounds found in cannabis. Research has found that the cannabis plant produces between 80 and 100 cannabinoids and about 300 non-cannabinoid chemicals. The two main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The most commonly known of the two is delta-9-tetrahydrocannabinol (THC), (Delta9-THC or Delta8-THC), the primary psychoactive compound in cannabis. The main difference between the two cannabinoids is that THC has strong psychoactive effects, meaning it makes a person ‘high’, whereas CBD is thought to have an anti-psychoactive effect that controls or moderates the ‘high’ caused by the THC.
There are at least 144 different cannabinoids isolated from cannabis, exhibiting varied effects. The three types of cannabinoids that people use are recreational, medicinal and synthetic. Cannabinoids are organic chemical compounds found not just in the oft recognized plant Cannabis sativa, but also in the human neural networks. In the brain and spinal cord they act as pain relieving molecules that serve to diminish incoming pain signals and provide relief from long term discomfort. This particular property makes them lucrative for pain management. CBD is also thought to reduce some of the other negative effects that people can experience from THC, such as anxiety. “are poorly served by current drugs. Cannabinoids also promise to offer breakthrough therapies for these debilitating Neurological and psychological conditions.
Research suggests cannabinoids might Reduce anxiety; Reduce inflammation and relieve pain; Control nausea and vomiting caused by chemotherapy; Kill cancer cells and slow tumor growth; Relax tight muscles in people with multiple sclerosis; and Stimulate appetite and improve weight gain in people with cancer and AIDS. The recent relaxation of cannabis legislation in Canada, many parts of the US, and several European countries has attracted a lot of investment. Across the Atlantic, the Montreal-based company Hyasynth Biologicals also aims to make cannabinoids using synthetic biology.
Cannabinoids are traditionally extracted from cannabis plants. But growing cannabis is neither cheap nor environmentally friendly. In 2016, 1% of the total electricity consumption in the US was used to cultivate cannabis. “While you can grow your plants at home, scaling up is expensive and you have to worry about pests and increased carbon output,” Hyasynth founder Kevin Chen said. Therefore there’s a growing interest in producing them using engineered microbes.
Synthetic cannabinoids are manufactured artificially. They encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids (cannabimimetics) including the aminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides as well as eicosanoids related to endocannabinoids
Synthetic biology to aid in efficient production of cannabinoids
Using synthetic biology tools, scientists can harness the power of fermentation to produce cannabinoids. To do this, they transfer genes from cannabis plants into yeast or bacteria to make them produce only the desired cannabinoid compound. “It is very difficult to get rid of THC in CBD isolates from plants. When you engineer a microorganism, you can select what your final product should be,” Nehtaji Gallage Danish startup Octarine Bio explained.
Microbial fermentation has recently emerged as a low-cost and environmentally friendly alternative. In 2019, researchers from UC Berkeley in the US were the first to produce THC and CBD in yeast, opening the doors to cannabinoid fermentation. “Our efficient [production] approach significantly reduces land and water use, decreases energy requirements and eliminates the need for fertilizers and pesticides,” said Eric Steen, CEO of Berkeley-based Lygos.
This production approach gives a clean final product, allows the production of rare cannabinoid compounds in high scale, and even lets scientists come up with new cannabinoid compounds with improved pharmacological properties. “We believe the benefits of a broader class of cannabinoids are just starting to be understood and realized,” Steen noted.
What is the best organism to produce cannabinoids? Each company makes a different choice. Yeast is a popular host, given the expertise in growing it and performing genetic manipulations. “Host matters!” said Gallage. “Both for strain development and scale-up, production platforms have to be highly amenable. That’s why we are happy with yeast”.
Roy Lipski, CEO of the San Diego-based startup Creo, favors bacterial production. The key reason is that it avoids the complex IP landscape of cannabinoid production in yeast, which is dominated by the US-based biotechnology company Amyris. Frankfurt-based Farmako is also following this avenue, working with the bacterium that is used to make tequila to produce hundreds of different cannabinoid compounds.
For its part, the Canadian biotech Algae-C is exploiting the benefits of producing cannabinoids in algae. “Algae can be grown in virtually any environment; they can use waste water and CO2 as a nutrient source; they are naturally rich in many of the precursors we require for high-value products; and, lastly, any leftover biomass from our process can be used as a high value protein source for the aquaculture industry,” Mather Carscallen, CEO of the company, told me. As for any other fermentation processes, the biggest bioproduction challenge seems to be efficient scale-up. “The biggest challenge in producing at a commercial scale is having the expertise and the scalable technology to deliver the specific product at the right price in the required timeframe,” Steen noted.
“[There are] so many different problems to solve: toxicity, inhibition, secretion, pathway balancing, different metabolic states in different growth stages, fermentation optimization, downstream processing…” Lipski explained. “From my experience, it’s the boring stuff that kills companies.” As Chen noted, there is the added challenge that there are no legally established practices on how to produce the compounds, especially in the case of pharmaceutical grade cannabinoids.
Soldiers prohibited in use of Cannabinoid
In 2018, Soldiers from Fort Bragg, and Marines from Camp Lejeune, have reported harmful medical effects believed to be caused by some vaping cartridges that are reported to contain cannabidiol (CBD oil). “Adverse health effects in Active Duty patients ranged from headache, nausea, vomiting, palpitations, dilated pupils and dizziness to confusion, disorientation, agitation and seizures, all of which are consistent with synthetic cannabinoids.”
“Although pure CBD oil has not yet been associated with adverse health effects, CBD vape oils most likely contain synthetic cannabinoids, concentrated tetrahydrocannabinol (THC) and/or other hazardous compounds in addition to, or in place of, CBD oil,” the warning reads. What makes CBD so appealing, especially for service members, is that it doesn’t get the user high. While most recreational marijuana users seek out this effect, many patients would rather avoid it. This has allowed CBD to take the main stage and to sidestep many of the social, legal, and political hurdles that have delayed the spread of medical cannabis.
The Department of Defense has a zero tolerance policy for the illegal or improper use of drugs by service members, which includes CBD oil. “It is common to see advertisements where CBD is listed as a treatment for many conditions, when in fact, there are very limited human studies,” said Dr. Erin Karschner, Armed Forces Medical Examiner System forensic toxicologist. “Researchers are also unsure of how CBD interacts with other medications that people may be taking and if adverse effects may occur after using CBD, particularly when CBD products are used for long periods of time.”
On December 20, 2018, the President signed into law the Agriculture Improvement Act of 2018, known as the 2018 Farm Bill, which defined hemp as cannabis containing no more than 0.3 percent THC by dry weight and legalized the production of hemp and the sale of its products. Cannabis containing more than 0.3 percent THC is still considered a Schedule I controlled substance. Prior to December 2018, hemp was a Schedule I controlled substance under the Controlled Substances Act of 1970.
“Even if CBD extract contains 0.3 percent or less of THC, service members put themselves at risk if they consume these products without being prescribed an [Food and Drug Administraion]-approved product by a medical professional,” said Air Force Capt. Marcus Walker, 436th Airlift Wing Assistant Staff Judge Advocate. “There are very few products that have been approved by the FDA, so the vast majority of CBD products we see on the market on a day to day basis remain federally illegal.”
There are no FDA regulations in place for CBD products and there is no mandated oversight or quality control for these products. “This means products may contain CBD in lower or higher amounts than what is on the product label or they may contain additional unexpected active ingredients, heavy metals, or pesticides,” said Karschner. “Products may contain more THC than expected and have the potential to cause a positive urine drug test and intoxication, which may affect military readiness. These products may also be adulterated with other active components, like synthetic cannabinoids, which may lead to intoxication and accidents.”
Even while hemp has been legalized in the U.S., the use of hemp and CBD products are still prohibited for use by service members. “The fact remains that CBD products remain heavily unregulated throughout the United States,” said Walker. “This means we don’t actually know what is and isn’t in these products.”
“Bottom line, even if legal on the state level, and even if the label of the CBD product states there is no THC content, CBD use remains prohibited for military members,” said Walker. “Current Air Force policy prohibits all marijuana derivatives, including hemp. If they use it, they risk a positive result for THC on a drug test, and as a result, they could ultimately face administrative or criminal action.”
The global cannabinoid market is now estimated to be multi-billion dollar industry. The global cannabis extract market size was valued at USD 7.3 billion in 2019 and is anticipated to register a CAGR of 16.6% over the forecast period 2020-2027. The key factors driving this market is the increasing adoption of medical marijuana for the treatment of chronic diseases like arthritis, Alzheimer’s, and cancer along with mental disorders such as depression, anxiety, and epilepsy. Another factor anticipated to propel the market growth is the rising legalization of medical cannabis in various countries that enables easy access to the patients.
Besides their recreational usage, cannabinoids find widespread use in the healthcare industry. Here, they act as pain relievers and mood stabilizers, and being organic the acceptance of this therapy is good among patients. Accordingly, few conditions they are used for are chronic pain of any origin, side effects such as vomiting and nausea associated with chemotherapy, anorexia, weight loss, IBS, spasticity, epilepsy, and a variety of psychiatric conditions.
Cannabis oil and tinctures are generally used for treatment of various conditions like psychological disorders, nausea, and cancer. In terms of legality, laws pertaining to extracts are quite lenient due to non-psychoactive properties of Cannabidiol (CBD) oils compared to other products such as buds and resins. Due to their easy consumption in vapor or in the form of gummies and slowly diminishing social stigma of smoking cannabis buds, these products are anticipated to gain momentum and the increase in demand in the forthcoming years.
A large number of people across the world are suffering from chronic conditions. Survivors of cancer often suffer from debilitating pain due to the disease itself or the therapy given. An increased requirement of pain management therapy due to growing number of cases of post cancer chronic pain is anticipated to drive the cannabinoid drugs market in the near future. Psychotherapy is demanding cannabinoid intervention on an increased scale given the benefits it has for patients with hyperactive disorders. Since psychiatric diagnosis has become reasonably accurate with time, this will upscale demand for cannabinoid drugs.
Due to strict regulations for THC, adoption of the full spectrum of cannabinoid isolates in a number of countries is low. Physicians are also prescribing the parts of medical marijuana owing to its entourage effect. But rising pressure from the medical community on legal bodies to legalize cannabis products is anticipated to positively influence the demand for full-spectrum extracts in the future.
Since 2012 cannabis usage has been legalized in the United States, with eleven states including the Columbia having taken steps in this direction. Moreover, a growing geriatric population in this region is expected to raise the prevalence of chronic conditions. The number of people aged 60 years and above will double till 2060 in the United States, according to the World Health Organization. Hence, North America is anticipated to be dominant in the global cannabinoid drugs market.
In 2019, Europe accounted for the second largest revenue share of the cannabinoid drugs market. Italy is regarded as the fourth largest consumer of concentrates of cannabis. However, stringent rules and regulations surrounding the sale and cultivation of cannabis plants may limit the overall growth of the cannabinoid drugs market in Europe. The Asia Pacific region (APAC) is yet to recognize cannabis as a potential drug therapy regime and hence the cannabinoid drugs market has little foothold here. The same holds true for areas of Africa and the Middle East. Thus, the cannabinoid drugs market finds acceptance only in the developed regions currently, though increased westernization of the developing world might fuel growth in these regions.
The number of players in the cannabinoid drug market is few, making the market scenario concentrated. These manufactures are engaged in improving infrastructure and funding innovation to help increase operational footprint. This is anticipated to help increase production to cater to increasing demands for cannabinoid drugs globally. There are now more than 30 companies developing biological methods for producing cannabinoids, though Lipski sees the industry evolving towards just a low number of big companies, with smaller businesses becoming part of the bigger players.
Aphria Inc.; Canopy Growth Corporation; Aurora Cannabis; Maricann Inc.; Organigram Holdings Inc.; The Cronos Group; and TilrayTikun Olam, Ltd. are the major players that are operating in the cannabis market. These players have established strategic partnerships with extractors and other parties in the value chain to significantly strengthen their market position. Canopy Growth Corporation, for instance, partnered with Danish Cannabis ApS and marked a new joint venture called Spectrum Denmark ApS. This venture aims at strengthening the foothold of the company in the European market.
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