A budding future for the cannabis chemical factory

PHARMACOLOGY
June ACCN
PHARMACOLOGY

The biotechnology research facility Anandia Laboratories is situated in a three-storey building at an undisclosed location on the University of British Columbia’s sprawling, 400-hectare campus.

Established there in 2014, Anandia is the brainchild of its co-founders: organic chemist John Coleman and botanist Jonathan Page, who serve as COO and CEO, respectively. The company’s exclusive focus on the research and testing of Cannabis sativa is unique in the Canadian biotech world, but that work has now become timely as Ottawa prepares to the plant for recreational use by adults age 18 and over.

The passage of Bill C-45, the Cannabis Act, is expected by late summer 2018 and will give marijuana a sanctioned social currency that has eluded it to date. From Anandia’s perspective, the new law will provide the leg-up needed to expand research in concert with the growth of a cannabis products industry that, according to cannabis investment platform ArcView Group, will reach $23 billion in North America in just a few years.

Jonathan Page, CEO Anadia Laboratories in Vancouver

Jonathan Page, CEO Anadia Laboratories in Vancouver

Throughout modern history, the pungent plant has been revered, feared, criminalized, or condemned for being an intoxicant, as well as inciting an outright panic in the 1930s that was immortalized in the propaganda film Reefer Madness. Illegality, as well as an association with what successive governments have perceived as unsavoury counterculture elements, has left much of marijuana’s pharmacological potential largely unexplored.

“Scientists were always curious about the plant, but it was pushed out of university and government labs because of prohibition,” says Page, who sees this limitation rapidly disappearing, thanks in part to his company’s 36-strong contingent of researchers, half of whom are chemists or have chemistry training.

“To understand cannabis,” he insists, “you really have to understand its chemistry.” 

Considering cannabinoids

Recreational users consume cannabis to achieve a state of euphoria caused by the psychoactive compound THC, or tetrahydrocannabinol. The compound, which can comprise more than 25 percent of cannabis flowers by dry weight, was first isolated in 1964 in Israel at the Hebrew University Medicinal Chemistry lab of Raphael Mechoulam. According to Page, THC drives most of the plant’s pharmacology.

Medical cannabis, which became legal 17 years ago under Health Canada’s Marijuana for Medical Purposes Regulations, includes types that have high levels of THC as well as those that contain THC and cannabidiol (CBD). Both are known as cannabinoids and although similar in structure — the two molecules are isomers and produced from a common chemical precursor — CBD is not intoxicating in the same way THC is. Nevertheless, it appears to play an important role in mediating some of the physiological effects of cannabis. CBD and THC are among an estimated 115 cannabinoids, about a dozen of which are found in fairly high concentrations in the plant.

“I think cannabis is like the Ferrari of the plant world,” Page observes, “in the sense that it makes such high amounts of the cannabinoids.”

Page, who is also an adjunct professor in the UBC Department of Botany, has contributed significantly to the knowledge base of cannabis. He spent a decade as a research officer at the National Research Council’s Plant Biotechnology Institute, where he co-led the Canadian team that reported the first sequence of the cannabis genome in 2010, which is now publicly available.

“It really is the raw material for a lot of other studies,” he says, noting that the resulting map of some 30,000 genes marked a crucial step toward tackling the plant’s complex biochemistry and improving our understanding of how cannabinoids are produced.

Since August 2016, Anandia’s activities have largely focused on the testing of cannabis products from private companies licensed under Health Canada’s Access to Cannabis for Medical Purposes Regulations (ACMPR). There are currently 105 enterprises producing dried or fresh marijuana and cannabis oil in Canada, more than half of which are based in Ontario. The rules require them to assess the THC levels in their products, a service that Anandia provides, along with checking for the presence of contaminants such as heavy metals and pesticides. As legalization turns cannabis into a mainstream agricultural crop, Anandia is beginning to focus on such concerns as plant disease, insect pests, harvesting, and outdoor versus greenhouse growing environments.

Page also sees other emerging areas of study around topics such as how cannabis compounds are absorbed into the body, depending on whether they are smoked, added to a drink, eaten, or absorbed in other ways, such as sub-lingual sprays. The effects of cannabis vary widely, from the well-known euphoric “high” to impacts on short-term memory, appetite, sleep, pain, and many other physiological activities. Enthusiastic users will tell you that the proportions of these effects vary with marijuana plant strains, a claim that may be upheld by analysis of the active molecules found in different varieties.

Rewarding the receptors

The most noticeable effects of THC stem from two receptors found throughout the human body: Cannabinoid Type 1 (CB1) and Cannabinoid Type 2 (CB2). CB1 and CB2 are G-protein coupled receptors, the most abundant receptor type in the human nervous system and which plays a fundamental role in how this extensive network functions. They respond to signalling molecules produced internally, known as endogenous cannabinoids or endocannabinoids, that mediate cellular signalling in the neurons.

“I liken the endocannabinoid system to the dimmer switch of our nervous system,” Page explains. “It slows things down and reduces neuronal excitation.”

He adds that in evolutionary terms the endocannabinoid system emerged millions of years before THC and is found in a wide variety of organisms. This raises the possibility of future veterinary uses for cannabis, in addition to those focused on human health.

THC achieves its effects by binding to CB1, a receptor that is an integral part of the central nervous system.” CBD, for its part, has low affinity for this receptor and instead acts as an indirect antagonist. This means that it can block other molecules, including THC, from reaching the receptors without activating them itself. This feature may be behind CBD’s purported ability to mediate or “fine tune” the effects of THC, accentuating some aspects while dampening others.

But there are more substances than just THC and CBD to consider. In addition to dozens of other members in the cannabinoid family, there is also another group of compounds called terpenes, which are responsible for the aromatic signatures of pine trees and lavender as well as the unmistakable scent of cannabis. Anandia is currently analyzing 39 of the terpenes found in cannabis, although the plant may contain hundreds.

Such complexity characterizes the challenge of studying cannabis. Unlike typical drugs, which contain at most a handful of active ingredients, cannabis is nothing less than a chemical factory churning out interacting compounds, creating what many in the cannabis research community refer to as the “entourage effect.” Page points to terpenes, which could be modifying the activity of the cannabinoids and leading to different effects among users. But it is unclear if this means that terpenes influence how cannabinoids enter the human nervous system or whether they have an independent pharmacology that influences the effect of cannabinoids.

“We’re now entering this stage where [we recognize that] THC, CBD, the other cannabinoids, and the terpenes all play a role,” says Page. “The important question is figuring out, on the plant side, how they’re all made and, on the human side, what effects they have together as a mixture.”

The sequencing of the cannabis genome opened up a breathtaking world of research around the plant’s metabolism: how it produces, secretes, and stores cannabinoids in the fine, hair-like appendages known as trichomes. Only small amounts of these agents occur in the plant, but genomic insights could lead to techniques for enhancing their extraction. Similarly, this work could reveal the enzymes and biochemical pathways responsible for synthesizing these molecules in the first place.

In a recent article published in PLOS One, Page and his UBC collaborators describe about a dozen enzymes responsible for producing various terpene molecules. They note that the terpene-rich and varied resin in glandular trichomes of the female plant’s flowers may “influence the medicinal qualities of different cannabis strains and varieties.”

Understanding the biochemistry behind these molecules could allow for the selection and breeding of plants that have higher amounts of trace cannabinoids, potentially opening the door to fresh pharmacological discoveries. For example, if certain biosynthetic enzymes can be turned off, it would allow for the removal of certain cannabinoids or terpenes and boost the expression and production of potentially more desirable compounds.

It has been a remarkable journey for cannabis, which was used as a medicine and an intoxicant for thousands of years until 20th century prohibition turned it into a pariah. Will legalization open a Pandora’s box of abuse or allow for progress toward innovative pharmacological treatments? Page, and other researchers at labs like Anandia, are betting on the latter. 

 


Designer drug

Terry Lake, former British Columbia Minister of Health, now VP Corporate Social Responsibility for HydropothecaryDr. Terry Lake, vice-president of corporate social responsibility at Hydropothecary, a medical cannabis producer located on a 58-hectare farm in Gatineau, Que., says that chemists will be key to unlocking Cannabis sativa’s vast, largely untapped pharmacological potential.

Hydropothecary offers four main medical cannabis products to customers in oil, powder or dried-bud form. The company is continuously refining its products, developing new extraction techniques, selecting for various cannabinoid levels, and developing treatments for various medical conditions — objectives made challenging by the complexity of the plant itself.

Already cultivating 3,600 kilograms of cannabis a year in 4,180 square metres of greenhouses, Hydropothecary has plans to expand production to 120,800 square metres, equivalent to about 125 football fields. According to Lake, extraction of terpenes and cannabinoids is crucial and Health Canada permits the firm to use only non-toxic agents like supercritical CO2 for that purpose.

As a solvent, supercritical CO2 works on the varying boiling points of different cannabinoids, separating and purifying them. Once a producer has isolated a particular cannabinoid, it can be distilled for further purification. For example, a producer might combine two or three different cannabinoids in different ratios, or two or three different terpenes assembled almost like a single-molecule drug.

“You put them all together in a design that you know will have a more consistent effect on an individual than the current complex culmination of different cannabinoids and terpenes,” says Lake, who was once British Columbia’s Minister of Health with the provincial Liberals.

He foresees a great deal of pharmacological research to be undertaken in concert with other research groups as well as post-secondary institutions such as the University of Ottawa, where Hydropothecary is currently conducting cannabis studies. Other areas of research should also open up outside of pharmacology, including the study of hemp fibre for use in biofuels or additives to construction materials like cement.

“This is the future of cannabinoid-based products,” says Lake. “This is where chemists will have a really big role to play. Instead of having this intricate mix of cannabinoids and terpenes, we separate out individual cannabinoids, individual terpenes, and then design a combination, after you’ve extracted them all, to get the right combination.”