Cannabis, the leafy group of plants including marijuana and hemp, is best known for the THC that gets people high. But cannabis can contain many other chemicals. Products with the non-intoxicating compound CBD, for example, have proliferated over the past five years. Now, pharmaceutical makers, product researchers and investors are wondering, what else do the plants have to offer?
Scientists say there are at least a hundred cannabinoids, a class of organic compounds found primarily in cannabis and often abbreviated to three or four letters.
THC and CBD are abundant, and the Food and Drug Administration has already approved them in some forms. But many other compounds may have therapeutic effects, and not every plant produces every cannabinoid.
Rare and intriguing compounds like CBM and CBD-V would require years of strategic breeding of plants to create a stable and inexpensive supply chain.
Researchers say a technique known as biological synthesis, a method that involves engineering yeast, algae or bacteria to produce compounds in a fermentation tank, will allow them to quickly generate molecules without the expense and complexity of growing hemp or marijuana plants.
This technology could fundamentally alter the way cannabis products are sourced and consumed -- and possibly help unlock the plant's potential as a source of medical therapies, say scientists.
Early studies show that cannabigerol, or CBG, for example, holds promise as a treatment for neurological disorders such as Huntington's disease.
Though questions remain about the efficacy of compounds isolated from the rest of the cannabis plant, the rise of biosynthesis will allow for a purified, consistent study drug, hastening scientific understanding of each compound's potential toxicities and benefits, cannabis researchers say.
Analysts at the investment bank Raymond James predict the nascent biosynthetic cannabinoid industry will be worth $10 billion globally by 2025. This is despite potential legal complications arising from selling cannabis-related products, even if the compounds were grown in a lab.
"The marijuana plant has tremendous potential, so the more access we have to the constituents of marijuana, the more we can continue to move the science forward," says Dr. David Shurtleff, the deputy director of the National Center for Complementary and Integrative Health at the National Institutes of Health.
The recent surge of research and development at biotech companies around molecular biosynthesis has implications beyond cannabis.
A McKinsey analysis from 2020 predicted that this kind of "biomolecule" will soon have an annual global direct economic impact in the trillions of dollars, for industries ranging from agriculture to health to energy production. Some vitamins are already produced biosynthetically.
In the cannabis industry, the technology has been particularly alluring, researchers and entrepreneurs say, due to the breadth of potentially therapeutic compounds, the dearth of existing research on those compounds, and the difficulty and expense of producing the compounds through either chemical synthesis or conventional plant breeding.
Here's how it works: First, scientists identify the enzymes in a cannabis plant that contain the chemical blueprint to produce the desired compound. Next, they sequence those enzymes to find their DNA, and then insert the genes into a microorganism like yeast, using gene-editing technology such as Crispr or a more traditional technique called homologous recombination.
From there, the yeast is fed oxygen, sugar and nutrients, and mixed with water in a fermentation tank, in a process similar to brewing beer. Within a few days, the yeast begins to secrete the cannabinoid. Finally, scientists add an organic solvent like oil to the fermentation tank, attracting the newly produced compounds and leaving a cannabinoid solution that can be further manipulated.
The whole process takes about a week, compared with up to six months to grow and harvest a single plant.
It is cheaper, more accessible and, without the need for entire fields of cannabis and energy-intensive extraction processes, more sustainable, says UCLA Cannabis Research Initiative founder Dr. Jeff Chen.
"This platform is a game-changer for research," he says. "It enables the study of what the individual cannabinoids are doing, which is very difficult if not impossible to tease apart when you're working with the plant material itself, or plant extracts."
Cannabinoid biosynthesis companies are generally not interested in THC because state marijuana markets are so tightly regulated.
Instead, they are looking at mysterious compounds that few humans have tried, with names like CBE and CBC. Each cannabinoid seems to have a unique effect.
Where THC has a propensity to induce hunger, also known as "the munchies," THC-V seems to take away appetite, according to early research. Other cannabinoids seem to influence everything from blood pressure to bone density, according to research done mostly in mice.
Cannabinoids "may have therapeutic potential in almost all diseases affecting humans," wrote NIH researchers Pál Pacher and George Kunos in 2013, citing early evidence of the comprehensive nature of how various compounds from the cannabis plant affect the body.
If that is true, biosynthesis may be the technology that allows researchers to puzzle out which compounds help, which hurt, and how they can be combined to treat various ailments.
Clinical research involving cannabis in the U.S. remains stymied by federal restrictions.
It is very difficult to gain permission to do trials in human beings, and it has been even more difficult to access a variety of cannabinoids from the University of Mississippi, home to the country's sole legal source of pot for research.
More thorough research on cannabis and cannabinoids tends to come from other countries, such as Israel and the Netherlands.
While it isn't yet clear how regulatory agencies would handle the legal status of biosynthetic cannabinoids, researchers are optimistic.
So far, products containing biosynthetic cannabinoids are few and far between. The skin care brand High Beauty sells an acne treatment that contains biosynthetic CBG, which early research suggests has anti-inflammatory properties, at Macy's.
The CBG is made by the Berkeley, California-based biotechnology company Lygos.
Other companies working on biosynthetic cannabinoids include the Vancouver, Canada-based Willow Biosciences, which is partnered with Curia Inc., and the Boston-based Ginkgo Bioworks, a synthetic biology company which is partnered with the Canadian cannabis producer Cronos Group.
Back in 2014, when Lygos bioengineer Jason Poulos started working with biosynthetic cannabinoids, friends joked that he was a stoner; now, he is hoping to mass produce cannabinoids for some of the biggest corporations and research institutions in the world.
"We want to be the supplier of these ingredients to everybody," Dr. Poulos says.
To be sure, some of these compounds may have negative effects at certain doses.
"It's a drug that is metabolized, and if it is overdone it will tax on your liver," Dr. Poulos says. "We should expect all the cannabinoids to have a similar toxicity window to CBD."
And for many cannabis researchers, activists and businesspeople, the quest to manufacture, understand and sell single-cannabinoid products is a waste of time.
No isolated cannabinoid, they say, will ever be able to replicate the benefit of the entire plant, with its mix of major and minor compounds -- a theory known as "the entourage effect."
"I'm still a believer that the whole plant is more therapeutically beneficial than any one cannabinoid by itself," says Dr. Malik Burnett, an addiction medicine physician at the University of Maryland Medical Center, who has experience in cannabis business and policy.
"The concept of using biosynthesis to increase production of lesser cannabinoids is not a scientific breakthrough, but there is a significant amount of potential to create products that can be marketed, and can convince people that they need to use them."