There are more than 100 cannabinoids you’ve probably never heard of before. While the science is embryonic, clinical research is key to unlocking the full potential of medical cannabis.
THC and CBD need no introduction, but they’re just the beginning of the cannabinoid story.
Actually, it’s more like a book: Cannabis plants have more than 100 other cannabinoids, not to mention a bustling stew of terpenes and other biologically active molecules that are not well-known or well-understood.
THC’s interaction with the human endocannabinoid has been observed and established, and a growing body of research supports the efficacy of CBD in treating epilepsy, insomnia, and addiction, but the rest of the exotic, or minor, cannabinoids remain squarely in a clinical gray area.
That hasn’t stopped the private sector from moving ahead with new products. As the cannabis and hemp industries mature in Colorado, California, and other states with legal cannabis, manufacturers are starting to dabble in products featuring such cannabinoids as CBG, CBN, and THCv, to name a few.
In Colorado alone, Planetarie is focusing on CBDa, Mary’s Medicinals sells a CBN-CBD extract, and CBDistillery introduced a CBD-CBG tincture in May 2020.
“We had a really, really good response on the initial launch of our first CBG products,” says Andy Papilion, the Sheridan, Colorado-based co-founder and chief
product officer of Balanced Health Botanicals, CBDistillery’s parent company.
In a cannabis plant, CBG is a non-psychoactive chemical precursor to a number of other cannabinoids. “CBG is known as the mother cannabinoid,” says Papilion. “People think of it as the stem cell cannabinoid. CBG, as the hemp plant matures, differentiates into cannabinoids such as CBD, CBC, and THC.”
Studies have found CBG prevents the reuptake of body-produced endocannabinoids, possibly reducing stress and anxiety while fostering a good mood. Papillon says some customers have reported more efficacy with a bottle with a balance of CBD and CBG than they experience with CBD alone. CBG’s observed “antibacterial and antifungal properties” make it a natural for inclusion in topical products. “We will be exploring that as well in the future,” he adds.
Being able to source high volumes of extracts and isolates is key for a commercial-scale rollout. “As the industry has scaled and new technology becomes available, CBG is the next cannabinoid behind CBD that’s become available at a large scale to us,” says Papilion. “There’s been a good amount of work done by hemp breeders who are basically able to get high levels of CBG while still saying THC-compliant.”
CBG won’t be the last minor cannabinoid in a CBDistillery-branded product, he adds. CBN could be next. First isolated in 1896, CBN is a product of the oxidization of THC and CBD. “In its naturally occurring state, as THC is exposed to oxygen or heat, it converts to CBN over time,” says Papilion.
Like CBD and CBG, it’s not psychoactive, but it bonds to the CB1 receptor in the human endocannabinoid system, only at a much lower rate than THC. A 2011 study found that THC and CBN can create a more relaxing effect than THC on its own, and other research has indicated CBN also has anti-inflammatory and anti-convulsatory effects.
Papillon says cannabinoids don’t necessarily have an effect when isolated, or else the effect is muted. He offers an analogy: “Think of an orchestra or a four-piece band, where the guitar — CBD — sounds really good on its own, but when you introduce the bass, keyboard, and dums, you end up with a musical feast that sounds much better than a component does on its own.”
“I think these minor cannabinoids will be the future of the industry,” he adds. “We’ll continue to see more of them created at scale, and we’ll continue to innovate in our product lineup.”
Shifting paradigms
Dr. Alan Shackelford of Amarimed of Colorado in Denver has conducted about 25,000 medical cannabis consultations in the last 11 years. This kind of experience fostered a notably broad view of the medical efficacy of cannabinoids.
Shackelford says there are “about 140 unique cannabinoids” in a cannabis plant; he cites “tantalizing” anecdotal evidence of the efficacy of various minor cannabinoids like CBG, THCv, and CBDv. “Inflammatory response can be modulated with some of these minor cannabinoids, and we know that THC, CBD, and the melange — the whole bunch of [cannabinoids] that are in the soup, if you will, after doing an extraction of a plant — are present, we know collectively they can have very powerful anti-inflammatory, even anti-infective effects and disease-modulating effects, but we really don’t know a great deal about the effect of these individual minor cannabinoids.”
And that’s the big caveat in the fine print of essentially every cannabinoid study. “More research is needed,” says Shackelford. “We know next to nothing about them. . . . We simply don’t know enough to be able to make knowledgeable therapeutic recommendations to patients, and people themselves don’t know enough, because there isn’t enough information to make knowledgeable choices.”
That’s starting to change, as companies large and small look to unlock the potential of cannabinoids within the existing pharmaceutical framework. Shackelford himself has partnered with Israel-based Dr. Avi Livnat found a startup, Shackelford Pharma. “It’s about to embark on a whole series of basic science and pre-clinical and clinical studies of cannabis and cannabinoids in Israel and Canada,” says Shackelford. “We’re going to start looking at pharmacokinetics and take it from there.”
Established in 2018, the company will explore the efficacy of cannabinoids on neurological, gastrointestinal, gynecological, pulmonary, and ophthalmological disorders in the longer term. “We have a very full schedule,” says Shackelford. “There are a lot of medical conditions that don’t respond well to conventional treatment.”
Shackelford says there’s a reason this research is being conducted outside the U.S. “The biggest difference is regulatory openness to approving projects,” he explains. “The U.S. is still mired in the archaic 1970s model of skepticism about cannabis, but in other countries there is a great deal more openness to approving not only basic science but also clinical trials.”
In Israel, for example, David Meiri’s research on isolated cannabinoids at the Technion in Haifa — “the MIT of Israel,” says Shackelford, or else “MIT is the Technion of the United States” — is increasingly tied to a broader network of scientists in progressive countries, and the U.S isn’t one of them.
He points to what he terms as excessive federal regulations for cannabis researchers in the U.S. that require a 750-pound safe (anything smaller must be bolted to the floor or wall) or else a vault surrounded by eight inches of reinforced concrete.
Shackelford says not only are Israel and Canada more open to cannabis research than the U.S., but Uruguay, Brazil, Colombia, New Zealand, Australia, the U.K., Germany, the Czech Republic, France, and Denmark likewise have less restrictive regulations. While many of the big breakthroughs to date have occurred in Israel, he notes, “Canada has the potential to be one of the most important centers of cannabinoid research in the world, and I suspect that’s going to happen very soon.”
Rigorous research “will change the entire field,” says Shackelford. “With more openness obviously comes a bit more scrutiny as well — and that’s not a bad thing.”
The industry needs to adhere to rigorous standards to advance, he adds. “If it does have that rigor, doctors will be much more likely to embrace it and recommend it for patients. It will change the entire field.I’ve been calling it cannabinoid medicine a long time, 10 years probably, and I think there will in fact be a legitimate field . . . to absolutely change how we practice medicine and improve people’s lives beyond anything that we can perceive right now.”
Because cannabis is notably safe in comparison with many medicines, the science has to a degree advanced through experimentation by the patients themselves. “You can’t really do a trial-and-error with opiates and opioids, because there is the potential for overdose, and that’s true for many different natural or plant-derived products,” says Shackelford. “Cannabis fortunately happens to be one where the side effects may be unpleasant, but they have never been known to be fatal.”
Shackelford says one of his patients had an outsized impact on public opinion of medical cannabis. He credits the late Charlotte Figi and her family for advancing the medical cause in the U.S. Figi suffered hundreds of seizures a week due to Dravet syndrome, then found relief in the form of a high-CBD, low-THC cannabis strain now known as Charlotte’s Web.
“Their willingness to go down a road that was not easy by any means, but it was necessary,” says Shackelford. “That changed the world in ways we don’t fully appreciate yet.”
The ever-broadening acceptance of cannabinoids as therapeutics is a sign of that change. Earlier in 2020, Shackelford testified at a hearing concerning the legalization of medical cannabis in Alabama of all places. “Human suffering knows no ideology, no political bents, no religion or race or anything else. If we can alleviate suffering — and everybody is going to have something — then we have an obligation to embrace that.”
A nascent movement
The founder of NuVue Pharma in Pueblo, Dr. Malik Hasan helped launch the Institute of Cannabis Research at Colorado State University-Pueblo in 2016 and serves on its governing board.
In Hasan’s opinion, comprehensive cannabis research needs to go beyond cannabinoids and also explore terpenes and other compounds. “Cannabis has about 545 active biological molecules,” he notes. “Sometimes, one molecule is not enough, you need a combination of molecules, but THC seems to be the most important one.” Hasan says he sees THC as “a catalyst, or activator, of the [other] molecules” in cannabis’ medical applications.
Hasan says there’s observational evidence for the efficacy of cannabis treating epilepsy, PTSD, chronic pain, and many other conditions, “but what you don’t know is which particular molecule is effective with which condition, or which combination of molecules is effective with which condition,” he observes. “And what dose should be given, how often should they be given, and what are the side effects? The basic 101 of the drug.”
He adds, “There isn’t a case of death from marijuana, but that doesn’t mean it doesn’t have significant side effects. A psychotic breakdown is not a picnic in the park.”
Furthering the body of research calls for extraction and isolation of the roughly 140 cannabinoids and the other 400-plus active molecules from consistently bred and grown cannabis plants. “That is a very big project. I don’t think I have the means to do it. I’m hoping it becomes legal,” says Hasan. “Honestly, Colorado State University doesn’t have the capability, either.”
It’s not just resources. It’s resources and the politics that surround a federally controlled substance. “Everybody’s afraid to do the human studies, even though it is legal in this state, because they don’t want to be at odds with the federal government,” says Hasan, noting that Colorado State University-Pueblo receives a good deal of federal funding. “If they are considered a rogue university, the federal grants would stop, and 70 percent of their budget comes from federal grants.”
Hasan says the unavoidable roadblock is federal funding, or lack thereof. “Other than cannabis, everything you see around you originated or started with the federal government. For example, Google was funded by the federal government. Apple was funded by the federal government. Cisco was funded by the federal government. Go through the list. It’s an endless list.”
As an example, he points to Tesla Motors. “They’re not interested in Tesla as a car,” he notes. Rather, it’s about better storage for the renewables-powered grid of the future. “That is why Tesla has received $1.5 billion from the federal government. They have no interest in developing a car; they have interest in developing an energy storage battery.”
“The federal government is the biggest venture capitalist in the world. For a private venture capitalist, if you have two successful projects out of 10, you’re considered a very smart venture capitalist. The government venture capitalist is successful 80 to 90 percent of the time.”
While critics decry corporate socialism, Hasan highlights the U.S. government’s track record, and says it’s about expertise and intellectual heft as much as it is about money. “If the government doesn’t do these things, you won’t have Google, you won’t have the Internet, you won’t have GPS,” he notes.
Cannabis research needs the same level of fiscal support, he argues, as the possible number of combinations of 540 different biological compounds might as well be as infinity from a research perspective. “It’s the curse of the plenty,” says Hasan. “When penicillin was discovered, it had only one biologically active molecule.”
Quinine has a similar backstory. “The shamans were using it, and it was effective against malaria so [Western doctors and missionaries in Africa] decided to use it themselves,” he says. “It also had just one biologically active molecule, so it was easy to take it and use it for that prime purpose.”
But the clinical overload stemming from cannabis will require countless hours from scientists all over the world in order to unlock its full medical potential. “You’re not going to have someone from the heavens shouting, ‘This is what it is,'” says Hasan. “You really have to find out for yourself.”
Eric Peterson is editor of CompanyWeek and the Cannabis Manufacturing Report. Reach him at rambleusa@gmail.com.
Cover photo by Pavel Ševela / Wikimedia Commons.
