Five years ago, few consumers or food producers had ever heard of cannabidiol (CBD), unless they also happened to be cannabis afficionados or medical cannabis consumers. Yet in the past three years, since hemp-based CBD became legal across all 50 U.S. states and cannabis was legalized federally in Canada, consumers had little time to learn about CBD before it was all around them. Due both to its clinically proven effects (which include anti-seizure and anti-inflammatory properties) and to aggressive marketing by CBD manufacturers, the cannabinoid has become known as a wellness buzz molecule, available everywhere from pharmacies to vegan smoothie shops to gas stations. Yet, the cannabis plant—which refers both to low-tetrahydrocannabinol (THC) hemp and higher-THC cultivars for medical or recreational use—has far more cannabinoids than the upstart CBD and best-known THC. The plant may produce as many as 110 individual cannabinoids, along with other potentially therapeutic compounds such as terpenes and flavonoids.
Since state-level legalization began in Colorado in 2015, researchers have been rushing to catch up on the 100 years of research that cannabis prohibition prevented them from conducting. As the cannabis industry has watched CBD’s rapid ascent toward multi-billion-dollar annual sales, everyone has been trying to determine which cannabinoids could be central to the next wellness bonanza. The two rare cannabinoids that infused-foods producers and consumers are likeliest to encounter today, outside of THC and CBD, are cannabigerol (CBG) and cannabinol (CBN).
“There are already various products on the market that have CBN [and CBG] present in various doses,” says independent cannabinoid researcher Winston Peki, who operates cannabis research-and-review site herbonaut.com. “Most of these products are a combination of CBD and CBN and are marketed as products for sleep [or] stress relief—not that different than CBD products, which are marketed for the same.”
For CBG in particular, it’s important for people to hear that no one is experienced with high concentrations of CBG because, historically, it hasn’t existed.—Kent Vrana, PhD
Unlike THC and CBD, which have usually been noticeably a part of cannabis as it has been consumed for millennia, CBG and CBN have, until the last few years, occurred only in trace amounts in the cannabis plant. CBG occurs as a precursor cannabinoid, which the plant produces and immediately turns into THC and CBD, leaving little or no CBG behind. CBN is different in that it occurs in trace amounts in fresh cannabis but can also occur as the product of exposing THC to sunlight or ultraviolet light.
“CBG and CBN usually occur in much smaller concentrations in modern cannabis that is used medicinally or used to manufacture cannabis products,” says Scott Churchill, VP of scientific development for Framingham, Mass.-based cannabis testing firm MCR Labs.
The fact that CBG and CBN are so naturally rare makes them significantly more expensive to manufacture than “native” cannabinoids THC and CBD, says Bryan Quoc Le, PhD, an independent food scientist and cannabis researcher in Washington. “We’re still learning more about them,” he says. “We are still uncertain of their safety profiles in humans, and more research is needed to uncover potential side effects from long-term consumption. But as researchers begin to unravel the potential benefits of rare cannabinoids, as well as develop technologies to manufacture them at lower cost, we may be seeing a higher prevalence of them in cannabis-infused foods down the road.”
The Research into Rare Cannabinoids
Dr. Le also stresses that cannabinoids are chronically understudied, and, given what we’ve learned so far about the therapeutic potential of CBD and THC, “rare cannabinoids are a potential gold mine of new pharmaceuticals, but we are still just learning how to produce them at the scale needed to do adequate clinical research on them.”
To begin manufacturing products containing CBG and CBN, researchers first must breed plants containing higher concentrations of those molecules, though as Mike Hennesy, VP of Innovation for edibles producer Wana Brands in Boulder, Colo., stresses, companies like his are looking beyond plant-based cannabinoids and into the use of yeast or bacteria to produce chemically identical cannabinoids out of raw ingredients.
Even as researchers study technologies that might help replace the plant itself, Hennesy’s company has long been looking past THC and CBD toward other cannabinoids, as well as terpenes, believed to have pharmacological effects.
Hennesy is optimistic: His company plans to develop products with these molecules as well as other rare cannabinoids, such as cannabichromene (CBC) and tetrahydrocannabivarin (THC-V). Wana Brands is preparing to launch a sleep-aid gummy product in Colorado that is infused with CBD, CBN, CBG, a low dose of THC, melatonin, and 30 terpenes. “We believe this market for these [minor cannabinoids] will continue to grow with increasing consumer demand for them, as knowledge and information about them continues to spread,” Hennesy says.
For food producers considering bringing minor cannabinoids into their recipes, Hennesy says there’s little learning curve, since most phytocannabinoids have similar chemical structures and tend to behave in similar ways. Accordingly, he adds that rare cannabinoids don’t require complete recipe overhauls to introduce them to a product. They can have different flavors, however, with some more and others less agreeable.
What We Know
Yet, like Dr. Le, Hennesy acknowledges that CBG and CBN are still little understood. There is a body of anecdotal evidence suggesting that CBN helps with sleep, supported by “only one study […] conducted in 1975 with just five participants,” Hennesy says, “so the jury is out on whether CBN truly deserves to be known as ‘the sleepy cannabinoid.’ That said, new research does come out nearly every month, increasing our body of knowledge about these new minor cannabinoids.”
What we know for sure about CBN, according to Dr. Le, is that, as a generally non-psychoactive compound, CBN has about 10% of the activity of THC and is metabolized more slowly than THC. Due to the difference in structure, CBN and other rare cannabinoids interact with the body’s endocannabinoid system differently from THC. Both Peki and Dr. Le say that CBN is believed to have a more sedative effect than CBD.
Kent Vrana, PhD, is the Elliot S. Vesell Professor and Chair of Penn State College of Medicine’s department of pharmacology. He says evidence is slim for the effects of CBG, but that the cannabinoid appears, in theory, to have activity that falls somewhere between CBD and THC, both in terms of its potency (how much it takes to have an effect) and the effects themselves.
In February 2021, Dr. Vrana and colleagues published “The Pharmacological Case for Cannabigerol” in the Journal of Pharmacology and Experimental Therapeutics. That paper acknowledged previously suggested therapeutic potential for CBG in treating neurologic disorders and inflammatory bowel disease, but it also noted (with uneasiness) the growing commercial interest in CBG as a wellness tool.
Dr. Vrana and his colleagues found that CBG had somewhat of an effect on receptors of the endocannabinoid system. “Looking at CB1, the receptor that gets you high,” he says, “THC is partially active, but CBD is not. CBG is someplace in between, both in terms of its strength at that site, and what it does when it’s bound to that site. It’s likely to cause a very mild high, and it all depends on how much of it you can get in the body.” He notes that the same thing occurs with receptor CB2, believed to be anti-inflammatory and the site where CBD has the most effect: there, CBG remains a partial stimulant.
Evidence outside the endocannabinoid system alarmed Dr. Vrana, however. “What we got interested in was based on one of its reported activities in a non-cannabinoid receptor called Alpha-2,” he says. “That receptor, 40 years ago, was a target for hypertension. So, my colleagues administered CBG to mice and we saw a dramatic drop in blood pressure. For me, that strikes me as a potential side effect that nobody’s thinking about.”
The paper predicts that, due to CBG’s effects on Alpha-2, pure or highly enriched CBG will have unintended consequences that will also be unexpected because they’ll come from outside the endocannabinoid system. “[CBG is] not just working on CB1 or CB2,” he says. “It’s potentially working on a dozen other receptors, all of which have differing activities, and no one’s ever taken CBG at high concentrations,” including, he notes, in the studies, which were conducted on mice. He says there is no data at all regarding humans and CBG, let alone CBG in a concentrated form.
For Dr. Vrana, that concentration is the very essence of the discussion about CBG, which under normal conditions appears in tiny amounts. “For CBG in particular, it’s important for people to hear that no one is experienced with high concentrations of CBG, because, historically, it hasn’t existed. Under normal conditions, I don’t believe [consumers feel the effects of CBG]. Cannabis doesn’t express a ton of this. The fact that the plant makes it en route to making THC and CBD does not make it ‘all natural.’ There’s also the misrepresentation of it as ‘the mother of all cannabinoids,’ which gives you the impression if you eat it, your body will convert that into THC and CBD. That’s simply not the case.”
Churchill concurs, saying, “There simply aren’t a large enough number of studies, specifically clinical studies in humans, for us to draw any firm conclusions about the effects of CBN and CBG. The studies that do exist rarely control for these cannabinoids in particular. That may be changing, but for now, any claims about effects are based on speculation or anecdotal evidence.”
Long-Term Research Still Needed
At the same time, Churchill also acknowledges there hasn’t been any proof that CBN or CBG are unsafe for consumption either orally or by inhalation. “It’s hard to ground their safety in science at this time, but the lack of reports of negative effects, even with cannabis use becoming increasingly common, is encouraging.” Because THC, CBD, and CBN all derive from CBG, and they share a similar chemical structure, Churchill thinks it’s likely that “CBN and CBG are no more dangerous than their more well-known cousins, THC and CBD.”
That’s nothing more than an educated guess, though. Churchill is quick to stress that we simply don’t have very much information about CBG and CBN, and it will take time and study to figure out exactly what these compounds do—or don’t do. He adds that long-term studies on cannabis use are still needed to be able to fully grasp the benefits and the risks that come with frequent cannabis consumption. “Until we know more about how [minor cannabinoids] interact with other cannabis constituents, we cannot predict the strength of physiological effects these cannabinoids may produce,” he says.
Dr. Le agrees that the safety profile for rare cannabinoids remains unknown, and he too calls for further testing. “It’s one thing to have rare cannabinoids at low concentrations as a side product of cannabis production. It’s another thing entirely to deliver therapeutic levels of these compounds to consumers.”
The good news, says Dr. Vrana, is that the concerns he has about CBG causing harm to consumers are limited to CBG being smoked or vaped. “If it’s not being smoked,” he says, “if it’s being taken orally, it’s not going to achieve terribly high concentrations and it’s going to be a slow onset. That’s why with edibles, you have such high concentrations [of cannabinoids]: It’s not well-absorbed into circulation from the GI tract. These compounds are metabolized by the liver very assiduously.”
Above all, Dr. Vrana argues that we shouldn’t presume that CBG, CBN, or other rare cannabinoids have therapeutic potential simply because CBD and THC do, because nothing yet has proven this to be true.
“Now, all of a sudden,” Dr. Vrana says, “we have CBG where we didn’t before, and people are making claims that it’s going to have some advantages that we simply don’t think are going to be proven true. They haven’t been tested, and it has the potential for side effects.”
The lack of regulation, Dr. Vrana believes, has allowed entrepreneurs to get out in front of the science, and that leaves him very uneasy about the future of rare cannabinoids. “I’m not here to be a Debbie Downer,” he says, “but when people make these claims, ask them: What’s the evidence for that? Tell me how you know that. I guarantee you they’ll have none, or it’ll be apocryphal.”