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Cannabeginners: Cannabinoids Without the Cannabis

Even though cannabinoids are named for the cannabis plant, cannabinoids and chemicals that interact with our endocannabinoid system (ECS) are not exclusively found in cannabis. Research going back more than 40 years has demonstrated that a range of plants can have pronounced impacts on our ECS, and more recent research has shown some of those plants to be capable of producing their own phytocannabinoids. 

Black pepper / Shutterstock

The First Dietary Cannabinoid: Beta Caryophyllene

Even though preliminary studies done decades ago hinted that some plants could impact the ECS, it took until 2008 to properly identify the first dietary cannabinoid, something that was not a cannabinoid but interacted with the ECS and was part of a normal human diet. Jürg Gertsch led a team of researchers looking at the impacts of β-Caryophyllene (BCP), “the primary sesquiterpene contributing to the spiciness of black pepper,” and a major terpene in cloves, hops, rosemary, and cannabis. In their pioneering study, Gertsch and his colleagues found that, despite BCP having a totally different structure than cannabinoids, it interacted with the CB2 receptor in a cannabinoid-like way, and produced a range of potential medical benefits. 

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Olive Oil and the ECS

It would seem that 2008 was a big year for researching cannabimimetic compounds (non-cannabinoids that interact with the ECS), and that same year a team of researchers looking at olive oil made some striking discoveries. They found that, “short-term feeding of  [a] Mediterranean diet high in monounsaturated fat, diet high in saturated fat, or diet high in polyunsaturated fat … can affect tissue levels of endocannabinoids.” By 2014, the Italian cannabinoid researcher Mauro Maccarone found that “By adding olive oil to an animal’s diet, we can restore a normal CB-1 receptor level that will protect cells against cancer.” The next study to advance our understanding of olive oil’s impact on the ECS found that “olive oil significantly induced CB2 receptor expression and it was able to control inflammatory and proliferative activity,” suggesting further benefits against cancer. 

These effects were so fascinating that by 2019 the Father of Cannabis Research, Raphael Mechoulam, was doing his own investigations. He told MG Magazine in an interview,  “we found the derivative [of olive oil] —an anandamide-like compound—which most definitely is a very potent anti-osteoporotic compound.” His findings suggest that the cannabimimetic compounds in olive oil were not just potent against inflammation and cancer, but also osteoporosis. 

Last week a study was released, offering the most current look at the “endocannabinoid-like mediators” found in olive oil. Their findings suggest that olive oil can both help rebalance gut microbiota but also could help prevent over-eating. 

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Wooly Umbrella: A Promising Alternative

Earlier this year the Internet was abuzz with stories about the wooly umbrella plant’s uncanny ability to produce more than 40 different cannabinoids. While that isn’t close to the more than 100 known phytocannabinoids in cannabis, it is the most cannabinoids produced by any non-cannabis plant, and offers a new and unique way to obtain cannabinoids. Wooly umbrella, also called Helichrysum umbraculigerum, is a perennial herb from South Africa with velvety yellow flowers, commonly used as an ornamental plant in gardening, related to daisies, sunflowers and lettuce. Even though wooly umbrella is not related to cannabis, interestingly, the biochemical pathway used to synthesize the cannabinoids is the same.

Wooly umbrella has long been burned in folk rituals to release intoxicating fumes, which may be why German scientists studied it more than four decades ago, and found evidence that it could produce cannabinoids, findings that were unable to be replicated until this year’s study. Specifically, the researchers found six cannabinoids that were identical to those in cannabis, including CBG, though they were not able to find THC or CBD. As CBG is derived from CBGa, which can also become THCA, CBDA and CBCA (which then convert to THC, CBD, and CBC), it wouldn’t be unreasonable to expect that you could find THC or CBD. In addition to the known cannabinoids found in wooly umbrella, the researchers discovered more than thirty new phytocannabinoids.

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Algae, Yeast, and Bacteria: The Cutting Edge of Cannabis-Free Cannabinoids 

So far we’ve been talking about naturally occurring cannabinoids and cannabimimetics found in plants, but what about cutting edge scientific efforts to tweak plants, fungus, and bacteria to produce cannabinoids?

A team of researchers out of UC Berkeley had the idea to tweak brewer’s yeast to brew up something much more interesting than just alcohol – cannabinoids. In 2019, they announced the “Complete biosynthesis of cannabinoids and their unnatural analogues in yeast,” effectively turning simple sugars into cannabinoids; in other words, spinning gold from straw. In a nutshell, they engineered a yeast to contain cannabis genes and produce the needed chemical precursors to make cannabinoids. “For the consumer, the benefits are high-quality, low-cost CBD and THC: you get exactly what you want from yeast,” said Jay Keasling, a faculty scientist at Lawrence Berkeley National Laboratory, “It is a safer, more environmentally friendly way to produce cannabinoids.” A 2022 study by a different group of researchers noted that this sort of engineering can be done not just with yeast, but also with bacteria. At least one company, Hyasynth Bio, has attempted to bring products to market made using cannabinoids from yeast.

It may not sound as appealing as using brewer’s yeast as the starting point, but multiple teams of researchers are tweaking algae to produce cannabinoids. As early as 2018, the US Patent And Trademark Office received at least one application regarding a “method for producing a cannabinoid in algae.” In 2020, a team of researchers based out of the University of Quebec, partnered with the Canadian government, announced they were “the first to demonstrate that cannabinoids can be successfully grown in microalgae.” While algae is large enough to be seen with the naked eye, microalgaes are single-celled organisms and may be prokaryotic (like cyanobacteria) or eukaryotic (like green algae). 

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Even More Sources of Cannabimimetics

While this article focused on black pepper, olive oil, wooly umbrella, and engineering algae or yeast, that is by no means an exhaustive list of non-cannabis sources for things that interact with the ECS. 

Gertsch, the same researcher who identified BCP as a dietary cannabinoid, followed up on his 2008 study with another two years later that did a deep dive into plants containing cannabimimetics. Back in the 1990s, some constituents in chocolate were shown to inhibit the breakdown of anandamide, offering some benefits to the ECS. Soon after, some alkamides in echinacea were demonstrated to interact with the CB2 receptor. Those benefits of chocolate and echinacea to the ECS were further supported by additional studies in the early 2000s. The common rue and brassica vegetables (i.e. cabbage, cauliflower, and broccoli) have been shown to contain the anticarcinogenic metabolite 3,3′-diindolylmethane, which interacts with the CB2 receptor. The hallucinogenic herb Salvia divinorum was also found to display “indirect cannabimimetic effects at CB1” but the mechanism of action is unknown. Finally, a 2018 study found that a chemical in liverwort “resembles THC in its 3D shape, and can bind to many of the same cannabinoid receptors as THC.”

Despite all these many ways to produce cannabinoids from something other than cannabis plants, none has seen mass use in the marketplace yet. It is only a matter of time before consumers will need to decide between more than just cannabis or hemp derived products, and may need to consider cannabinoids from yeast, bacteria, algae, or even wooly umbrella. 

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