Cannabinoids Chemistry

The Past, Present, and Future of Cannabinoid Medicine as Told by Dr. Ethan Russo

The days where we look at cannabis as nothing more than a natural vehicle that carries delta-9-tetrahydrocannabinol (THC) are over. Terpenes are properly in vogue, and scientists are routinely validating the value of minor cannabinoids like cannabigerol, cannabichromene, and the varins (cannabidivarin or CBDV, and tetrahydrocannabivarin, THCV), not to mention cannabidiol (CBD), now that cannabis can be legally researched. To date, the historical record always points to the general usefulness of the cannabinoids.

These compounds (and many others) are native to cannabis, and the scientific literature has demonstrated the power of whole plant extracts of cannabis that contain all the parts of the whole compared to isolated cannabinoids. The idea that these molecules work better together as a community was popularized by Dr. Ethan Russo, and I recently spoke with Dr. Russo to learn more about recent developments in cannabinoid medicine.

I first asked Dr. Russo which cannabinoids he’s most excited about.

“Far and away, CBG, he said, “as it’s becoming more accessible through greater amounts of acreage.” Russo said that he’s felt it was great therapeutically for its activities, and recently published the results of a survey of 127 people who have used 50%+ CBG products. [1]

“We saw great results,” Russo elaborated. “CBG demonstrated good efficacy for treating pain, insomnia, and anxiety. The CBG preparations were better than traditional drugs and had no particular side effects or withdrawal symptoms.”

Other attributes of CBG that Dr. Russo discussed were its distinct activity against methicillin-resistant Staphylococcus aureus, a difficult to treat Staph infection that demonstrates resistance to antibiotics. [2] Russo also pointed to CBG’s potential anticancer properties through its interaction with TRP receptors that are important for treating prostate cancer [3]; its anti-anxiety effects; and he highlighted the fact that higher doses of CBG have not caused any health issues, in contrast to CBD.

Moving on from CBG, Dr. Russo next mentioned THCV.

“THCV hasn’t gotten its dues yet,” he said. It’s a neutral antagonist at the CB1 receptor and has demonstrated the ability to reduce hunger in rodent models, potentially meaningful for weight loss and pre-diabetic metabolic syndrome. [4,5] Its effective against neuropathic pain as well, and has anti-convulsant properties. Although THCV is typically found in lower concentrations in most cultivars, Russo discussed certain South African cultivars containing higher levels of this cannabinoid.

Like THCV, CBDV also has anticonvulsant activity, and Dr. Russo pointed to two clinical trials where this cannabinoid was utilized on focal seizures. [6,7] “The studies did not read out positively,” he commented, hypothesizing that it was due to their use of CBDV isolate. As mentioned above, Dr. Russo strongly believes in entourage effects.

Another cannabinoid Dr. Russo discussed was tetrahydrocannabiphorol (THCP). “This cannabinoid is said to be 23 times more potent than THC. Most people hear this and get excited, but I don’t because too much can have undesired consequences. Our endocannabinoid systems (ECS) require gentle nudges to get them back into balance.”

Russo is currently working with Dale Hunt, Ph.D. via Breeders Best. The group has access to a receptor-based assay instead of a more traditional analytical biochemical analysis to identify new cannabinoids. “This approach is potentially 1,000,000 times more accurate,” Russo reported.

Reflecting on the power of cannabinoids to help heal us in diverse ways, I was curious as to which cannabinoid(s) Dr. Russo thought may gain FDA approval next?

“That depends on the industry,” Russo answered, “but CBG has great promise. I’m a proponent of whole plant extracts and of rationally combining specific cannabinoids and terpenes. Particularly where THC is concerned, it’s a lousy drug as an isolate. No one can tolerate it, but when you combine it with CBD or terpenes to counteract the side effects, you can have a great product.”

Because of the value of these so-called minor cannabinoids, I asked Dr. Russo what his thoughts were on alternative ways to get higher quantities of minor cannabinoids besides cultivating the plant? Dr. Russo again pointed to the entourage effects available from components in the plant.

“I’d say you can turn to selective breeding. With proper selective breeding, you can get the plant to do almost anything. I’m not sure if all of the technology is necessary or desirable. If the agenda is to make massive amounts of isolate, I’m not sure that’s the best path.”

As an example, Dr. Russo pointed to Gingko biloba. “In France, they took one component to treat septic shock but it didn’t work as well as a whole leaf extract. The active ingredients of Ginkgo are actually three sets of molecules that work in botanical synergy. These things work in concert much better than a single compound.”

In my research for the book The Cannabis Terpene Experience, I noticed how many terpenes have very similar therapeutic properties. I asked Dr. Russo if this was also the case with cannabinoids?

“They sure do,” he answered. “They are often similar, but distinct as the mechanisms of action are different. They act as a cocktail of agents. This is the same with current cancer treatments designed to knock everything out. Most common cancer therapies are toxic to all cells. The traditional approach is to kill the cancer before you kill the patient. A mixture of cannabinoids could be a good way to definitively deal with a tumor because they can suppress or eradicate cancerous tumors without damage to normal cells. Individual cannabinoid distinctions matter. If they work through various pathways, that’s a big advantage.”

“The cannabis plant is 30 million years old. Why does the plant expend all of this energy to make this stuff? This plant makes these compounds for its defense; it ain’t to get us high. That’s a happy accident of Nature. Some of the bitter sesquiterpenoids exist to deter grazing animals because they taste bad. The plant has tremendous capabilities.”

Switching gears, I asked Dr. Russo what the average consumer could look for when shopping the myriad products and product labels at their local dispensary? How can we make sense of what a given product might do?

“Every consumer deserves to have the ability to see a certificate of analysis that lists the cannabinoids, terpenoids, heavy metals, residual solvents, etc.,” he replied. “It’s incredibly confusing but the best option I’ve seen is the PhytoFacts report from Mark Lewis in terms of what’s in the product that the consumer needs to know. Plus, PhytoFacts contains feedback from consumers.”

“PhytoFacts monitors the 17 most common terpenoids – if you’re assessing those, you’re going to have a reasonable understanding of what the product will do. Of course, there are underlying ECS matters, or tolerance matters, but this system provides a great starting point.”

For my final question, I asked Dr. Russo what his thoughts are on the delta-8-THC craze?

“Straight out of the chute, it is a natural substance,” he answered, “as it’s found in some types of cannabis but in very small amounts. That’s the good part. To the best of our knowledge, its milder than delta-9-THC, and its more shelf stable. Delta-8-THC was used in a study in Israel in the 1990s. [8] Researchers gave it to kids who had nausea from chemotherapy. Kids under 10 are really resistant to the intoxicating effects.”

“The products that we see on the market currently are not from natural delta-8-THC, however. Now, people are making it from CBD. Delta-8-THC is not innately bad but we are hearing more stories about people having issues with the products. None are pure. There’s contamination with delta-6-THC,  delta-10-THC and unknowns, and we know even less about these molecules.

“These compounds may not be inherently dangerous, but some people are seeking to make money to the detriment of consumers. Although the DEA came out and said it was legal, it could be considered illegal with the Analogues Act. Once any therapeutic claims are made, the DEA will likely be interested. I’m not in favor of prohibition of anything, but in a properly regulated cannabis environment, delta-8-THC wouldn’t be necessary.”



[1] Russo EB, Cuttler C, Cooper ZD, Stueber A, Whiteley VL, Sexton M. Survey of patients employing cannabigerol-predominant cannabis preparations: Perceived medical effects, adverse events, and withdrawal symptoms. Cannabis Cannabinoid Res. 2021 Sep 27. doi: 10.1089/can.2021.0058. [journal impact factor = 5.800; times cited = 0]


[2] Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30. [journal impact factor = 4.05; times cited = 384]


[3] De Petrocellis L, Di Marzo V. Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J Neuroimmune Pharmacol. 2010 Mar;5(1):103-21. [journal impact factor = 4.147; times cited = 158]


[4] Wargent ET, Zaibi MS, Silvestri C, Hislop DC, Stocker CJ, et al. The cannabinoid D(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013;3(5):e68. [journal impact factor = 5.097; times cited = 73]


[5] Riedel G, Fadda P, McKillop-Smith S, Pertwee RG, Platt B, Robinson L. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol. 2009;156(7):1154-1166. [journal impact factor = 8.739; times cited = 111]


[6] Cannabidivarin (CBDV) vs. Placebo in Children with Autism Spectrum Disorder (ASD); Identifier: NCT03202303;


[7] Safety and Tolerability of Cannabidivarin (CBDV) in Children and Young Adults with Autism Spectrum Disorder; Identifier: NCT03849456;


[8] Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci. 1995;56(23-24):2097-102. [journal impact factor = 5.037; times cited = 143]

About the author

Jason S. Lupoi, Ph.D.

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