Beyond THC: Understanding the Full Therapeutic Potential of Cannabis (part 2)
Part 2: A Sophisticated Synergy: Terpenes, Minor Cannabinoids & the Therapeutic Edge
Interview with Dr Ethan Russo
Read time: 6-7 mins
In this instalment of The Insiders Extract, we jump into Part 2 of our interview with renowned neurologist and cannabis researcher Dr. Ethan Russo, diving into the sophisticated interplay between cannabinoids and terpenes.
Often referenced but rarely well understood, the Entourage Effect comes into clearer focus as Dr. Russo unpacks how compounds like CBG, THCV, and CBC offer unique therapeutic properties and how formulation science is paving the way for more targeted cannabis-based treatments.
From treating anxiety and pain to optimising focus and mood, this conversation sheds light on the next generation of cannabis medicine—personalised, intentional, and precise.
Adam Isaac Miller: So I guess as a follow-on then, how do terpenes and cannabinoids work together? You're famous for your work in pioneering the entourage effect hypothesis. Just as a quick breakdown, how do they work together?
Ethan Russo: Well, first of all, they're produced in the same place. The glandular trichomes of the plants, the little spheres that one can see under magnification of the cannabis flower. So there are 200 different terpenoids which have been described in cannabis.
So far, none are unique to cannabis, but each of them has effects. The plant uses these as protection to either repel bugs, attract bugs, as the case may be, to help prevent infection of the plant. A happy accident of nature is that these also work on human physiology, particularly in the brain. There are many emotion-modulating compounds that are among the terpenoids that give the plant its characteristic odour. Where the cannabinoids don't have any odour.
Well, on that, what is the relationship, or how does limonene specifically play into something like anxiety management? And regarding cannabinoids, how does CBG also enhance effects when it comes to mitigation of anxiety?
Sure. So you've managed to hit the two publications we had earlier this year. And these are available free at ethanrusso.org at the library tab. So first, limonene.
Limonene is going to be a familiar scent. It's the base compound in the essential oils of citrus. So anybody that takes a fruit, citrus fruit, lemon, lime, orange, grapefruit, run your thumb along it, you're releasing limonene and some other components. So there's a reason why when you walk down the detergent aisle in the supermarket that you smell citrus. One is from an advertising standpoint, this smell connotes to the brain cleanliness. Oddly enough, limonene is a very good solvent, cuts grease, and is in detergents for two reasons. One is it helps clean things. And second is it elevates mood. Sometimes it's too much, and usually it's an artificial scent with other components.
Going back to the 1990s, there was a study done in Japan by Komori et al, where they used a citrus scent that was wafted in the air in a ward of hospitalised depressed and they were able to cut Hamilton anxiety scores in half and get people off antidepressant drugs. So, I mean, this is something that's been known for a long time. We had never tested it in relation to cannabis.
So, together with Ryan Vandrey and other colleagues at Johns Hopkins, we did a double-blind controlled study. People were exposed via vaporisation to different concentrations of limonene; different concentrations of THC; or the two together. Followed by tests to see how they compare.
So, what was shown was that there was a dose-response curve where people got more anxious as the THC concentration went up, but higher concentrations of limonene counteracted that, and these were statistically significant results.
Yeah, wow. How does it work?
You know, we don't know absolutely. It's not through the cannabinoid receptors, but it is affecting emotional areas, the limbic system and the brain.
With cannabigerol, it's a different situation. So, cannabigerol, for people who are not familiar with it, I like to call it the mother of all cannabinoids because it is first in the biosynthetic pathway before THC and CBD are made. But normally, most cannabis plants don't stop there; they go on to the other substances. However, it can be selectively bred so that CBG concentration is higher, or even that it's the only cannabinoid. There are plants now where, through mutations, they don't have the ability to go beyond the production of CBD.
So, cannabigerol. In work with Kerry Cutler at Washington State University, we gave people 20 milligrams of CBG in a tincture and compared that to a placebo. The placebo was a diluted chartreuse liqueur, which had a very strong taste. But at the dose given, wouldn't be overtly psychoactive. And similarly, we induced anxiety situations and were able to show that CBG had a very pronounced effect on anxiety and reducing stress. And again, statistically significant.
Then a very surprising finding. There was actually an improvement from CBG in verbal memory tasks. So not only was it not producing impairment or sedation at all, it was actually making people remember better. So this is a very striking finding.
How it works, again, we can't be absolutely certain, but there are two likely possibilities. One is effects on GABA, which is an inhibitory neurotransmitter. This would tend to reduce anxiety. Another is effects on the serotonin 1A receptor. It actually is an antagonist there, which is opposite of what you might expect for an anti-anxiety, but it works selectively in areas of the brain that may produce this effect. So it's one of those where we can't say exactly how it works, but it works very well.
We've been using CBG in our formulation work, and I think it has a profound effect on reducing the anxiety that THC engenders. And thereby makes for better-tolerated medicines. And often a better experience for people who are seeking that, in other words, recreational use.
So, in the controlled studies with the CBG, what type of processes were being used to induce anxiety?
And then a follow-up to that would be, what have you seen by way of observation is the potential optimal dose for CBG, independent of other substances, and then in conjunction with THC?
Sure. OK. How do we make people anxious? Well, it's sort of diabolical. One of the things was, the examiner, a graduate student, would tell the person, “We are going to give you a few minutes to prepare, and you need to come back and give a speech about why you should have your ideal job”. In the meantime, she goes and puts on a white coat, which is anxiety-inducing by itself. Most people are not used to public speaking, even though this was done in their own homes over Zoom.
So that's one way that we made people nervous. Then there was another one where they started at a high number, say 1,117, asked the person to subtract 13 and to keep going. Every time they made a mistake, they had to go back to the beginning. Well, I mean, these don't sound terrible… but they're very effective in making people nervous.
So, as little as five milligrams of CBG can have an anti-anxiety effect. Ten milligrams would be about standard. We use 20 because we wanted to make sure we showed an effect. The effect began within 20 minutes and was sustained throughout the examination.
Now, what's the ceiling? Well, we're not sure. We're currently doing testing in lab that's associated with other measures, blood pressure measures, and measures of pain. With that, we're trying 50 milligrams, which I think is more than you really need. So again, I'm going to say that 10 milligrams is a pretty good place to start for most adults.
And, what kind of form was this administered? Is it a broad spectrum?
What we used was a tincture derived from cannabis and it happened to be from a plant that was one of these cannabigerol-only plants. So there was no THC, there was no CBD, there was a small amount of carry off, which is not considered overtly psychoactive. It could have been even more powerful if there had been linalool or an anti-anxiety terpenoid in it, because these seem to work in conjunction. But we wanted a relatively clean prep without using a synthetic CBG. And so I think we're quite successful there.
In relation to THC, any amount of CBG seems to help. If someone's got a lot of THC on board, I think 10 milligrams of CBG would make a big difference. Still, it's always subject to inter-individual variability, meaning people are different in what they can handle.
So my last question on that thread would be what extraction process did you use for the CBG for the tinctures?
Cold ethanol extraction, so pretty simple.
So CBG, from my perspective, I wouldn't call it a minor cannabinoid, but what are some of the more promising minor cannabinoids that deserve some attention in both the medical and adult use spaces from your observation?
So another one would be THCV, tetrahydrocannabivarin. So this is like THC, but it has a three-carbon side chain instead of five. It's a very interesting compound in that at low-moderate concentrations, it actually is what's called a neutral antagonist at the CB1 receptor, where THC is stimulatory.
So that might sound like it's a buzzkill, but it doesn't function that way. When we have THCV and THC together, to use perhaps a strange word, it produces a more mellow experience. It really takes the edge off some of the associated side effects of THC. People will feel like they have some energy, that they can feel high, feel good, but still function very well. It also, as opposed to THC, reduces hunger, which can be a benefit. This has been looked at medically as a treatment for diabetes, obesity and metabolic syndrome. So that's a very promising molecule.
Another one would be cannabichromine, one of the big three, you know. However, normally we don't see a lot of CBC. It's produced as opposed to THC and CBD, which are made from dominant genes; the gene that makes CBC is recessive. However, CBC has a variety of attributes that make it medically advantageous.
It works against many cancer types. For pain reduction. It also has the ability to stimulate the production of brain cells. So it could be useful in recovery from head injuries. It could be very useful in a lot of contexts where there are neurological impairments. But this has been very little researched as compared to the others, mainly because of lack of availability. And it's harder to breed and harder to get concentrations of it. But certainly, this is an area where we need more people to try to use cannabichromine and also investigate its attributes.
Do you know of any companies the development of these minor cannabinoid profiles in the harvest or the cultivation stage of production?
Well, they're individual breeders. Very few companies are looking at it. I'm the Chief Medical Officer for a company called Andira, out of Vancouver, Canada. A combination including CBG has proved to be a remarkable wound dressing in its ability to prevent infection, including antibiotic-resistant infections on bad actors like MRSA (Methicillin-resistant Staphylococcus aureus). Unlike the cannabinoids alone, this triple combination works on gram-negative, as well as gram-positive bacteria. So those gram-negatives are especially hard to kill, and most conventional antibiotics are losing their effectiveness.
The other attribute is that, unlike some of these increasingly ineffective antibiotics, tests to date show that it's unlikely that bacteria are going to develop resistance to this combination. Yeah, wow. So if the question is “what's CBG good for?”, that's already proven in studies, and it's on its way to commercialisation.
That's remarkable! You've obviously spent plenty of time testing various ratios of different cannabinoids and terpenes. How do you develop your scientific hypothesis to combine these? Because there's hundreds, the combination potential is almost limitless.
Well, part of it is looking at what do we know about these substances? Have they been tested in animals? What were the effects? At the same time that I was taking a deep dive into cannabis pharmacology and cannabinoids and the endocannabinoid system in the 90s, I was doing the same with terpenoids because I realised early on that most available cannabis had some amount of THC, but the effects of that one and this one were very different, and it had to be due to the terpenoid content. And taking a deep dive, I at least had ideas of what some of these things should be doing. Then it was a matter of trying them.
In the early 2000s, I did a series of experiments. Initially, these were blinded and with a vaporiser, trying different terpenoids alone and in combination with THC and seeing how it modulated the effects. And the results were really striking to me. It's just that it's taken 20 years to do similar experiments like the limonene study that we discussed earlier. Again, ingesting THC alone, this can be very disoriented, create a scattered feeling or be anxiety-producing - that is substantially changed with limonene. With limonene, it's brighter and more controllable; it's sort of an enhancement.
And with alpha-pinene, there was actually an elimination of the short-term memory impairment. With THC alone, it's hard to maintain a train of thought. You're always forgetting where you were because you're off on some other tangent, again, feeling scattered. With alpha-pinene on board, it's like, “I feel the effects of THC, but I can concentrate. I could work or study”. Interesting. So, someone who's trying to treat their chronic pain - they don't want to be high. They want to be able to function and have pain reduction. And that is attainable with the proper combination.
So, could you not put this all together in a single compounded combination from mechanical terpenes?
In formulation, that's often what we're doing. In doing this kind of work, I often have in mind, well, we want so much of this and so much of that to treat this particular condition. The chances of breeding a plant that's going to supply those exact ratios is… you could spend 20 years trying. So often, we'll start with a base, that's an extract of one plant that might have a favourable profile and then add things back from there. Ideally, this is all cannabis derived, whether it's specific cannabinoids from the plant or terpenes from the plant. Essentially, that's how we're trying to make better medicines at this point.
So, let’s say you have two side-by-side formulation options: one containing THC isolate combined with limonene and alpha-pinene derived specifically from cannabis, and the other using the exact same formulation but with the terpenes sourced from other botanicals. It sounds like you’d lean toward the cannabis-derived option. If that’s the case, I’d love to understand your reasoning behind that preference.
Yeah, well, it's twofold. One is that these substances may have different three-dimensional configurations. So they can come in right-handed and left-handed versions. And how the body reacts to them can be different. There's a substance called carvone. It is present in caraway and in dill, however, they look different in each plant. They're both called carvone, but they have different scents and tastes. And if you have a limonene that's from a botanical source, it may not be exactly the same as what's in the cannabis plant. So that's one reason.
The second reason is, if you're going to make a pharmaceutical from this based on cannabis, it all has to be derived from cannabis. That is the goal. We're trying with partners to develop what are called APIs, active pharmaceutical ingredients, that are specific cannabinoids and terpenoids from the plant, which can be used in this context to produce optimised pharmaceutical agents from cannabis. But that's difficult and expensive, but it is a worthy goal and quite interesting.
So one of the questions I wanted to ask is, we've covered a lot of ground here. I'd love to understand more about the concept of the therapeutic window, what role does it play in both medical cannabis applications and adult use?
Sure. Well, for better or worse, cannabis isn't a one-size-fits-all. For example, if we have a 50 kilo woman and a 100 kilo man, they both have strep throat, they may get the same dosage of an antibiotic to treat it. What is required to treat symptoms with a cannabinoid will depend on some intangibles. What is the state of the density of those people's CB1 receptors? Are they active or inactive? What is the concentration of endocannabinoids, anandamide, and 2-AG in their brains? How active are the enzymes that break them down?
These are things that we can't easily measure, certainly not without well recognised techniques. So, the bottom line is you can't look at somebody's weight and tell what an effective dose is going to be for them. You can have a ballpark idea, but the actual dosage that they're going to take should be decided by their reaction to it.
We use the adage start low and go slow. It's a big mistake to take too much initiative with dosing - people have a bad experience and you've lost the chance to give them a medicine that might work better than anything they've taken before, meaning conventional medicine.
So it's better, usually in this type of medicine, where we're dealing with chronic conditions to go slow. The idea is to get better, but do it slowly. Start with a very low dose, make sure that it's tolerated and work up to the point that there's symptom control without side effects, and that's the aim of treatment. For those purposes, being too high is certainly a side effect.
It can be like nailing jelly to a wall, it sounds.
Well, it sounds impossible, but people figure this out on their own very well. Unfortunately, I heard a figure, I can't tell you the source, but the average person that's looking to use cannabis therapeutically typically spends six months finding the preparation that helps them the best.
That's a great detail to know.
If things are more focused and based on a rationale of what component is doing what, and what is indicated to treat this condition? That should be a lot easier. It's possible, but again, we're somewhat hamstrung by the continuing legal restriction on cannabis use and research.
Yeah, that’s a really important point. I often find myself educating people about the value of what’s commonly criticised as ‘strain surfing’—the process of trialling different cannabis products in search of the right fit. As you’ve just articulated, it’s less about randomness and more about identifying symptom- or effect-specific profiles that align with an individual’s desired outcome. Whether people are aware of it or not, this process can be an intentional and valid approach to personalised cannabis use.
So to wrap up, I’d love to know, what are you currently most excited about in your research? What developments or investigations are capturing your attention right now?
Well, it's basically the things we've mentioned. Demonstrating the utility and therapeutic effects of some of these other compounds. How to make a better, safer medicine out of cannabis. That's been my working motto for many years.
Dr. Ethan Russo is a board-certified neurologist and globally recognized authority on medicinal cannabis and the endocannabinoid system. As founder and CEO of CReDO Science LLC, he builds upon his previous work as Senior Medical Advisor at GW Pharmaceuticals, where he helped develop groundbreaking cannabis-derived medications including Sativex® and Epidiolex®. Dr. Russo's pioneering research on the "entourage effect" and clinical endocannabinoid deficiency has fundamentally transformed our understanding of cannabis therapeutics, while his extensive publication record—over 50 peer-reviewed articles and several influential books—has established him as a prominent bridge between conventional medicine and ethnobotanical traditions. Combining rigorous scientific methodology with deep respect for traditional plant medicines, he continues to advance the field of cannabinoid science through research, education, and advocacy.
Disclaimer: This information is shared with a global readership for educational purposes only and does not constitute medical or business advice. All patient-related information has been de-identified OR fictional to protect privacy. Nothing in this article is intended to promote the use or supply of medical cannabis to members of the public.
