For this special first episode of the Subsistence Crop podcast, Cal Poly Humboldt Cannabis Studies students interview Dr. Ethan Russo about his past cannabis use, the ongoing medicinal significance of cannabis use around the world, specific projects he is working on now, and his aspirations for the future of the cannabis industry.
Join us at the Cannabis Studies Lab for some substantive conversation on cannabis, the subsistence crop.
Subsistence Crop Podcast Season 1 Episode 1: Dr. Ethan Russo Interview Transcript
Jada Morrison 0:02
Hi everyone and welcome to Subsistence Crop, a podcast cultivated by the Cannabis Studies Lab at Cal Poly Humboldt, where we talk about human cannabis relationships beyond commerce and prohibition.
Jannella Stebner 0:12
Good afternoon. Welcome to Subsistence Crop. This is a podcast by the Cannabis Studies majors at Cal Poly Humboldt. Today we’re talking to Dr. Ethan Russo: Cannabis Pioneer. Pioneer in the healing properties of cannabis and welcome to our cannabis studies lab, Dr. Russo.
Dr. Ethan Russo 0:32
It’s a pleasure to be with you.
Jannella Stebner 0:34
All of the students here are very excited to be able to speak with you about this plant, which started out as a subsistence crop. I guess that leads us right to our first question. So what is a subsistence crop? And what does it have to do with cannabis?
Dr. Ethan Russo 0:49
Well, some of the early earliest references to cannabis were as a grain, particularly in China where it was considered one of the five key crops in ancient times. Additionally, the same was true in Europe. Particularly in Eastern Europe, a lot of people had hemp seed as part of a porridge. And you know, it’s not the kind of thing and extended to the higher classes, but it certainly was good nutrition for the poorer people that were were using it.
And considering the fact that it’s one of the best sources of protein and all the amino acids that you require, and also high quality oil including gamma linolenic acid, which is an essential fatty acid. That means that we don’t make this, you have to get it from your diet and there are very few sources. One is mother’s milk and it’s also in borage seed and evening primrose along with hemp seed. So, in this instance, unlike some subsistence foods, which you rely on, as a matter of absolute necessity, ah, because of lack of other food. This is a desirable subsistence crop.
Jannella Stebner 2:14
Sounds like it? nutritious?
Dr. Ethan Russo 2:17
You betcha.
Marlene Rodriguez 2:19
What sparked your interest in the cannabis field?
Dr. Ethan Russo 2:23
Well, it started a long time ago. In this context, I can admit that yes, I smoked cannabis in college. That was a long time ago for me, but even then I understood it had medicinal uses but subsequently I went to medical school and learned about standard pharmaceuticals. And it was only after a long period of time and interval where I turned back to studying cannabis. And this came about because as a neurologist, I was using drugs that were increasingly toxic with less and less benefit to my patients. And I turned back to an earlier interest in my life in medicinal plants that sent me to the rainforest in Peru for my sabbatical in 1995. A little bit untraditional. But when I came back, it was 1996. And that was the year that Prop 215 was being voted on in California. And that was really the genesis of the medicinal cannabis movement in this country.
From there, I very quickly became enamored of the study of cannabis in all its complexity. Meaning, its various pharmacological effects, but as well, its husbandry, how do you grow it, and clearly the medicinal aspects of what cannabis had taught us about how our own physiology works. What’s called the endocannabinoid system, the cannabinoid system within our bodies, which helps explain why cannabis is so versatile in treating so many conditions that are otherwise are not addressed well by conventional medicine. So that was 27 years ago now, but it never gets boring.
Jannella Stebner 4:32
One of our students, Kaid, has a question for you.
Kaiden Chapman 4:35
Yeah, yeah, I do. So I know we talked a little bit about this yesterday, but could you tell us what were some of your first experiences with cannabis maybe, particularly the varieties that you were consuming but also maybe you could touch on the brother story when he came back from college?
Dr. Ethan Russo 4:56
Well, I you know, I did that in class yesterday. I’ve never talked about it publicly, but I guess I’m less worried at this point. Yeah, to make a very long story short, how much time do we have? You know, I was a child of the 60s and I may have inhaled accidentally in 1968. But without real intent to become high. However, in 1970, as I was graduating from prep school, I understood that all my friends had been using cannabis and I was sort of left out.
I asked my older brother about it before he was going off to summer school at Stanford. And he said, Yeah, you need to do it. And I tried all summer, took me seven times to get high. And now it’s only after he came back from summer school with Acapulco gold, which was the premier Mexican cannabis available in 1970.
And clearly, that worked with a lot of effort. And very soon after that, I was off to college and there was wide availability of cannabis, cannabis in various forms. And I quickly learned that I really liked hashish.
Being on the East Coast, there was a lot of hashish available. From various places, Lebanon, Afghanistan, occasionally Morocco. And for better or worse, I consider myself a hash snob: a connoisseur of the different varieties. But again, life goes on eventually, you know, by the time… Well when I was in medical school, I was still using cannabis. Later on, when I became a father, I found it inconvenient. And, you know, keeping in mind cannabis was still illegal throughout all this interval. So there were many years where I didn’t use it at all. And then again, after I became involved in cannabis research, I would use it when I needed to, for investigating things, but not on what people would consider a recreational level.
Jannella Stebner 7:39
So we hear a lot about legacy genetics, importance of preserving different kinds of genetic combinations. Tell us what your definition of legacy is?
Dr. Ethan Russo 7:51
Well, I guess I would answer that in terms of what we call landraces. So a landrace is a type of cannabis that’s been grown in its local environment over a long period of time, I mean generations, so that it’s habituated to its ecological niche. It can deal with the diseases and pests that might be present in a given area. But it also extends to the effects of the cannabis. Clearly, at least in the past, cannabis that came from different geographies had very different characters.
For better or worse, mostly worse, I would say, our cannabis industry has become very homogenized in that basically, California and Amsterdam have been the source of the genetics that are spread around the world. And to use the term advisedly, those genetics have supplanted the landraces in places like Jamaica, Morocco, even in Southeast Asia, so that in many of these places, you don’t have the original varieties. And it brings up a serious question as to what we’ve lost. Often this means that you’ve lost cannabis varieties with suitable disease resistance.
But it also extends to the effects. If you talk to old guys like me, they will often wax prosaic about the cannabis of the past and the effects that they have that they don’t find today. Now, it wasn’t because the cannabis back then was so much more powerful in terms of THC concentrations, but it’s also a mistake to think that there was nothing that was strong, they there were strong types of cannabis available. They were less prevalent than they are today. But what we’ve seen is a movement towards high THC concentrations to the exclusion of more diverse cannabinoids. And so it’s gotten to the point that everything is high THC and high myrcene. And that particular combination is really prone to producing couch lock, or the phenomenon where people partake and they can’t get off the couch. And that’s fine if you need it. But it’s not the effect that most people are really seeking.
You know, when I was a real cannabis consumer, I liked it for its ability to help me introspect or commune with nature, or discover things in music that I hadn’t heard before. Or to think differently. I’ll borrow a story from a friend. Lester Grinspoon was a famous psychiatrists that investigated cannabis throughout his career, and he often would tell the story that when he had a thorny problem that he needed to address he would examine the situation when he was straight and he would examine the situation again when he was high. And he felt that he made better decisions with those different perspectives.
Jannella Stebner 11:28
Very interesting.
Caleb Chen 11:29
Yeah, I believe that as well. The same. So you touched a little bit on why these legacy genetics are interesting to you and other cannabis researchers at large. Jazmin has a question about historical cannabis populations coming right up.
Jazmin Ruiz 11:55
Hi you guys, so my question was, what historical cannabis populations did you guys find coincide with which cannabinoids?
Dr. Ethan Russo 12:05
Well, again, back in the day, for example, a lot of the hashish that I was so fond of from Lebanon and Afghanistan would have been 1:1 combinations of THC and CBD. And in this country, you really didn’t see that available until about 10 or 15 years ago. Again, breeding was all towards high THC and CBD basically disappeared for about 30 years.
So it’s quite different. And then the rest of it would depend on the terpenoid content. For people not familiar with it – terpenoids are essential oil components that give cannabis its distinctive aromas and tastes but also greatly influenced the high. So I mentioned already myrcene, which is very sedating with THC. But when you had other components like alpha pinene, that would be a clear high, where somebody could be very high, but still concentrate and not lose their train of thought so easily.
If there were linalool in and it would be a calming effect. If there were limonene in it, which is the scent of citrus, it would be a very bright and happy kind of high. So all these things are influences on the experience. And again with this homogenization where everything is THC and myrcene. It’s sort of a unidimensional experience.
And so again, back in the day, and to a lesser extent now, cannabis from a certain locale, might be something that you would use for a certain purpose. So you would want this kind of cannabis to help you sleep, but the other kind of cannabis to help you clean the garage. So again, being fit for purpose with different chemovars and a chemovar is a chemical variety. You’ll notice I don’t use the word strain. There are no strains in cannabis. “Strains” applies to bacteria and viruses. So I’m a stickler on some of the nomenclature again, you won’t hear me talking about sativa and indica because those terms have no scientific validity at this point.
Jannella Stebner 14:50
To the point with your, the bacteria and viruses, I’ve heard you speak recently about Cannabigerol – is that the correct pronunciation?
Dr. Ethan Russo 14:59
Sure.
Jannella Stebner 15:00
All Right. There’s some things you’re excited about in terms of research, right?
Dr. Ethan Russo 15:05
So first, yeah, what is Cannabigerol? Easy for me to say. So that’s C-B-G, as opposed to C-B-D.
I like to call it the mother of all cannabinoids because in the synthesis in the plant of the substances of which there are 150 that have been identified in cannabis, it’s first in line. So all the others derived from it there have to be enzymes that make the subsequent different cannabinoids. In most plants, it doesn’t stop there. It’s sort of a high throughput highway to the other cannabinoids, most often THC and CBD. But in certain plants, there’ll be an accumulation of CBG. Or, in plants that lack the enzymatic equipment to go further, they’ll produce CBG only. In any event, its effects are very interesting. So this is not an intoxicating cannabinoid the way THC is. So it doesn’t make you high. However, it has a very profound anti-anxiety effect, without being sedating. And without being addictive. So it is quite distinct from drugs that are typically used to treat anxiety, which have these liabilities of being very sedating or addictive.
An obvious example would be Valium, and the other benzodiazepines. So people that are on those, it might work, but they’re sedated and getting off of them can be terribly difficult and dangerous. So this is quite different. Additionally, CBG has been used to advantage with people with a wide variety of conditions, particularly painful conditions. Additionally, it has a very pronounced antibiotic effect. And there are now drugs and treatments in development that will incorporate CBG as one component in treating bacteria that are antibiotic resistant.
Jannella Stebner 17:29
Jada has a question.
Jada Morrison 17:30
Yeah. So you mentioned like the past like 30 years of high THC like represented throughout the industry, and just take us through the timeline after the 90s and Prop 215? What kinds of new cannabis varieties did you see pop up and like maybe where?
Dr. Ethan Russo 17:46
Well, you know, I won’t be applying a bunch of names. Because part of the problem is the street names of cannabis are notoriously unreliable, and may mean different things, different places, even though the name is the same. And this has been amply demonstrated when those varieties have been put through analyses, showing that there just is no consistency.
But again, it’s interesting how politics intrudes on the whole situation. But after Prop 215, there was a strong movement towards medical types of cannabis. So we did see eventually, the advent of more cannabidiol along with THC, and having varieties where people had reported that it was good for treating multiple sclerosis, or good for treating chronic pain or good for sleep. And these would then be shared or sold for those kind of specific purposes. But then as things progressed, some of the states that had had medical allowance, then became legal. So what happened in many instances was that the medical market and availability of medically specific types of cannabis dried up because under legalization all of a sudden the focus was back on high THC.
Now, to be fair, part of this was due to uninformed consumers that would think that that was what they wanted and would come in to the dispensary and ask for the highest THC available. And I know this firsthand, my son some years ago was voted runner up for Best Budtender in Seattle. And this was a real pet peeve of his that people would come in and ask for the most potent material and he would try to tell them look, you know, what’s the experience you’re trying to have?
It doesn’t necessarily mean it should be 25% THC, you might do better with something else. And he would explain this and the rationale behind it, but most often people would still asked for the highest potency THC. And this is really unfortunate because again, they could have a much richer and better or more therapeutic experience with something else.
Jazmin Ruiz 20:34
Thank you.
Jannella Stebner 20:37
In terms of knowledge of budtenders, and getting the information about the Endocannabinoid and what different combinations of cannabinoids and also these terpenoids now… I read that there was a society of clinicians that had trainings for doctors that you mentioned once. Is this something that could be used for budtenders as well?
Dr. Ethan Russo 21:05
Sure, yeah.
Jannella Stebner 21:06
To allow them a little more…
Right. So yeah, let me plug the Society of Cannabis Clinicians. if I’m remembering correctly, it’s cannabisclinicians.org. And that’s a good resource, particularly because anybody can go on there and find a doctor or caregiver in their geographic area that has passed a test indicating that they have competency in the background information to be a good person as a resource who knows about cannabis and what might be suitable to treat their condition?
Dr. Ethan Russo 21:49
I’m not aware of a prominent organization for budtenders. But that’d be a great idea. Maybe? Yeah, so maybe that would be something to do in this area. I’m sure there are educational programs online by subscription that include budtender education. But again, I’m not aware of national standards at this time, but that again, would be a worthy goal.
Caleb Chen 22:24
A worthy goal indeed. Kaid is back with another question.
Kaiden Chapman 22:28
Yeah. Yeah, I think one thing that a lot of us are really eager to know is when did you officially become a formal cannabis researcher? And maybe how did you meet Clark and Watson? If that ties into it with GW Pharma.
Dr. Ethan Russo 22:43
Ah. yeah! you’re drawing all these personal stories out of me that I have never discussed in public. Okay, well, the first part is easy. So after I came back from the rainforest in Peru, as I mentioned, Prop 215 was happening. I got in touch with Rick Doblin at MAPS, the Multidisciplinary Association for Psychedelic Studies. He was looking for someone else to help try to do government approved cannabis research. Along with Donald Abrams, who was pioneering that effort, he ended up more successful than me because he got the material.
He used sort of a backdoor approach where he was, was asking to look at the harms that might happen by using cannabis in patients with HIV/AIDS. On the other hand, I wanted cannabis to treat migraine and I wasn’t willing to say we’ll look at migraine patients and see how they’re harmed by using cannabis. So I never got the material, but through my streak of adolescent rebellion in my 40s it made me want to study it more, but really, I was seduced by the beauty of the science behind cannabis and the endocannabinoid system. So this all started in 1996. interesting sidelight. I was, was and remain interested in psychedelics. So in 1996, I got a schedule 1 license, which allowed me to possess these forbidden substances. In the space of two weeks after I got the license, I was able to obtain a variety of psychedelic substances, including psilocin, what’s known as SDP, mescaline, and ecstasy in little bottles from a chemical supply house with my schedule one license. However, it took me a year to get a small amount of low grade cannabis to study from the National Institute on Drug Abuse and as I mentioned, I never got permission to use that on humans.
There was a second part to the question, I lost my train of thought, but it’s not pharmacological I will tell the audience.
Kaiden Chapman 25:16
Yeah, no, it was how did you meet Clark and Watson?
Dr. Ethan Russo 25:19
Oh, very important. So, I knew of these guys. My first meeting of the International Cannabinoid Research Society was in Acapulco, Mexico in 1999. And the person who was to become my future boss at GW Pharmaceuticals, Jeffrey Guy was there and so were Clark and Watson and David Pate. So they were for people who don’t know, these were three American expats, who had gone to live in Amsterdam, where they got a license to grow and study cannabis. They had developed some of the first modern cannabidiol predominant chemovars of cannabis, and the first tetrahydrocannabivarin (THCV) types of cannabis.
There came a point about that time in 1998, when they weren’t going to get their license renewed. And along came Jeffrey Guy from England, who had permission from the British Home Office to grow and develop cannabis as a pharmaceutical. So he acquired their genetics and that was the start of the first cannabis based pharmaceuticals. So yes that is how I met them.
Caleb Chen 26:58
Very interesting. Do you have any more information you can share about how Clark and Watson amassed their genetic library and where from?
Dr. Ethan Russo 27:09
Yeah, you know, it was from their travels all over the world. Both of them were extensively, extensively traveled. You know, there used to be in the 60s and early 70s – You could go overland from Amsterdam, all the way to India or Nepal. At that time you could travel through Afghanistan. I don’t recommend anybody to it now. But it was different. I mean, I had a friend who smoked hashish in a chillum in the Taj Mahal. I don’t think that happens today.
But they acquired seeds here hither and yon and certainly had contacts in the Netherlands who had genetics. But in this situation, they were doing analyses and looking for specific profiles on cannabis. So they were applying a scientific approach to the breeding.
And through the efforts of brilliant Dutch geneticists Etienne Meyer, who worked with them at Hortapharm was the name of the company in Amsterdam.
Kaiden Chapman 28:34
And so what did you do at GW Pharma?
Dr. Ethan Russo 28:37
Well, a lot of things. My position was Senior Medical Advisor, but it encompasses a lot of things. I was involved in about 25, phase 1 to 3 clinical trials. Phase one would be basic science studies. Phase 2 is giving it to people initially. And phase three is bigger studies and bigger groups of people aiming at treating a specific substance. So I was pharmacovigilance officer, meaning keeping track of side effects and addressing those when they came up during the trials. I was a medical monitor, so I was involved in helping doctors recruit patients to the studies. I was also a liaison to basic scientists. Part of what GW Pharmaceuticals was doing was supporting research among scientists around the world looking at mechanisms of how these different cannabinoids worked. And that would include things like how did they work to treat cancerous tumors? How did they treat pain? How did they produce anti inflammatory effects? So, it was a tremendous opportunity to work and watch scientists involved in these kinds of studies.
There was a tremendous amount of travel involved. I can’t remember… Let me think. Yeah, I either worked in or consulted in 60 different countries in the course of doing this kind of work. Most of that 60 was acquired while I was at GW over the ensuing 11 years.
Kaiden Chapman 30:40
Was there any specific genetic varieties from Clark and Watson that you were just really excited to work with?
Dr. Ethan Russo 30:48
Yes, but some of them haven’t reached us. So the lead drug from GW Pharmaceuticals was Sativex. Sativex was composed of a combination from two sets of plants one set was very rich in THC, the other set was very rich in CBD. While you might wonder why not one plant that had both, well, that can be done. But in fact, type 2 plants with combined THC and CBD have about half as much of each. Whereas you could get higher concentrations of each if they were the only cannabinoid.
So that was developed, initially to treat spasticity in MS, and that now is an approved indication in 30 countries, but not in the US. Okay, so that didn’t quite happen. We had gone through a program to treat cancer pain and found that it worked in the American subspecies, but it didn’t work and as well in the patients in Eastern Europe, that were much sicker. And that was the reason: If somebody has already failed to treat their pain with optimized treatment with morphine or other opioids and then get Sativex, it’s less likely to work whereas earlier, it works better. So it it really had a lot to do with patient selection.
Subsequently, through this breeding of cannabidiol predominant plants – what became known as Epidiolex, which developed to treat severe seizures. The syndromes, called Dravet and Lennox-Gustaut Syndromes and that is an approved indication. That drug was approved in 2018 in the US and remains the only true cannabis based pharmaceutical – FDA approved – in this country.
So there were the THC predominant plants, the CBD predominant plants, but they also develop THCV and CBG predominant plants that really haven’t gotten into commerce or medicine specifically, but that’s work that continues and we certainly hope to change that situation.
Jannella Stebner 33:32
I understand the federal prohibition that has limited to say the least, funding for study in the United States, despite the NIDA National Institute for Drug Abuse studies, right. We hear a lot a lot about Israel. Can there any other countries you think that have really made a lot of progress and have been doing this a long time as well that should you know that or that you use as a resource for some of your understanding
Dr. Ethan Russo 33:59
Yeah. There are actually a lot and they wouldn’t be surprising to a lot of people. So Israel is a small country that certainly has been been preeminent in a lot of areas, mainly through the influence of Raphael Mechoulam who we lost in March at age 92.
But a lot of work was done in England, as I’ve mentioned. Other countries in Europe, probably at the top of the list would be Spain and Italy. To a lesser extent Germany interestingly, but certainly there are very good researchers there. There’s been some brilliant work from Hungarians, some in country, some expats. And Canada certainly punches well above its weight considering population. A lot of great researchers there. There has been tremendous interest in Latin America. You know, less available resources in many instances, but a great promise there as well. And there’s been a lot of work in Australia to, but a weird situation there. They’ve had great support for research. But it’s very hard to do clinical trials there because the national law says that if you have a preparation with any amount of THC, you can’t drive, and you know, someone can be sick and stone want to drive and it’s a very big country need a car to get most places. So you can see how that would really hamper on recruiting for clinical trials.
Kaiden Chapman 35:44
Going back to breeding, are there any trends in your time that you spent with the plant that you’ve seen with cannabis breeding? Maybe other than the push for high THC flower? Yeah.
Dr. Ethan Russo 35:57
These days, I am told that in the dispensaries, if it ain’t purple, it don’t sell.
And so this is a cosmetic idea. And yeah, sure, purple plants are pretty, but it doesn’t mean that it necessarily as the chemical profile that you want. But I mean, that’s really prevalent. And in all seriousness, I’ve been told that… I’ve been involved with an outfit called Breeder’s Best that is trying to get intellectual protection for new varieties, things that are really novel that someone produced through their efforts and wouldn’t necessarily have happened spontaneously in nature. But again, we find that there is not commercial success unless it’s the right color. So, you know, sometimes these trends happen, but it may not be for the right reasons.
Caleb Chen 37:02
So, in your time seeing how legalization has impacted cannabis growers and cannabis breeders kind of around the world is there. Do you have any thoughts on like, if there’s a better form of legalization that maybe places that are still under the prohibition can strive for given all the experiments we’ve had.
Dr. Ethan Russo 37:26
So you’re looking for a model? Yeah, right now it doesn’t exist. I think we need to create one, that’s it’s going to be better.
So if you’re asking how do I think it should be done, this plant doesn’t need to be rescheduled, it needs to be descheduled. So currently, meaning this day in September 2023, they’re talking about moving from Schedule I forbidden drugs to Schedule III. However, that might have advantages in terms of making it possible to get a bank account on other restrictions business wise.
However, it really doesn’t fit a schedule three drug is supposed to be one that’s FDA approved in a pharmaceutical form. And that’s not what is the situation with cannabis. So I believe that it should be legalized but subject to regulation, that makes sense. So in other words, good safety data. Good and accurate testing and labeling and this is for safety purposes. So people know what they’re getting, have a reasonable expectation of how strong it really is, and that it’s free from solvents, heavy metals, bacterial contamination, and all that stuff.
So that’s what I’d like to see happen. But the problem is that these rules are made by politicians with the least understanding of the technical aspects, instead of scientists and physicians that hopefully would know more, or care more about what it really means.
Caleb Chen 39:20
That goes into the next question.
Jada Morrison 39:22
Yeah, perfectly, I think. Can you just explain how legalization impacted certain legacy cultivators and cannabis, cannabis based communities, like for example, Humboldt County growers?
Dr. Ethan Russo 39:35
Yeah, this is a sorry story, but I think I’ve alluded to previously the idea that initial movements and liberalisation were towards medical use of cannabis and the industry develop then with on dedicated breeding for medical purposes and under legalization it’s actually been a regression towards again the high THC varieties.
We’ve also seen a commoditization, particularly of cannabidiol. What has happened now, since the so called Farm Bill of 2018 was that high CBD varieties were allowed – anything up to and or below was 0.3% thc was allowed. So there’s been an explosion of these products, but with no concomitant quality control.
People have grown massive amounts of cannabidiol, which has led to the collapse of the price on huge stocks of surplus, people have needed a way to get rid of this stuff. So it has led to the explosion of synthetic Delta-8 THC, and other synthetics that, again, with poor quality control and definite dangers of toxicity. I think the situation has really deteriorated. In a situation that should have been promising in terms of being better for the public health. Instead, it’s worse on and it’s had a horrendous effect on people trying to make a go of it in cannabusiness.
I heard a figure that something like 7 out of 10 cultivation sites in Mendocino County, county are illegal under the law now, because of the onerous kinds of controls there are. So it’s a tough time to be in this business. That needs to change for a variety of reasons, including public health, but also giving people a reasonable livelihood. So things can be a lot better.
Caleb Chen 42:23
Thank you very much for that. This leads into a question about genetic bottlenecking.
Keaghan Morrisey 42:34
with another question, you guys,
Jazmin Ruiz 42:36
So my question was, what do you think about the idea that genetic bottlenecking in cannabis has led to the average cannabis consumers experience being akin to monotherapy?
Dr. Ethan Russo 42:46
Well, I again, I’d to emphasize that we’ve had this convergence towards high THC to the exclusion of other components. And, you know, nobody’s gotten to 100% purity, but we we seen near that in some of the concentrates and vape pens. And clearly, with extractions, you can get to a point of just very, very high percentages of THC without any of the other concaminant things that make it safer and better.
THC. pure THC is a lousy drug. We’ve had this available as Marinol since 1985. And it really has never had a lot of traction in the medical world on because nobody can tolerate it.
It is quite different to the cannabis experience where hopefully there are other components that take the edge off and make it a more acceptable drug. So cannabis we think of as producing euphoria and feeling better whereas Marinol produces dysphoria. That means unhappiness and people feel scattered on it. To a person… Anybody who’s tried Marinol as compared to herbal cannabis notice the difference and prefers the herbal approach. And there’s been no street value to Marinol you don’t see it sold along with oxy on the street. So that should tell you something.
Caleb Chen 44:35
Keaghan has a question too that end.
Keaghan Morrisey 44:45
Yeah, so my question was kind of about added terpenes into especially distillate and how that affects kind of trying to emulate like chemovars.
Dr. Ethan Russo 44:59
Well, there’s a lot of science behind this. But again, things can be better. Ideally, we should be looking for selective breeding, not just for the cannabinoids, but for the terpenoids to create the kind of profiles and experiences that people want.
Um, there’s also a problem because of sourcing, a lot of terpenes are produced as petroleum distillates. And they’re not necessarily medical grade, there are only pure up to a point and they’re supposed to be for industrial use. Often it’s cleaning agents or that kind of thing. But, and this is where it gets a little technical.
They may not be the same thing. The they might have this same chemical formula, but their structure in three dimensional space is different. And even terpenes. And terpenoids derived from plants may not be identical to the ones that are produced in cannabis.
So an ideal situation would be that everything’s cannabis derived. And insofar as making medicines meaning pharmaceuticals, from cannabis, it’s going to need to be all from one species: Cannabis sativa. So it’s not a situation where you could get linalool from lavender and add it to the cannabis and get that through the FDA. But for flavored vapes, in that kind of situation that’s commonly done. It’s not always a bad thing. But again, as an ideal I want to see everything be cannabis derived and there are companies that are attempting to do this.
Now I can mention again, conflict of interest, I’m a consultant to the company True Terpenes they now have a very big cultivation program in Washington State to grow hemp in the fields organically and extracting terpenoids from the plant to make their products. So that’s a trend I’d like to see continued.
Keaghan Morrisey 47:32
On that kind of same note, could you tell us a bit more about non DEA semi synthetic cannabinoids like THC-O and HHC?
Dr. Ethan Russo 47:39
Yeah, don’t go there. So what are these things? Well, let’s back up a little bit. What’s THC? THC is is known as a weak partial agonist at the CB-1 receptor. Let me explain.
So, THC works akin to something called anandamide – an endogenous cannabinoid in our body. And a weak partial agonist means that it sticks to this receptor, but it’s not super strong. But this is a system that works with a great deal of subtlety, I’d like to say that it needs a little nudge, not a hard push. In contrast, these synthetics are what are called full agonists at the CB-1 receptor, so they are way too strong. This increases the likelihood of misadventures, which can mean all kinds of things like… Additionally, they can be toxic. or the way they are made can produce residual solvents that are toxic. A lot of these other stubstances will have what are called off-target effects. Meaning that they can produce damagge to the heart or kidney and again this is not like your brain on drugs, Friday situations.
You know, but what I’d like to point out and I keep repeating is, these things would not exist in commerce, but for prohibition, they are a by-product of prohibition. So if we had legalized cannabis, I don’t think anybody would be using these things. And it is very well documented in the medical literature that the synthetics are associated with a great number of problems and some deaths. And, I just, I can’t recommend them for anyone.
Caleb Chen 49:41
So back to non synthetics, Jada has a question that goes back to what you said about cannabis as a pharmaceutical.
Dr. Ethan Russo 49:49
Sure.
Jada Morrison 49:50
So see a particular legacy cultivars particularly effective for some purpose, what would the path to FDA approval be as a botanical requirement?
Dr. Ethan Russo 49:59
Long, hard, and expensive. So yeah, the process would involve off first, growing it through what’s called good agriculture, good agricultural practice, and extracting it through what’s called Good Manufacturing Practice.
The FDA, and there are people that disbelieve what I’m about to say, but they’re never going to approve any, any drug that smoked. I don’t think that they will approve easily any drug that’s inhaled unless it’s treating the lungs. As an example, there have been efforts to create inhaled forms of insulin. And even that’s been tough. An important thing to try to do. But the lungs are vital organs, you can’t allow damage there to create a situation where… You can’t do without your lungs.
So there’s a problem there. But any drug has to go through a process to demonstrate that it is safe, effective and consistent. With safe and effective, that’s pretty simple. If it goes through clinical trials, and it helps in a demonstrable way to treat a condition: That’s effective. Safe means that you can use it without undue adverse events, but we call side effects in common parlance. Consistency is the hard part. Because cannabis as a pharmaceutical is what’s called a botanical. It’s not one component like Marinol with THC that’s synthetic, but rather a combination of different ingredients. That’s got to be identical throughout the program, within very tight tolerances. And I know what those benchmarks are, they’re hard to achieve. And so that requires genetic stability. And it requires uniform growing conditions, uniform extraction conditions, all of that every step of the way. So it has been done, it will be done again, but it is not easy.
Caleb Chen 52:26
So to that end, you mentioned that the FDA is unlikely to ever prove anything smoked or inhaled in the cannabis space. But if there were a variety or chemovar discovered that had a specific effect, that was desirable. Would it be the same when it’s extracted and then eaten through a delivery mechanism that the FDA would approve?
Dr. Ethan Russo 52:52
Maybe. But, again, there are all kinds of considerations. Obviously, inhaling cannabis preparation is a lot faster than taking it orally. You know, again, there’s a lot of investigation about transdermal – through the skin approaches. Up till now that hasn’t been practical, but a solution may be in sight. Currently, I can’t say too much about it. But again, I’m working with another company that may have solved this problem. So there’s a big difference in what’s called the pharmacokinetics. That’s the idea of how much gets into the blood, how fast. One issue with inhalation is obviously it’s fast, but it goes away more quickly, too. So people can’t see this on the radio. But it means that you’ve got this peak, very narrow peak, it happens fast. Onset and offset are both fast. With a chronic condition, and that’s most often what we’re treating with cannabis, it’s ongoing, you have chronic pain or you have chronic spasticity. This means that you probably want an oral preparation that’s going to come on slowly, lasts longer, so that you can take it two or three times a day and not have to inhale every couple of hours. And yeah, they both can work, but the oral approach is going to be most often the most applicable.
Jannella Stebner 54:36
You did some work with Ryan Vandrey, Professor of Psychology and Behavioral Science at Johns Hopkins correct. There were some double blind psychometric study, right you did with some participants with various levels of THC and then adding terpenoids. Can you tell us a little bit about how that works?
Dr. Ethan Russo 54:55
Sure. So I’m not going to claim credit for it being my idea but the ideal place to do it. So, you know, there’s been a lot of interest in what’s called the entourage effect. And this is a term that was coined by Professor Mechoulam and Professor Ben Shabbat. This is back in 1998. And it is the idea that applies to a botanical medicine, of not having a single active ingredient, but rather, this entourage of substances that work in concert, hopefully, even with synergy.
Now, there’s been a lot of debate about whether this exists. The fact is, there’s been a tremendous amount of both basic science and clinical work that shows that this is a valid concept. We wanted to prove it better. So the idea was to use what I call a deconstruction/reconstruction approach. So in these experiments, which are double blind, which is a way of saying that the subjects or patients don’t know what they’re getting, and the experimenters don’t know what they’re getting. But you use some codes and all so that you don’t find out until later what was what. So by combining THC in different doses with myrcene, or alpha pinene, or limonene in different doses, you can build up a picture of what the effects are. So far, we see that limonene reduces anxiety induced by too much THC. Hopefully we’re going to show that alpha pinine reduces short term memory impairment from THC, which is the “uh… I lost my train of thought, dude,” – that phenomenon.
So yeah, I mean, that’s Cheech and Chong, and everybody laughs. But, again, trying to show how there is a modulating influence of these terpenoids on the effects of THC. Hopefully, this’ll put the, the issue to rest, but there are always skeptics.
Caleb Chen 57:22
So, how far out do you think similar studies are with the esthers, the thiols, the other secondary, tertiary metabolites that are found?
Dr. Ethan Russo 57:31
Yeah, well, it’s a really great question. You know? We don’t know at this point. So what people should understand is esters are fruity kinds of scents and there are very, very low concentrations of esters in cannabis. We’re not sure what they do. Do they have a pharmacological effect? Do they affect the high or the experience? And the answer is maybe, at this point, so it needs some study, then the thiols or something else. So these are sulfurous compounds. And for example, in what’s called Skunk, you’d find these but the concentrations are absolutely tiny, even though we don’t smell as well as dogs apparently, a few molecules of these can be perceived by humans.
I would have thought it was unlikely that they were pharmacologically active, but they can be I mean, people have discounted what the terpenoids do because the concentrations are so low. But again, we’ve demonstrated and I’m absolutely convinced that they absolutely affect how THC or other cannabinoids work. So people should not be fooled by the fact that there are only low amounts of certain compounds. They still may be bioactive.
Caleb Chen 59:08
As a similar question, in your research, have you found that certain terpenoids are associated with certain cannabinoids? Like I’ve heard from one breeder that he’s finding a lot of CBG in his plants that are showing a lot of gerinol?
Dr. Ethan Russo 59:24
Sure, yeah, that that may occur, they may be coupled in some way. Why would that be? Well, it could be because they were selectively bred that way. But what’s more likely is the plant is producing these in response to an ecological need. In other words, this type of insect is attacking me and I need to produce this chemical to ward them off.
And this is an area for you students out there. We need a lot more work on why does the plant act the way it does? And again, it isn’t to get humans high. At least that’s not willful on the part of the cannabis plant itself. But it is doing what it does because of need.
These are called secondary metabolites. So sugar would be a primary metabolite. But a plant invests a lot of metabolic energy to produce these weird substances. And there’s a reason for it, again, for its own needs in response to its environment.
Caleb Chen 1:00:38
Not the humans.
Dr. Ethan Russo 1:00:40
Right. So we would like to anthromorphize. Yes, we’re influencing the plant. The plant is influencing us. But I don’t know how much intent to please the humans there is on the plants part. Hopefully they are benefiting and being grown and promulgated. Yeah, it raises some interesting philosophical issues.
Jannella Stebner 1:01:08
I think Michael Pollan had an interesting take on the relationship and his Botany of Desire.
Dr. Ethan Russo 1:01:12
Sure
Jannella Stebner 1:01:12
Which was pretty interesting. Who’s, who’s getting who to do what.
Dr. Ethan Russo 1:01:17
Right.
Caleb Chen 1:01:19
So I had a other genetics question, kind of relating to potential areas that Clark and Watson didn’t collect from. What remaining populations of cannabis do you feel are likely closest genetically to the extinct wild cannabis ancestor?
Dr. Ethan Russo 1:01:38
Well, you’d probably want to go to the source which be somewhere in Central Asia. I met a guy who had been in Kazakhstan and swears that there were feral wild cannabis plants as far as the eye could see in this area that he was.
Other people say there is no wild cannabis. We don’t know what the original cannabis plant looked like. It’s sure different than its closest relative in the cannabacea family, which is hops, very different plants.
So, yeah, Central Asia. But again, wherever it is in the world, I think we need to find out where there is the old guy that’s growing the original landraces, and has resisted the temptation to grow seeds from California or Amsterdam.
We’re gonna find very important traits that could be incorporated in modern breeding to the advantage of a greater diversity of chemical components as well as disease resistance.
Jannella Stebner 1:02:59
You mentioned some folks in BC doing some really exciting work with regenerative agriculture and growing and I know, over 150, maybe up different kinds of cannabinoids. Can you tell us a little bit about what you think the regenerative farming approach is and how that’s affecting things?
Dr. Ethan Russo 1:03:19
Right? Well, you know, they’re diverging approaches to cannabis culture. Again on pharmaceutical development, things are very standardized, I can say that GW Pharmaceuticals, when the clones the clonal propagation was done, plants were rooted, and they went out on the floor on the glass house so called and it was then exactly 77 days until harvest, not 76, not 78. There was always somebody there on day 77 to harvest the plants with controlled soil, heat, light, inputs, and integrated pest management without pesticides. So very formulaic.
However, in contrast to that is growing plants in the ground under ideal conditions. But this is tricky when we have global warming. We have forest fires and smoke everywhere. So it’s getting harder but to answer the question.
Our friends in British Columbia using regenerative agriculture techniques where for example, Hugelkulture where you dig a pit and you have logs on the bottom and tree branches on top of that and then leaves or grass clippings, compost and top quality potting soil.
What we’ve got is ultimately a very rich environment with the natural bacteria and fungi, establishment of what’s called myorrhizal arrangements.
Most plants have a relationship with fungi that’s a mutualistic situation: they feed each other. But under these ideal conditions, the plant has access to every possible nutrient it could have. What we see as a result is plants with a tremendous chemical diversity. So they’re not producing just THC and CBD. But we’ll see significant amounts of six even eight cannabinoids. And instead of having a predominant terpenoid, maybe a couple others that register, we see that they have 10 or 12 and in insignificant amounts. So that’s a plant that’s going to be healthy and disease resistant and showing its full potential. And when people use this type of cannabis, almost invariably, they like it and they find it helpful for a wide variety of conditions.
So part of the problem is that’s difficult. It’s dedicated, kind of involvement with the plant. We’re not likely to see a lot of those made into pharmaceuticals, FDA approved drugs, but they may be very desirable for the consumer, whether again, for its so called recreational reasons or, you know, again to treat a medical condition.
Caleb Chen 1:06:59
So, to transition a little bit to the, from the past to the present?
Jada Morrison 1:07:06
Yeah, just going off of that. Can you just tell us a little bit about CReDO Science and how it differs from Western medicine?
Dr. Ethan Russo 1:07:13
Ah, well, okay, so this is a company that we began right before the pandemic with my business partner, Nisha Whitely. We wanted to develop a company whose motto would be making cannabis safer and better and now that entails a lot of things. We have seven patents pending related to different technologies and approaches.
We developed a test for cannabinoid hyperemesis syndrome, we have a breeding program of our own. We’ve developed an extraction technique we call cryo kief. And we’re also engaged in formulation service both for the supplement industry, but also pharmaceutical industry. So we’re trying to apply what we feel are best practices to different aspects of the industry, that we hope will be better for consumers of any type.
Jannella Stebner 1:08:28
So you mentioned being in 60 different countries, the US we have our own particular issues with the plant, obviously, what do you see as the biggest hurdles to mainstream medicine in the United States really being able to embrace the endocannabinoid system?
Dr. Ethan Russo 1:08:45
Well, for better or worse, it’s a fact that my erstwhile colleagues in medicine, for the most part with exceptions, are never going to accept any form of cannabis that isn’t FDA approved. They don’t know it, they don’t understand it, they’re not necessarily going to take the time to get educated on what it’s about. It is really complex and it takes a lot of effort or to get this kind of certification from the Society of Cannabis Clinicians that you just don’t rubber stamp it after studying for an hour.
So, again, I think that there is room for and the need for many different echelons of activity in different approaches. I think it’s come out during our time together that I’m in favor of regenerative agriculture. On the one hand, I’m in favor of pharmaceutical development of cannabis based medicines. These aren’t mutually exclusive. And again, we’re trying to promote the industry and all these aspects.
Caleb Chen 1:09:59
We have one last question.
Jada Morrison 1:10:01
Yeah, just one last one. What do you feel cannabis enthusiast, such as everyone in this room, can do and think about to move in the best direction for future moves of regulation?
Dr. Ethan Russo 1:10:10
Well, I think you’re doing it. I’m so pleased to be here and realize that there’s an actual Cannabis Studies Program at a major university. I’ve been really impressed with the level of interest and sophistication of the people involved with the program. And I think great things can come from it, and similar programs across the country. And it’s through these kinds of efforts that we’re going to see the kind of progress that we’ve been desiring.
Caleb Chen 1:10:43
Thank you very much for your time, Dr. Russo.
Jannella Stebner 1:10:46
Thanks.
Dr. Ethan Russo 1:10:47
My pleasure.
Jazmin Ruiz 1:10:48
Thank you.
Kaiden Chapman 1:10:53
Thank you for growing with Subsistence Crop, a podcast by the Cannabis Studies Lab at Cal Poly Humboldt.
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