This is a production of Cornell University. So welcome everybody. Hello, my name is Tony Baracco and I currently assist Zachary Stancil, who is our hemp curator at the USDA ARS. And we help run this hemp germplasm repository, which you can think of as a seed bank.
And so our goal is to collect a diverse genetic hemp. And our second goal is to make this diverse population of hemp available. And so we, all of this information that we gather will be available on GRIN Global, and that'll be a tool that researchers and educators can use to replicate findings and have better reliable information. And so today, I would like to introduce our speaker, Ethan Russo. He's a board-certified neurologist, psychopharmacology researcher, and author.
He is the founder and CEO of Credu Science. Previously, he was the director of research and development of the International Cannabis and Cannabinoids Institute based in Prague, Czech Republic. And he was a medical director of Phytex, a biotechnology company researching and developing innovative approaches.
targeting the human endocannabinoid system. And from 2003 to 2014, he served as senior medical advisor, medical monitor, and study physician to GW Pharmaceuticals in the United Kingdom for a numerous phase one to three clinical trials of Cetivax for alleviation of cancer pain, unresponsive to optimized opioid treatment, and initial studies of Epidolax for intractable epilepsy. So without further ado, I'll give Ethan the room and take us away, Ethan. Thank you.
Thank you so much. It's a pleasure to be with you. I should mention that my late father was an alumnus of Cornell starting back, I believe, in 1938. Anyway, so it's a pleasure to be with you.
So I have a difficult task today to sort of summarize the endocannabinoid system and the pharmacology of hemp, but I tried to make this complimentary. to other lectures in the series. My email is listed here and I'd be happy to hear from you with questions subsequently.
This is my disclaimer. I'm not going to spend a lot of time on this. I deal with a lot of different companies in one capacity or another. Most of these have not been remunerative and they would have no bearing on the particular content today. The material that I'm going to discuss is mostly not approved by the U.S.
Food and Drug Administration. If people were to use any of these materials, their results might vary. So we're talking, of course, about cannabis sativa, cultivated cannabis.
This is how we came to learn of the thing called the endocannabinoid system. So this makes cannabinoids glandular trichomes on unfertilized female flowering tops that give us tetrahydrocannabinol. And it was through research of this molecule that it was discovered that there were endogenous cannabinoids, particularly anandamide and 2-arachidonoglycerol, that actually lodge on cannabinoid receptors.
And so these are called endocannabinoids. Um, the... Endocannabinoid system is an internal homeostatic regulatory system in chordates, and there are three components.
The endogenous cannabinoids, as mentioned, the CB1, CB2, and what's called the TRPV1 receptor, probably other receptors such as serotonin 1A receptor, also includes the regulatory enzymes. In the nervous system, The endocannabinoids are produced on demand and travel in a retrograde fashion to the CB1 receptor where they then inhibit the release of neurotransmitters. In this instance, glutamate is a stimulatory neurotransmitter, so if this is inhibited, there's a net loss of function.
If, however, there is GABA here, which is an inhibitory neurotransmitter, the net effect is a stimulation. In the endocannabinoid system, there are probably 98 other molecules that resemble anandamide and 2-AG. These active and inactive components work together in what's been called an entourage effect.
The CB1 expression in the brain is extensive. There actually are more CB1 receptors than there are for all the neurotransmitters combined. CB1 is highly expressed in areas of the brain that pertain to pain responses, balance, emotion, and reward pathways. And although it also is in the brainstem, there are barely any cannabinoid receptors in the medullary areas that subserve respiratory drive.
And so there is no dose of THC or related cannabinoids that can cause apnea or stopping breathing like the opiates do. The endocannabinoid system is also throughout the other areas of the nervous system, including the spinal cord, the periphery, and the gut, the enteric nervous system. The role of the endocannabinoid system has been summarized as relax, eat, sleep, forget, and protect. but we could provide about 30 other adjectives that would also apply. And so it is the thing that modulates pain, memory, movement, emotion, appetite, whether someone will vomit or not, have a seizure or not, gastrointestinal movement and secretion, and just about any other function.
There are also CB2 receptors. These are mainly peripheral. This is a non-psychoactive. receptor that modulates immune responses and inflammation.
It also has an antifibrotic effect. So there are many conditions where stimulation of this system can be helpful. The CB2 has been typified as a protective system for all these different organs. And we'd single out the liver where it...
Stimulation of this would seem to have a role in preventing cirrhosis and other problems in the liver. It's also in the skin, both CB1 and CB2. The familiar cannabidiol, in addition to being anti-inflammatory and bacteriostatic, it works on another receptor called TRPV4 and actually inhibits the release of sebum. which is the oily stuff on the skin that is the place where the bacteria that produce acne feed. And again, throughout the body, although this looks like a heartless and spineless individual, all those functions are also subserved and modulated by the endocannabinoid system.
In fact, cannabidiol was recently shown to stimulate bone fracture healing. and may actually be indicated for athletes in the future if the laws change. Now, let's turn to the plant, which I think is going to be of more interest to this audience. So again, cultivated cannabis, probably the most useful single plant on earth, in that it provides food from the seed, fuel from the seed oil, fiber from the stocks and pharmacy, mainly from the infertilized female flowering tops. And this is a diaceous annual that's been assigned to the Cannabaceae family along with hops and a few others.
There is a chemical typology of cannabis that was developed by Ernest Small going back clear into the 70s. Type 1 is the more familiar high THC chemovirus chemical varieties. There are no strains in cannabis.
Strains are for bacteria and viruses. Type 2 is mixed generally with THC and CBD of equal proportions. Type 3 are the CBD-predominant chemovirus that have come into the fore, particularly since the Farm Bill.
This is from an article a few years back, and it shows the different parts of the plants and the heterogeneous production of chemicals in the different parts. Again, the greatest concentration of cannabinoids and monoterpenoids and sesquiterpenoids is in the glandular trichomes of the unfertilized female flowering tops. But they're totally different chemicals in the roots, triterpenoids and alkaloids. And in the seeds, we have essential fatty acids, high quality adestin protein, and there are various anti-inflammatory compounds throughout.
In terms of the distribution of THC and other cannabinoids, this again is greatest in the ganjar of syncemia. unfertilized female flowering tops much greater than those that are fertilized and very much higher than the leaves and there's almost none elsewhere. A close-up of the capitate glandular trichomes.
These are of the highest volume. These are found on the bracts around the unfertilized female flowers. as opposed to sessile trichomes found in the leaves of a much smaller volume, also qualitatively different. These tend to be higher in bitter sesquiterpenoids that discourage grazing, such as by deer and other ungulates. These are the 12 best typified phytocannabinoids, cannabinoids from plants.
We see the familiar THC and cannabidiol. And we've also got the cannabinoid acids that are the precursors in the fresh state. Each of these has unique pharmacology, and we'll get into that in a little bit. This is the biosynthetic pathway of the cannabinoids, generally starting with these two precursors, olivetolic acid with a five-carbon pentulocyte chain.
and geranyl pyrophosphate. So these start out being the parent compounds for cannabidiolic acid and subsequently that goes down to tetrahydrocannabinolic acid, THCA, and cannabidiolic acid. Any of these under heat or light will get decarboxylated to the neutral cannabinoids. Now geranyl pyrophosphate can also react with diverinic acid which is has got a propyl side chain, and this produces the propyl cannabinoids that we see on this side.
Additionally, geranyl pyrophosphate is also the parent compound to the monoterpenoids and the sesquiterpenoids. So the terpenoids and the cannabinoids are both produced in glandular trichomes, and they're half siblings based on a common parent. Why does the plant make these?
Well, I can tell you, it was not put on God's green earth to get people high. Humans are perhaps several hundred thousand years old. This plant is 30 million years old.
But the endocannabinoid system has been present in animals for 600 million years. So just to get an idea of the ontogeny of this all. But THC is production is greatest in bright light and it may be there to reduce ultraviolet light damage to the genome. CBG and CBD are both antifungal.
The trichomes form a mechanical insect trap and some of the acitocannabinoids are actually insecticidal. They also produce necrosis in plant cells. A bushy plant at the beginning will prune itself.
towards the end to look more like this, very lanky. And this is its final efforts at gaining fertilization, which we humans prevent to increase the amount of cannabinoids. So talking about THC, so this obviously is the major psychoactive component of cannabis, not isolated and identified until 1964 by Professor Mishulam.
In Israel, it's still active at age 91. It is a weak partial agonist at both the CB1 and CB2 receptor. It is painkilling, analgesic, prevents itching. Also bronchodilatory.
In the 19th century, cannabis cigarettes were used to treat asthma. It's also a neuroprotective antioxidant. It has 20 times the anti-... inflammatory power of aspirin and twice that of hydrocortisone. So muscle relaxant, that's the basis for the approval of Sativex in 30 countries to treat spasticity, muscle tightness associated with multiple sclerosis.
It's well known as an anti-emetic, helping prevent nausea and vomiting in chemotherapy patients. And it is neither a COX-1 or COX-2 inhibitor like the non-steroidals. A very interesting property is it seems to prevent, build up a beta amyloid in Alzheimer disease.
Cannabidiol is not intoxicating. It is psychoactive, however. Its pharmacology is actually broader, although this is much less potent molecule per molecule. It was isolated in 1940, but only identified positively in 1963. It does not bind directly to the CB1 receptors, but rather is what's called a negative allosteric modulator.
It binds to another receptor and affects the... binding in a way that reduces the psychoactive effects of THC. Again, a neuroprotective antioxidant, it's stronger than vitamin C or vitamin E in this regard. Like capsaicin, it is an agonist at the TRPV1 receptor with about equal potency.
It may desensitize the receptor, which is helpful in pain responses. It also increases the... gain of the endocannabinoid system by inhibiting the uptake of anandamide and inhibiting its breakdown. Contrary to popular belief, this is a stimulatory compound. It's an anticonvulsant.
This is the basis for its FDA approval as epidiolex in treating Dravet and Lennox-Gastaut syndromes. In high doses, it is an anti-anxiety agent. Cannabidiol like the other cannabinoids, has a cytotoxic effect against multiple cancer cells, while at the same time being preservative for normal cells. So this is quite different to conventional pharmacology agents used in chemotherapy that tend to be generally toxic. Oops.
It also acts on a thing called tumor necrosis factor alpha, which is important in rheumatoid arthritis, inflammatory bowel diseases, and other autoimmune diseases. Again, not a COX-1 or COX-2 inhibitor. Our group identified this as an agonist at the serotonin 1A receptor, and that's the basis for its effect on anxiety, also to reduce damage due to strokes and problems in thinking related to liver failure. It also works on the adenosine receptor A2A, may have a role in preventing slow virus infection, and as mentioned previously, stimulates bone fracture healing. Now, there are a lot of misconceptions about cannabidiol.
A lot of companies sell products where there's a tiny amount, five milligrams here, 10 milligrams there. Generally, When cannabidiol is used as an isolate, very high doses are needed to have the desirable effects. Again, it's commonly reported to be a sedative, but it's not. The early chemovars available in the U.S. with cannabidiol in them tended to be very high in mercine, a sedating terpene. This produced the misconception that it's sedative.
You will hear that this is legal in all 50 states, but this is still a matter of debate. Yes, certain commerce in cannabidiol was allowed under the Agriculture Farm Bill in 2018, but it remains a Schedule I product outside of its use as epidiolex. So according to the FDA, it's still illegal. There's also a misconception that it turns to THC in the body.
Last year, a group in Brazil had a very interesting trial. They used hundreds of milligrams of pure cannabidiol in a great number of patients and recovered no THC as a metabolite. This is a schematic of the natural history of CBD from a hemp field in Kentucky, showing the glandular trichomes.
And then again, the biosynthetic pathway to cannabidiolic acid, which is decarboxylated by heat, light, or aging to produce cannabidiol. This is what the pure crystals look like. And again, in normal hepatic metabolism, we get 7-hydroxycannabidiol. We don't get THC. Now, we're going to turn to some applications.
First, epilepsy. As mentioned, CBD as Epidiolex has been approved to treat a couple of rare but important seizure syndromes called Gervain-Lennox-Gastaut syndromes, but at very high doses. THCs can be pro-convulsant, produce seizures in rodents at extreme doses, but this is not substantiated in humans. There are other anticonvulsants in cannabis, including tetrahydrocannabivarin, linalool, which is a terpenoid, and likely tetrahydrocannabinolic acid. Interestingly, although in full-spectrum products, reportedly there have been results in treating seizures that are as good as CBD at about five times the dose.
Now, to be fair, Epidiolex went through randomized controlled trials, whereas these other preparations, these are observations that were not controlled. with placebos. CPD has also been used in treating schizophrenia. THC as cannabis is widely used by psychotic patients, perhaps trying to cover some symptoms.
We know that early use in the susceptible patient may precipitate earlier expression of schizophrenia. but only in those with a seeming predisposition. In other words, there's no evidence that you make someone schizophrenic if they did not have a predisposition before that.
There have been two phase two randomized controlled trials of CBD at high doses in the 800 to 1000 milligram day range, both effective on positive and negative symptoms of schizophrenia, equivalent to the results with atypical antipsychotics, but with fewer side effects. So this is something that definitely should be pursued. The biosynthetic pathway here is that for cannabigerol, which is the next one I'd like to discuss.
And it's particularly pertinent because there are now chemovars of cannabis available that are predominantly or solely cannabigerol. with no THC, and these can qualify as hemp, quote-unquote, under the farm bill. So much as before, we've got olivetolic acid, geranyl pyrophosphate to cannabigerolic acid. Under heat or light, there's decarboxylation to cannabigerol, and this is a picture of a cannabigerol-only chemovar from GW Pharmaceuticals. The science of CBG has been less investigated, but is very compelling.
This is first isolated in 1964 from Lebanese hashish, again by Professor Meshulam. They call this the missing link in the plant synthesis cannabinoid constituents. It is the precursor to the others. Initial studies really didn't show much in the animal studies.
It was synthesized in 1971. This was shown to be a GABA uptake inhibitor that could explain some of the roles as a muscle relaxant and an anti-anxiety agent. It has antifungal properties. It has analgesic pain-killing properties.
Like THC, it may lower pressure in the eye on glaucoma, although these are greasy molecules and nobody's figured out how to apply it directly. effectively. And there were pain-killing properties that were noted in this experiment. Like CBD, this is cytotoxic for a variety of cancer cells. In 2005, a CBG-only plant was developed.
It just doesn't have the enzymatic equipment to go beyond CBGA. This has been effective in various cancer cell lines. breast cancer.
It showed antidepressant effects in animals, lowers blood pressure. It may reduce the production of keratinocytes in psoriasis. It has only a weak partial agonist activity at the cannabinoid receptors, a tenth of that of THC, and even in high doses doesn't seem to be intoxicating the way THC is. Fascinating study from 2008 showed powerful antibiotic activity against gram positives, especially methicillin-resistant staphylococcus aureus. It also stimulates several TRIP channels, especially TRIP-NM8, which suggests benefit in bladder cancer.
And like CBD, it also inhibits anandamide uptake and may increase the gain of the system. It also affects PPAR-gamma, a nuclear receptor. and down-regulated tumor necrosis factor alpha.
And there was a recent study that showed that it worked on glioblastoma multiforme, the worst form of brain tumor. Interestingly, this molecule, both cannabigerolic acid and cannabigerol, have been found in South African DAISY called helichrysum and brachylogeram, but only in trace amounts. Last year, our group studied cannabigerol, the first human subject study.
We put this through an institutional review board, worked online, and required that people be adults. and that they had used a CBG predominant product, at least 50% CBG in the past six months. And this just shows the demographics. We had 127 completers of the survey, predominantly female.
Women are better at following directions on surveys. And unlike most studies of patient groups using cannabis, the majority were... working. So most of these people were high functioning. The average duration of use was nine months and people had an average of about three and a half grams of CBG flour a week or a gram of concentrate a week.
That's lower than what we usually attribute to THC predominant chemovers. A variety of conditions that you see lifted on the left were treated by these patients with cannabigerol. Over half used it medically with only a small percentage that they feel it was recreational and it was a mix of 36.2%.
The most common conditions cited were anxiety, chronic pain, depression, and insomnia, which are odd. quite similar to the demographics that we see for other forms of cannabis used therapeutically. In terms of the efficacy of the CBG treatment, the majority of conditions reportedly were much or very much improved.
Although the numbers were small on each, two-thirds of the people who used it for endometriosis found it beneficial, and three-quarters of those with inflammatory bowel disease, and for a greater number for irritable bowel syndrome. Interestingly, in no instance did people think the conventional medicine that they had taken previously was superior to CBG for any of the conditions. We're always concerned about whether the withdrawal effects, but a number of people actually were able to... discontinue antidepressants, non-opioid painkillers, and protein pump inhibitors after taking CBG.
In terms of side effects, 44% reported none. When there were side effects, the most common were dry mouth, sleepiness, increased appetite, dry eyes, which all really are likely related to some amount of THC in those preparations. because with CBG preparations, we don't see these complaints. 10% reported side benefits.
On terms of withdrawal from the medicine itself, 84.3% reported no withdrawal symptoms. And compared to non-CBG cannabis, the more typical THC type cannabis, there were many fewer issues. So conclusions of the survey study.
We know that usage of this is increasing, particularly in the Pacific Northwest, where I live. This was the first study of potential therapeutic effects in humans. Anxiety, pain, depression, and insomnia were the most commonly reported target symptoms.
The perceived efficacy was quite high with few adverse events. The efficacy that was reported in inflammatory bowel diseases also goes along with reports of CBG being beneficial in animal models. We believe that the survey...
supports the idea that CBG would be safe for future randomized controlled trials. How does CBG compare to CBD? Well, both can treat pain, anxiety, and need sleep. Both affect the TRP channels, have antibiotic properties, and are cytotoxic for cancers and may increase endocannabinoid tone.
However, cannabigerol is a lot more potent than CBD. Basically, that means fewer milligrams are necessary to be effective. For example, anti-anxiety effects of CBD may require 100 to 400 milligrams, whereas 10 to 20 milligrams of CBG seem to be effective.
Again, CBG-only chemovirus are available in some jurisdictions, whereas it's very hard to eliminate THC completely from type 3 CBD chemovirus. Compared to THC, cannabigerol likely would be a useful adjunct to many THC chemovirus by providing synergistic benefits on pain, sleep, and mood. Because CBG has a strong anti-anxiety effect, it may increase the therapeutic index of THC, giving you more leeway. dosing.
And what do we expect from this? Well, one of the things the world needs now is a safe, non-sedating, non-addictive agent to treat anxiety. And CBG may be the best candidate I've ever seen.
It seems to be quite safe and versatile. So its addition of various cannabis-based preparations makes sense. It could be an impressive agent for primary cancer treatment.
Again, because it kills cancer cells, but it doesn't kill normal cells and is not intoxicating like THC. And this could be an antibiotic of the future, especially for MRSA and another resistant bug, vancomycin-resistant enterococcus, VRE. Another agent in cannabis, hard to come by, is cannabichromine.
This is produced by a recessive gene. Usually there are only trace amounts, if any, in most types of cannabis. It's also antibiotic and antifungal, cytotoxic, extract produced antidepressant effects in rodents. Again, working on various trip channels and inhibiting the breakdown of anandamide. But again, selective breeding may make this more available.
Now, turning to the cannabinoid acids, cannabidiolic acid is what the plant makes before CBB. So this is the predominant phytocannabinoid in fresh hemp. It is a natural herbicide. This one can produce Cox inhibition, but only at extreme doses, which should never be necessary.
It's a powerful agent as an antiemetic, preventing vomiting. This is mediated through the serotonin receptor, and it's about between 100 and 1,000 times. more effective than CBD itself.
Based on historical data of how hemp was used by the Renaissance herbalists, it may be useful in treating tumors. I think we skipped something here. Okay, no, that's fine.
In relation to the entourage effect, we mentioned this before with the entourage of endocannabinoids. but the same may apply to phytocannabinoids. Quote from 1999, this type of synergism may play a role in the widely held but not experimentally based view that in some cases plants are better drugs than the natural products isolated from them.
Well, that was 1999. Actually, we have a lot of ammunition to support the idea of synergy of the entourage effect in cannabis. And we see this clinically in combinations of full-spectrum products. But again, cannabis doesn't just make cannabinoids.
It also makes the terpenoids, which may be painkillers, anti-inflammatory, have mood-modulating effects, and reduce the side effects of THC. We see here some of the main terpenoids found in cannabis, also other plants that are common to produce the same ones. Going through these very quickly, the most prevalent terpene in cannabis is beta-mercine, also found in celery leaf. I call this the primary couch lock factor in cannabis because it is extremely sedating when combined with THC.
And the sedation is a narcotic-like effect. It is a painkiller, but it can be antagonized by naloxone, the thing that they give as an antidote to opioid overdoses. So it's working through a different mechanism. There tends to be a great deal of this in most kinds of cannabis, and we usually want to see less so that the results are less sedating for the chronic pain patient.
Interesting, but less seen in cannabis these days is alpha-pinene. This is the most common terpene in nature from pine needles and other conifers. It's bioavailable via inhalation. It is a bronchodilator like THC.
It has wide-spectrum antibiotic activity. Its greatest effect, though, is as an acetylcholinesterase inhibitor. Acetylcholine is the memory molecule neurotransmitter in the brain.
And because alpha-pinene reduces its breakdown, its presence in cannabis may reduce or eliminate short-term memory impairment by THC. It also may have a neuroprotective effect, as we see here. All this is supported by the fact that... Walking in a pine forest or what the Japanese call shinrin yoku or forest bathing is very good for clearing the head.
Another agent we'd like to see more of in cannabis is D-limonene. The scent is going to be familiar to anyone who's been near citrus, whether it be lemons, limes, oranges, etc. In humans, this has had a potent antidepressant and immune stimulating effect that was shown in... hospitalized depressed patients in Japan, lowering Hamilton depression scores and allowing discontinuation of standard antidepressants.
This also may be useful as a dietary aid. It increases mitochondrial biogenesis and may turn white fat, the storage fat of obesity, into brown fat, which is more metabolically active. Linolul is a odd terpenoid, common to lavender, well known as an anti-anxiety agent. This again has been shown in humans, particularly demented patients with Alzheimer's disease that get ornery at night. Also prominent local anesthetic effects and anticonvulsant effects.
And again, this has been demonstrated clinically. Caryophyllene is a very interesting compound. It's a sesquiterpenoid. 15 carbons.
It has strong anti-inflammatory properties comparable to phenylbutazone that's used as a non-steroidal in horses, but not people. But unlike the non-steroidal drugs, it protects the stomach from ulcers. This actually is also a cannabinoid. It's a selective CB2 agonist. So it's not intoxicating like THC, but...
can produce those anti-inflammatory benefits without producing psychoactive effects. And this is what's called a Phytofax demonstration of cannabinoids and terpenoids in this particular chemovar. The most prevalent cannabinoids, this is CBD and CBG, very lower up.
much lower amounts of THCA. What patients report in terms of the aroma and flavor if inhaled, and the effects that they report. This one's high in comfort and calm. And we see the predominant terpenoids here is limonene and caryophyllene with very low myrcene.
So this is a type 3 because it's predominantly CBD. This should be a non-sedating agent, very low in THC and mercine. but high in caryophylline, limonene, and humulene, patients report comfort, and likely this would be helpful in treating pain, inflammation, and both CBD and caryophylline can be helpful in treating addiction. Also may be good for anxiety and depression.
So this is how we analyze what's in cannabis to see what it might be good for in terms of treatment. And I would refer you to ethanriso.org. There is a library of all my publications in PDF form, which you can download there. Because it's my personal website, you shouldn't be breaking any copyright laws, is my understanding. And I'll thank you for your attention and hope that I've left plenty of time for questions.
So thank you so much, Dr. Dr. Rousseau, that was an absolutely gripping and fascinating talk. I think I can speak for everyone that we fully enjoyed it. I also want to just give a quick thanks to our interpreters.
That was probably tough. And then as well as Tony, George, Gemma, and Kim as well for making this happen. So we're so proud at the USDA Plant Genetics Resources Unit to... host this kind of knowledge and information sharing. And again, we just want to thank you, Dr. Russo.
So I believe Tony and George have some questions from the Q&A. It looks like there's a lot. Yep, we got a lot of questions.
So we'll try to get through as many as possible. First question, are there phenotypes of cannabis described by Small published in 1975 still relevant for modern varieties? Is there any research?
planned or currently working on reevaluating the 0.3% threshold on THC? The 0.3% threshold is a political act and has nothing to do with science. What I would mean to you is the concentration is much less important than the total dose. So let's say that we had material that was 0.25.
a percent THC. Well, if you take too much of it, you could become intoxicated. By the same token, you could have 5% THC material, but if only a small amount is taken, it would not necessarily be intoxicating. So to be fair, this was an effort to allow commerce in material that the government hoped would...
not create other problems. But what's happened is people have taken the abundant biomass of CBD predominant material and transmogrified it into Delta-8 THC and other items, which clearly are intoxicating. So we obviously need to do better.
And my suggestion would be that the politicians speak more to scientists that are experienced in this area. Awesome. Another question comes in. Do you, do other plant groups produce cannabinoids at all? Yeah, I've got an article that's on the website ethemirsa.org called Beyond Cannabis Plants in the Endocannabinoid System.
In terms of things that might be cannabis-like, there is a component of cava cava, Piper methisticum called yangonin, that seems to be an agonist at CB1. There's also the New Zealand liverwort, Radula marginata, that has THC-like molecules. But the problem there is this is a rare plant and it grows a millimeter or two a year.
So the prospect that this is ever going to be an agricultural crop is probably minimal. And there are lots of other examples. There are things that...
that work on various receptors of the broad endocannabinoidome. And even prebiotics and probiotics affect endocannabinoid, the endocannabinoid system. So yeah, that article would point to other plants, foods, and crops that could be leveraged to benefit endocannabinoid system. Awesome. A question in from Ernie Siebert from Alabama A&M asks, is the American Medical Association and the NIH on board with full-scale clinical trials, research, and prescribing cannabinoids to patients?
I'm afraid he's asking the wrong person. I've been doing this for 26 years. I tried to do... clinical trials of cannabis and migraine back in the 90s and really got stonewalled. I got the FDA cleared it, but the National Institute on Drug Abuse had then and pretty much still has a monopoly on the supply and would not provide the material for those clinical trials.
Although the situation has improved, it's testament to the fact that it's still hard to do this kind of work. spent most of the last 26 years working for foreign companies. There's a reason for that.
So yeah, there's a lot of room for improvement in the capability to do this kind of research, which should not be ceded to other countries around the world. Awesome. Question comes in.
Would you elaborate a little further on why cannabis is not referred to as a strain? I investigated this in the article by Lewis et al., in which I was co-author. We go into some detail on this. Strains is a useful term for viruses and bacteria. A better term.
for cannabis would be chemical varieties, chemovars, or even cultivars. And this also should be used instead of the terminology sativa and indica, which have nothing to do with the taxonomic descriptions of the plant in the 18th century by Linnaeus and Lamarck. So what's called indica today doesn't look at all like what Lamarck described.
You know, he had precedence. But as best we can ascertain, there's one very promiscuous species of cannabis. You can interbreed any type of cannabis with another. But what differentiates them is their effects.
And this is mediated by their chemical contents. And that's why I prefer the term chemover. Tyler Gordon asks, can CBG be manufactured in a lab?
or is it easier to extract from plants? Yes, it can be made biosynthetically. There are various groups working with yeast and E. coli to biosynthetically produce cannabinoids. However, this hasn't been scaled up to be practical yet.
Can it be done? Likely. However, this is a weed.
It's relatively easy to grow if you know how. And additionally, I think I'm no Luddite. I think the science of the biosynthetic approaches is fascinating. However, to me, it will never equal what the plant can do.
This is a plant that from its flowering tops can produce upwards of 30% cannabinoids, which is phenomenal for any secondary metabolite of a plant. I'm not sure of a parallel to equal it. Additionally, it doesn't produce one thing generally.
It produces this entourage of compounds that are synergistic to one another, and no bacterium or yeast is going to do that. It will never happen. So I'm a strong proponent of the plant.
I'd also add the genome of the cannabis plant is so plastic. that you can make it do anything you want through good selective breeding with conventional methods. I'm not a fan of genetic modification, and particularly for cannabis, this should never be necessary because you can make it do almost anything you want.
Awesome. Another question from Dr. Sarah Eichler asks, is research on potential agro... cultural pest control applications using various cannabinoids available.
Yeah, it's a very interesting question. On the Credo Science website, you'll see that one of our projects relates to development of cannabis-based treatment for head lice. Obviously, through the question, it was understood that there are insecticidal properties of the acitocannabinoids in particular.
So, yes, this could be leveraged to produce agricultural products that... would be safer as not just insecticides, but possibly as herbicides as well. So we're really interested in this. So far, this hasn't taken off in the industry, probably because of remaining constraints.
With legalization, I think this would be an avenue of greater interest. We certainly are interested in it. Awesome.
Someone asks, are any of the compounds full agonists at CB1 or CB2? No, fortunately. And that's a good thing. Even THC alone is really too strong.
THC is a synthetic. It's been available as an FDA-approved drug called Marinol since 1985. However, it's had very poor uptake. And the reason is... Most people can't tolerate it.
It tends to produce dysphoria, unhappiness, rather than euphoria. And even experienced cannabis users don't tend to like it. We do see full agonists among the synthetic cannabinoids, K2, Spice, and the like, that are very prevalent as alternatives to cannabis.
Again, this is a byproduct of prohibition. For the most part, those aren't identified on urine drug screens, and so people turn to them, but those are overtly dangerous. The endocannabinoid system is a very subtle system.
It needs gentle nudges, not huge pushes pharmacologically, as would be provided by pure THC or a full agonist at the CB1 receptor. There may be a natural... full agonist in the form of THCP, tetrahydrocannabifluorol, which is like THC, but with a seven carbon side chain. However, this has only been found so far trace amounts, and that's just as well because it's 23 times more potent than THC itself.
Awesome. One question I think is directed towards your CBG study. And they're asking, what were the doses used with the many promising results?
And at those doses, what were the negative side effects found? And how complete are the risk assessments? Yeah, the exact dosing, again, would depend on how often the person used it a day. So we couldn't stratify the data that way. However, we know from speaking to people and observations that 10 to 20 milligrams at a time seems to be quite effective for most people for most things, particularly in treating anxiety.
I know of people inhaling 40 milligrams of pure CBG at once with no adverse events. So I don't know what the upper limit is. It probably is very high because it's just not intoxicating and there's no withdrawal effect.
So, you know, less is more. If a person is getting the desired effect at a lower dose, that's what we recommend. There's no point in wasting material, even if it doesn't have obvious side effects. Another question asks, do you know of any early production of sensimilia cannabis prior to the 1970s?
It would seem that it would have happened earlier, given human plant understanding. Yeah. there's a place called the India where ganja has been grown for thousands of years. So this is a technique that was known to the ancients. Awesome.
Someone asks, Dr. Russo, would you say that the misconception of sedation can be related to the actual receptor behaviors while connecting and interworking within the anatomy? I think this is in relation to CBD. Yeah.
In this instance, again, at extreme doses, like 1,500 milligrams a day. CBD has been observed to produce sedation, but this is in the context of patients on polypharmacy. Generally, these are patients with severe epilepsy that are on scads of drugs at once. And so there are drug-drug interactions, additive sedation, et cetera.
But at low and moderate doses, CBD is stimulating. I have friends in California that use a dose of CBD in the morning instead of caffeine these days so yeah and that's been tested by electroencephalography and sleep studies etc um great another question comes from phoenix saying thank you for your contributions to cannabis uh what is the status of the current research on chs which i believe he means cannabinoid hyperemis syndrome um yeah there are two articles on our website on the uh EthanRusso.org, the library, and it'll be on the first page. We did a survey that's the largest database to date on cannabinoid hyperemesis syndrome. For those not familiar, there is a small subset of people who use cannabis chronically in high amounts that develop a syndrome of abdominal pain, nausea, vomiting, and with a strange behavior of hot water bathing, sometimes hours. a day to allay symptoms.
This affects certain people and not others. We hypothesized that there was a genetic cause, and that turned out to be true. We identified five statistically significant mutations in CHS patients as compared to control patients who use cannabis at high rates but did not have the symptoms. And so that's available. There's also a commercial test.
that's available. And that's accessible at what-is-chs.com. And again, the paper is there for you to download.
Awesome. Somebody's asking, does CBD work better with a small amount of THC included? Absolutely.
Now, I'm fond of saying that there's nothing that CBD that can't be enhanced by a tiny amount of THC. I mean, this is the way it comes in nature invariably. Epidiolex probably is 97% pure because the FDA was THC-phobic. They didn't like the idea of giving THC to kids, even though the benefits would far outweigh the risks. These children with Lennox-Gastaut and Gervais syndrome are severely cognitively impaired in general and have sometimes hundreds of seizures a day.
So any negative effect of THC really pales in comparison to the benefits it might have therapeutically. Awesome. There's another question related to the cannabinoids and insecticides. And this is basically asking, are there any terpenes like alpha-pinene or limonene used as insecticides? Yeah, absolutely.
So, yeah, I mean, basically the cannabis flower is really designed to keep the insects at bay. So there are insecticidal properties from the cannabinoids, the terpenoids, and also If an insect touches the trichome, it'll tend to burst and then polymerize. And so there's a mechanical insect trap. So it's a really elegant system to try and control predation. Awesome.
I think we have time for maybe one last question. So have fungi or mycotoxins been looked at as a trigger or factor for hyperemesis conditions? Yeah, that ain't it. The symptoms don't match. Also implicated by some people have been pesticides and neem.
But the toxicology of those substances doesn't match CHS. And we've identified the genetic cause. Unfortunately, people are always looking for other explanations and find it hard to believe that THC is the culprit. So in this instance, it's too much of what can be a good thing is a bad thing for certain people. So we've really bombarded Dr. Russo with a lot of great questions today.
And I just want to thank you again so much for your vast knowledge and insights. I know I've learned a lot. I hope everyone else has as well.
So thank you once again on behalf of the USDA Plant Genetics Resources Unit and Cornell University at Cornell Agritech. So once again, thank you. It was a real pleasure. Thank you.
Appreciate it. This has been a production of Cornell University, on the web at cornell.edu.