Project CBD: I’m Martin Lee with Project CBD, and today we’re speaking with Dr. Ethan Russo, a neurologist and past president of the International Cannabinoid Research Society. Dr. Russo was also formerly the chief medical director of GW Pharmaceuticals and in that capacity he was involved in developing the drug called Sativex, which is now approved in, I think two dozen countries – but not in the United States. It’s a formulation including both CBD and THC. And Dr. Russo was also involved in research that culminated in the FDA’s approval of Epidiolex, a CBD pharmaceutical that’s now prescribed for three different pediatric seizure disorders. Currently, Dr. Russo is the founder and CEO of CReDO Science, and we’re going to be speaking a little more about that in this conversation. Thank you for joining us, Ethan.
Dr. Russo: Thank you. A pleasure to be here.
Project CBD: Today we’re going to discuss an article you co-authored that was recently published in the journal Cannabis and Cannabis Research. The article focused on a phenomenon known as Cannabis Hyperemesis Syndrome. Maybe you can start by explaining what is syndrome?
Dr. Russo: Sure. Well properly speaking it’s called Cannabinoid Hyperemesis Syndrome [or CHS] because it actually can occur with synthetic cannabinoids – anything where there is a chronic high potency exposure to the CB1 [cannabinoid] receptor. So what is Cannabinoid Hyperemesis Syndrome? It’s a constellation of unusual circumstances that heretofore has been of enigmatic origin. It consists of nausea, vomiting, abdominal pain, and a strange behavior of hot water baths or showers that seem to alleviate symptoms. This was first reported in 2004, but the index patient went back to 1996. This was in Australia. Subsequently it’s been found all over the world, but nowhere more prevalently then in the US, as you might imagine, given the pre-eminence of the United States in the development of higher-potency cannabis chemovars, and particularly concentrates.
Project CBD: I’m a little bit confused about something: When I think of cannabis or cannabinoids, I think of something that actually helps nausea in the context of the medical cannabis phenomenon in the United States that emerged legally in the 1990s. I think that was one of the main conditions for which cannabis was helpful. You’re saying that, in this case, it’s just the opposite. Maybe you can shed some light on that contradiction.
Cannabinoids are subject to what’s called the biphasic effect. They may do one thing at a low dose but do the opposite thing at a high dose. And that’s precisely what happens with THC.
Dr. Russo: Sure. This is a really deleterious association because many people who develop CHS hold that same view without realizing that cannabis, and particularly THC, has the capacity to be pro-emetic, in other words causing vomiting, if the dosage is too high. So, it’s been known for decades that THC in low doses is anti-emetic, helps prevent nausea and vomiting, especially associated with chemotherapy. And it was actually the synthetic form of THC, [known] as Marinol, which was FDA approved in 1985 in just that setting for people who had cancer and were having vomiting problems associated with their chemotherapy. But most cannabinoids are subject to what’s called the biphasic effect. In other words, they may do one thing at a low dose but do the opposite thing at a high dose. And that’s precisely what happens with THC. At high doses, it can provoke vomiting, but usually this is a self-limited condition.
What is distinct in Cannabinoid Hyperemesis Syndrome is that the vomiting becomes a cyclic, chronic phenomenon that really can be abrogated by a couple of interventions. Specifically, haloperidol works better than most standard anti-emetics, the drug that’s usually used to treat schizophrenia. And capsaicin ointment – the ingredient in hot chile peppers – applied to the skin is absorbed and seems to help. And the hot bathing behavior seems to temporarily alleviate the symptoms. But the definitive treatment in this instance is abstinence from cannabis, because when people re-initiate use of cannabis, especially after they begin to develop tolerance to THC again, inevitably they have recurrence of the condition.
Project CBD: I wonder about when you mention capsaicin as a topical that would be used sometimes to ameliorate this condition. I think of topicals usually as working locally not actually getting into the blood and having a systemic effect. What’s going on there?
Dr. Russo: Well, there are substances that get through the skin perfectly well, and capsaicin is one of them. Also, essential oils like the terpenoids in cannabis can penetrate the skin. For better or worse, the cannabinoids get through into the bloodstream very poorly. Interestingly, people probably think the way that capsaicin, hot chiles, are normally used by ingestion, in other words, eating them. But actually gastrointestinal absorption of capsaicin is very poor. Evidence for that is sometimes the food that’s hot on the way in is also hot on the way out. I don’t think it needs to get more graphic about that. But, in fact, the bioavailability, the ability to get into the bloodstream is greater after application on the skin than it is by mouth.
Project CBD: Before we get into some of the specifics of the study that you conducted to write this paper, I’m wondering how CBD might factor in as a remedy. CBD is often thought of as kind of countering the effects, or tempering the effects, of THC. Would that apply?
Dr. Russo: In this instance, we don’t have the definitive answer. One of the first things I asked a couple of people I knew with the condition to try was CBD preparations to see if people fared better. There’s some indication that the answer is “perhaps.” However most people do not find that it prevents the episodes of abdominal pain, nausea, vomiting, etc. Part of the problem is, as you’re well aware, there are problems with quality control in the industry, and it may be that particular preparation is billed as being CBD only, an isolate, but often that’s not the case. Often there is contamination with THC. So, if the question were “what would happen with pure CBD” like Epidiolex or genuinely pure preparation of CBD, would that not have this effect? The answer is, probably not.
But things get really complicated. In our discussions with people with CHS, they have found often that they develop triggers to the nausea and vomiting even without using cannabis. And this can be strong smells, including the smell of cannabis – and it makes you wonder about a conditioned response. That’s the idea like Pavlov’s Dog that when people develop certain associations they develop a reaction, a bodily reaction, that’s triggered by something else. So, in this instance the smell of cannabis could be a trigger, just like walking into the chemotherapy clinic before you even get the medicine, what’s known as anticipatory nausea.
Additionally, I should mention, CBD is anti-emetic itself, so there’s reason to think it could be helpful, but what we really would need would be an experiment in double-blind fashion to use the purest CBD product to see what happens. So the answer is maybe, but we’re not sure.
Project CBD: You mentioned triggers that might set off this experience. It’s been brought to my attention some of the theories that might cause this phenomenon – pesticide exposure – maybe you could run through some of these and explain or shed light on this.
Dr. Russo: Sure. Let’s run through some theories. We’ve mentioned already that high doses THC can produce nausea. But what about the rest of it? That wouldn’t quite explain it. There’s the prevalent theory among people with CHS that this is due to pesticide exposure. However, the symptoms of pesticide exposure are quite distinct from what we see in CHS. Plus, there’s an extremely well-documented case of a person who had used cannabis and seemed to have CHS but had stopped entirely for six months, and this was confirmed with urine toxicology screens that he needed for work. So there was no exposure to THC, but he started using synthetic cannabinoids. These are high potency CB1 agonists like K2, Spice, etc. And he had CHS, subsequently diagnosed, he had a negative urine screen [for THC]. But he had a positive urine screen for the synthetic cannabinoids. And once he stopped the synthetic cannabinoids, then he had remission from the disorder. So it’s absolutely clear that this can happen with other agents now. I’m not saying that any of the synthetic cannabinoids are safe – nobody should think that they are. They’re quite different from cannabis. But the point being that there would be no reason to expect to find pesticides in the synthetic cannabinoids.
Another one related to this is the use of Neem. Neem is derived from the seed of a plant that grows in India and it’s used in organic agriculture. But again, there’s no toxicity attached to it that matches what happens with CHS. Then there’s another theory that’s come along. Many cannabis varieties now are infected with plant viruses, or what’s called hop latent viroid, which really interfere with growth and production of the cannabinoids. However, there’s no proof that this is related [to CHS]. We know that plant viruses actually can live in the human body and appear in the stool. But exhaustive work on this has not shown that any of the plant viruses can affect human disease. The additional evidence I would offer is that we believe that we’ve discovered the real factor behind Cannabis Hyperemesis Syndrome and that is a genetic predisposition to developing the disorder.
Project CBD: I was going to say, a lot of people these days are using very high THC cannabis, but obviously not everyone is experiencing this syndrome. So I guess two questions in one: To your point we’ll get into the genetic basis of this that your paper goes into, or the potential genetic basis. But also how prevalent is this really? And how dangerous is it? We hear so much over the years, you might say slander about cannabis even, so many things have been said that’s basically misinformation going back to the Reefer Madness days, so I think there’s an unfortunate tendency among cannabis partisans – at least some – who just disbelieve anything that’s critical of cannabis. So if you could give some context here. What are we really dealing with? And then let’s look at some of the genetic potential causes.
Dr. Russo: Sure. So CHS is a very dangerous condition. People often lose a lot of weight, they often can’t work. They will have many diagnostic tests done, end up in the emergency room, or hospitalized. We’ve seen estimates in the literature of cost expenditures attached to getting a diagnosis between $25,000 and $95,000 per patient. And this was borne out in the survey that we did as well. There’s also been at least two deaths attributed to complications of CHS. If someone vomits continually their body chemistry can become disturbed. This is a very serious disorder. How prevalent? We really don’t know. But as you mentioned, we know very clearly that not everyone who uses high amounts of cannabis seems to get this. Well why would that be? There are these genetic differences, which we’ll get into shortly. But how prevalent is this? Again, we don’t know, but I’ve seen estimates in the literature that vary on the low side from 350,000 Americans up to 2.75 million Americans. It’s a hard thing to ascertain because a lot of people that have this are not seeking medical help. And so we really don’t have reliable figures.
Project CBD: What about the genetic correlation here? What’s going on with a person who would be experiencing the syndrome? What are some of the factors you discuss in the paper?
Dr. Russo: We started out with a survey online with 585 people. We were extremely rigorous in making sure that people had all the symptoms of Cannabis Hyperemesis Syndrome, that they were ongoing, and they had a formal diagnosis. That whittled it down to 205 people who were offered the possibility of genetic testing with a swab in the mouth. We also needed controls but it couldn’t just be anyone. We wouldn’t know if someone that never used cannabis would be susceptible to the condition if they hadn’t had the exposure. So we found as controls people who had high amounts of cannabis intake. And it was comparable. Both groups averaged about 4 grams of cannabis use per day. Again, that varied. But ultimately there was a mismatch between people who were offered the test and the ones who agreed. Of the 205 CHS patients who had a diagnosis, all the symptoms that were ongoing, 99 said they’d take a test kit but only 28 returned them. And this was due to some [undetermined] interference with their study. There was a lot of resistance to this.
We believe that we’ve discovered the real factor behind Cannabis Hyperemesis Syndrome and that is a genetic predisposition to developing the disorder.
So there were 28 CHS patients who had genetic testing, and 12 controls. However, despite those relatively low numbers that we wished had been higher, we ended up finding five statistically significant differences in genetic mutations. These were very illuminating. One was one that we hypothesized. Could there be a problem with the metabolism of THC, in other words, how it’s broken down in the body? Well the main enzyme that breaks down THC is something that is called CYP2C9. And we found a mutation on it. (I’m going to refer to notes here so that I get things right.) We found this mutation on the CYP2C9 gene in 46.4 [percent] of the CHS patients and only 10 percent of controls. So that was statistically significant. Because if this enzyme isn’t working properly it could lead to THC build-up, which again could lead to two things that are undesirable: one would be flipping over to being pro-emetic rather than anti-emetic, and it also would raise the possibility that it is producing other products rather than the normal 11-hydroxy-THC. In other words, there could be potential toxic byproducts from such a problem.
Another enzyme that we looked at was the CNR1 gene that codes for the CB1 receptor where THC does a lot of its work. So we thought there could be something there. In fact, we didn’t see it in the CHS patients. But this is important because there is another condition called cyclic vomiting syndrome that does have mutations on the CNR1 gene, so this provides a point of distinction between the conditions that can get confused.
Also important, we had hypothesized that perhaps the TRPV1 receptor where capsaicin works might be involved. And in fact it was. We saw a mutation on that gene in 71.5 percent of the CHS patients, and only 30 percent in controls. So this was statistically significant. Now that’s important because TRPV1 has a lot activity in the body. It influences pain. It influences gut motility, how the gut moves. It also is involved in nausea and vomiting reactions in the brain. So this was illuminating.
Additionally, we found mutations on two genes related to dopamine. One was on COMT, that’s catechol-0-methyl transferase. That is the enzyme that breaks down some of the neurotransmitters, particularly dopamine. So we saw mutation there in 57.1 percent of the CHS patients and only 10 percent of controls. This explains a lot because if that enzyme isn’t working properly there’s too much dopamine and this leads to all kinds of problems. First, it produces nausea; second, when there’s dopamine excess it’s associated with a whole bunch of problems, including compulsive behavior that can include compulsive eating, a lot of addictions to various kinds of substances, gambling, etc. But it’s also associated with a lot of psychiatric issues including depression, rumination (not being able to get a thought out of your head), increased alcohol intake, attention deficit, anxiety, and psychosis. Unfortunately, these are all risk factors for somebody who has that kind of mutation.
As if that weren’t enough, there was a second gene related to dopamine and that’s called the DRD2 gene which codes for the dopamine-2 receptor. We saw mutation there in 60.7 percent of the Cannabis Hyperemesis Syndrome patients and only 20 percent of controls. This mutation is associated with depression and anxiety, also nicotine addiction and chronic pain. So we’ve got this sort of double whammy related to dopamine, and we think that this explains a great deal.
Finally, there was a mutation on what’s called the ABCA1 gene, the ATP-binding cassette transporter. We saw that in 67.9 percent of the CHS patients and only 20 percent in controls. So again, that was pretty highly statistically significant. This mutation relates to cholesterol metabolism. Unfortunately, it points to a susceptibility to development of Alzheimer’s disease later in life. Also to risk for Type-2 diabetes and coronary artery disease.
These were very sobering results because while they explain a lot of the phenomenology of Cannabis Hyperemesis Syndrome. They also point to a lot of dangerous comorbidities. In other words, folks that have this may be susceptible to a whole bunch of other problems, including these psychiatric diagnoses, and risk of dementia and heart disease later in life. We think it’s really important that people that have these symptoms consider having this genetic screening to find out if they have other susceptibilities. Also, as a possible confirmatory way of ascertaining CHS risk.
Project CBD: It’s actually quite sobering and fascinating what you’re describing. A last question: Perhaps you could tell us a little bit about the work of CReDO Science that you’re focusing on? Is this a typical study that you’d be doing? What’s on the horizon for CReDO that we might be on the lookout for?
Dr. Russo: We call CReDO Science an intellectual property holding company – meaning that, we’re trying to develop products and services related to cannabis and the endocannabinoid system. One of our mottos is that we’re trying to make cannabis safer and better. But part of that is having a genuine understanding of the risks and benefits. Now, you know, and I hope that much of your audience knows, that I’ve been a great proponent of therapeutic cannabis usage over time. However, we need to counter the mythology that cannabis has no side effects and really tell the truth. CHS happens to be one of the few serious side effects associated with excessive cannabis usage. We’ve really not encountered this in therapeutic cannabis usage at low doses. It seems to only occur with high intake where tolerance has developed and over a long period of time.
So to answer your question, we have one other diagnostic test we’re researching related to the endocannabinoid system. We should have an answer on that very soon. We have nutritional products. We have a product related to head lice. We’re also engaging in a lot of formulation work for the supplement industry and potentially for the pharmaceutical industry to try to provide optimized formulations for specific conditions. Right now, as it is, there’s a lot of hit-and-miss when it comes to attempts to use cannabis therapeutically. And I would maintain that most preparations have not been properly constituted to do the job in the most effective and safe manner.
Project CBD: We look forward to hearing more of the results of these efforts. Thank you, Dr. Ethan Russo.
Dr. Russo: Thank you.
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