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Ep #9 Transcript | Ethan Russo: Medical Marijuana, Plant Medicine, Cannabis & the Entourage Effect

Full episode transcript below. Beware of typos!

Nick Jikomes

Ethan Russo, thank you for joining me. Pleasure. How are you and where are you?

Ethan Russo 1:59

Well, I'm at my home my home office on vashon Island near Seattle.

Nick Jikomes 2:06

Cool Yeah, that's that's close to me. For those who don't know, I'm in Seattle as well. And we're gonna talk about a lot of stuff today related to cannabis, cannabinoids, terpenes, the entourage effect all that stuff, medical cannabis. Can you start out by just briefly describing your technical background?

Ethan Russo 2:24

Sure. Well, I'm a neurologist by training, but for last 30 years I have been heavily involved in medicinal plant research. Really accelerating after sabbatical in the rain forest in Peru in 1995. Thereafter, I quickly became embroiled in the cannabis controversy and tried to do clinical studies through the FDA, getting stonewalled initially by the FDA and then by nyda. But during that time, I was learning a great deal about cannabis and the endocannabinoid system on led to my first publication in the journal pain in 1998. And began my association with GW Pharmaceuticals the year they began. Subsequently, in 2003. They asked me to come on full time as senior medical advisor. So for the next 11 years, I was involved in the Sativex and epi dialects development programs. So I've worked in the cannabis space for 25 years and culminating this past year and the beginning of my own intellectual property holding company called credo science. And we're also involved in creating cannabis based formulations for industry or whether it be supplement companies or hopefully eventually a pharmaceutical company as well.

Nick Jikomes 3:59

Wow, that's so it's a fascinating background. There's a number of things I want to go back to, I think later in the discussion about about your background. But you mentioned Sativex and epidiolex. And so to start with, I thought maybe you could describe what are canap plant cannabinoids, let's just start with the two big ones THC CBD to set the stage for everyone. And then can you talk about Sativex and epidiolex and what those you know official approved medications actually are.

Ethan Russo 4:26

So can ammonoids initially referred to substances that the plant cannabis ativa makes on there been upwards of 150 of these identified the two best known being THC tetrahydrocannabinol which is the main psychoactive ingredient of cannabis. And it works analogously to endogenous cannabinoids endocannabinoids particularly Amanda mide, in that it likewise is a weak partial agonist on the CB one and CB two receptors can have a dial in contrast as a non intoxicating cannabinoid, but which is nonetheless psychoactive and this is a misconception I see a great deal in the literature let alone in common parlance. CBD is definitely psychoactive because it has strong anti anxiety and anti psychotic effects, among others. Also very useful and the ln side effects associated with THC. Beyond that there probably 10 other cannabinoids in the plant about which we have at least partial pharmacological information. But that leaves about upwards of 140 where we just don't have enough information and that's one of the gaps in our knowledge and I'd like to see fill full, filled in coming years. So in addition to plant based cannabinoids, or Phyto cannabinoids, there are rare examples of other plants that have cannabinoid like activity or specifically can Abba Gerald has been found in a south south african plant.

Nick Jikomes 6:15


Ethan Russo 6:16

Yes, cb J. So that's the plant is let me think a minute. I'm hella crisis I'm braclet jerem sometimes the neurons don't connect too fast. Um, but that's in trace amounts there. In general, the best source of plant cannabinoids is cannabis. So in addition, we have what I mentioned before endo cannabinoids, cannabinoids within our bodies. And they're also synthetic cannabinoids like synthetic form of THC in Marinol culture NAB and all on NAB alone, which is a a an analogue of THC. And then there are many others whose structures can be quite different. So those are the three classes of cannabinoids.

Nick Jikomes 7:10

So you know cannabis is a schedule one controlled substance in the United States. So it's highly regulated. But we do have a small number in the US and in other countries. It depends. The medications that are approved and they're made of cannabinoids, the two the two that come to mind are Sativex and epidiolex. So can you just talk about what those medications aren't what exactly is inside of them?

Ethan Russo 7:33

Sure. So these are both medicines that are cannabis derived on Sativex is a combination of two cannabis extracts, one high in THC and one high in CBD. So it comes out is basically about a one to one mixture with a smattering of terpenoids as well on this is in a spray that sprayed in the mouth to the mucous mucosal surfaces. That is approved in 30 countries for treatment of spasticity and multiple sclerosis and also approved in Canada for treatment of cancer pain. Right then, um, epi dialects is basically a purified CBD extract. It's about 97% pure CBD. In addition, on the US we have a couple of other medicines not used so much. One is synthetic THC or Marinol, which is approved in 1985. And then its counterpart NAB alone, which is a semi synthetic, longer acting 10 times more potent. But again, neither one of these is really gained a lot of traction in the clinical realm. When people have the opportunity to try both and variably they prefer herbal forms of cannabis or these extracts.

Nick Jikomes 9:02

So Sativex, it has its THC and CBD, it's about a one to one ratio. So it's actually a plant extract if they're combined. Yes. And then that's used to treat spasticity for multiple sclerosis that's used to treat some symptoms related to cancer. And then epidiolex is the one that people have probably heard about in the last year or two. That's the epilepsy treatment.

Ethan Russo 9:24

Sure. Now specifically that one is approved in the US for three indications now in 2017. It was approved for two forms of epilepsy called Lennox guest Oh syndrome and durveys syndrome. These are two severe epilepsy syndromes, mainly of children, but also some surviving adults. And this past year was also approved for seizures associated with tuberous sclerosis. Now, that because it's a purified medicine, and CBD is not enormously potent on its own, usually very high doses of that are required. And that's a factor in this being a very expensive medicine. If someone were paying for it, it's estimated that the annual cost for a patient with one of these severe epilepsy syndromes would be $32,500.

Nick Jikomes 10:23

So in a single dose of epidiolex, about how many milligrams of CBD would be in that,

Ethan Russo 10:28

um, I think it's 100 milligrams per milliliter, but people are using large amounts, 1500 2000 milligrams a day. Those it's a liquid net, those higher doses, there can be some associated diarrhea. They've been some drug drug interactions, most of the patients with these syndromes are on polypharmacy multiple drugs on so again, because of the high milligram amounts of CBD there is the potential for drug drug interactions.

Nick Jikomes 11:03

So at least for epilepsy, you need those high doses, and then the flip side, so you've got this medical application for CBD that's been approved. But then CBD is this health and culture phenomenon. Right now if you walk into a dispensary or you walk into Walgreens, you can buy CBD products, these typically have five, maybe 10, maybe 15, or 20 milligrams per dose, whether it's an edible, whether it's an A tincture, or whatever. So what do we know about dose and the effects of CBD? Are those low doses likely to be doing anything for people?

Ethan Russo 11:36

Ah, well, you know, there are various factors and ascertaining whether medicine is effective and really ultimately is up to the consumer to decide. For better or worse, as I mentioned, CBD is a very versatile medicine, but it is not potent, usually need a lot, even in something less serious on terms as compared to epilepsy is treatment of anxiety. And we know from experiments mainly done in Brazil, that you need a few 100 milligrams of CBD to treat anxiety effectively on its own. Now, its strength is really in herbal preparations or in extracts where there's some combination of CBD with THC. I like to say that there's nothing that CBD does, that won't be enhanced by at least having a tiny amount of THC. So the two synergize. Together, they work as an ensemble, that's better than either one alone. th sound its own is a lousy drug that's poorly tolerated. You know,

Nick Jikomes 12:59

so so let's unpack that a little bit for people because I hear that all the time, especially in in the cannabis community that CBD needs a little bit of THC to work now is can you can you differentiate between that statement and save the ability of CBD to mitigate some of THC side effects? Is it true that CBD can't do anything without a little bit of THC?

Ethan Russo 13:22

Ah, no, no, it's been proven to the satisfaction that the FDA that high doses of CBD are effective at treating these serious forms of epilepsy. Full stop, okay. But again, Pamplona did a meta analysis and showed that, at least anecdotally, because these weren't randomized controlled trials, when people are using CBD, as an extract, you seem to get similar results in these serious seizure syndromes with about 20% of the dose that's required when it is pure, and with fewer drug drug interactions. So again, this is an area of controversy, you know, the vested interests on both sides. I'm a firm believer in whole plant and extracts and the entourage. Whereas, you know, it's expedient for some people to think in terms of synthetics, or single molecules as treatments. But when we're dealing with complex human disorders, it's not always and most often is not sufficient to have one target and one molecule treating it rather often we need multiple drugs. Fortunately for mankind, cannabis is polypharmacy and one agent. It evolved With this combination of different chemical components that seem to work in concert very well for a wide variety of conditions, tapping into the endocannabinoid system and other mechanisms. So again, I'm a firm believer in this synergy are boosting of effect. And that can consist of additive effects towards the same man because THC and CBD both have some pain relieving properties that both anti inflammatory but again, CBD has this wonderful ability to reduce side effects of THC, including anxiety, panic, rapid heart rate, and it will do that at lower doses than not several 100 milligrams that we're mentioning, in relation to its use. For single conditions. I should add at this point, that using 800 to 1000 milligrams of CBD is a pure compound a day has also been proven in schizophrenia and two randomized control trials, phase two. So yeah, it is a proven efficacy. It's just that we have gas station CBD and online CBD. As he mentioned, a lot of these preparations really don't have enough that we would think that they're really doing with job. If however, people take them and feel better, they're going to continue to buy them. Now how much of that is placebo effect? Well, probably good amount. But ultimately, people use what helps them so it's a complex issue.

Nick Jikomes 16:48

Yeah, there's a lot I want to go into on this stuff. Let's let's unpack some of the basic biology a little bit more you were talking about? polypharmacy? Can you describe what that is a little bit more with respect maybe to CBD and how many different receptors it touches.

Ethan Russo 17:03

Sure, so polypharmacy, this means more than one drug. There are established about 30 mechanisms of action of CBD doesn't act. Interestingly, it doesn't act directly on the CB one receptor like THC. However, it acts on what's called an allosteric site as a negative allosteric modulator. This means it changes the conformation of the main receptor and makes the binding of THC a little bit harder. Now, you would think that that would detract from the clinical efficacy of THC, when in fact it doesn't. So somehow, this complex relationship that nature has produced, is very beneficial. And again, is led to combination THC and CBD herbal combination inside of x that's approved in 30 countries just outside the US.

Nick Jikomes 18:10

So CB one that's the receptor in the brain in the body that's primarily responsible for the psychoactive effects of THC. Correct. CBD has a very different relationship to that receptor, it will bind to the receptor in a different way it will prevent THC from interact with that receptor. And this is at least part of the synergy or the interaction that can happen for THC and CBD. Yes,

Ethan Russo 18:34

that's, that's quite true. Now in addition to that CBD is an agonist a stimulator of a different receptor, the trip v1 receptor, which is the same place where capsaicin, the active ingredient, the hot stuff, and chili peppers works. Now this is a receptor related to pain, temperature control, etc. And it's also in proper doses can affect anxiety in the brain. Now, unlike capsaicin in the chili peppers, CBD is not caustic, it doesn't produce a burning feeling. But like capsaicin, when there's enough of it, it can desensitize the receptor which is helpful in pain control. So that's another mechanism. Additionally, a lot of the benefits of CBD seem to derive from its effect on a third receptor, which is serotonin one a receptor. This is a basis for its benefits and anxiety, but also has proved to be the way that it treats nausea and vomiting. I'd also reduces brain damage related to a paddock encephalopathy when people's livers have gone bad and they get too much ammonia in the circuit. lesion that's toxic to the brain, but some of the damage can be allayed by CBD. There's also activity on related to what about 27 other items. The more we dig, the more we see.

Nick Jikomes 20:19

CBD is just doing a lot of different stuff.

Ethan Russo 20:21

You bet. Now, generally, that's what is called the proverbial dirty drug, meaning that it doesn't do one thing, you know. So it's unlike some of the biological agents where it's an antibody. It's designed to take something out. In order to reduce function of a specific target. This is very different. It's working on many different targets. And usually that produces more side effects. What's unique about CBD is despite all these mechanisms of action, almost none of those activities are bad for you. CBD is a remarkably benign drug. In terms of its side effect profile, this is all a good thing. One other mechanism of action I should report is CBD also inhibits for fatty acid amino hydrolyze, which is the enzyme that breaks down an and amide then Endocannabinoid in the brain and elsewhere. So it may boost what we call Endocannabinoid tone, the overall activity of the endocannabinoid system which is generally going to be a protective mechanism, and keeping our physiology in balance. So over time, with this boosting of Endocannabinoid tone, it's generally going to be helpful in a large variety of disturbances, diseases.

Nick Jikomes 22:00

And so you mentioned also Marinol synthetic THC that's been around for a while, but it hasn't really caught on. It's not really used very much. So what's what's going on there? How does the synthetic THC compared to other forms of cannabis?

Ethan Russo 22:15

Okay, well, it is THC without everything else. And as I mentioned, on pure THC is a lousy drug. It doesn't make people happy, it makes them dysphoric. unhappy. Also, people take it feel very scattered, hard to think, hard to function on, it was proven effective in treating nausea associated with chemotherapy and was approved by the FDA clear back in 1985. Then in 1992, it was also approved for AIDS wasting associated with HIV.

Unknown Speaker 22:49


Ethan Russo 22:52

it's never been popular. It's never been had an active following on the black market such that by 1999, it was rescheduled from schedule two to schedule three less restrictive, because there wasn't evidence of its abuse. Even people who are accustomed to cannabis who tried Marinol, tend to find it hard to handle and don't like it. So it's not often used in clinical medicine. Right. So basically, it's THC without anything else, it doesn't have benefit of CBD with it to allay side effects, or terpenoids that contribute to the beneficial properties and also reduce the adverse event profile. Right.

Nick Jikomes 23:46

Interesting. So pure THC is behaving differently, presumably because it doesn't have these other compounds around that are interacting with it in some way. People don't tolerate it as well. And we know that there's a lot of other stuff in cannabis. One more question before we go to the herbal side of things. You mentioned that epidiolex was I think 97% CBD. So do we know what the other 3% is? Or at least whether or not the other 3% is efficacious with respect to its epilepsy treatment?

Ethan Russo 24:20

Yeah, I'm gonna say probably not. I mean, there's just a trace of THC. FDA remains a bit THC phobic at least cannabis based medicines on there's probably a trace amount of other cannabinoids and terpenoids but it's pretty stripped down.

Nick Jikomes 24:40

Okay, so we've got epidiolex that's mostly CBD. We've got Sativex that's THC CBD. We've touched on this idea that there are interactive effects between THC and CBD. We've discussed Marinol synthetic THC and how it doesn't behave the same as herbal you know, plant derived THC. We've touched a little bit on some of the other minor cannabinoids, can you start talking a little bit about this concept of the entourage effect? And maybe let's, let's actually back into it from the plant's point of view. So Are there examples of entourage effects in nature and why would a plant be making a cocktail of stuff?

Ethan Russo 25:18

Okay, wait, let's use a different plan is there an example gingko biloba traditionally used to treat dementia and elderly people. This is derived from leaves of the gingko biloba tree on it is normally there's a thing called egb 761 extract of ginkgo biloba. 761, which has been used in most of the randomized control trials are going back over the last three decades. That is standardize to three different sets of components, not single molecules, but classes of components. Because there's never been established that gingko biloba as a single active ingredient, rather, it is the combination of these three sets of components. Now, some time ago, in France, there was a single molecule derived from ginkgo biloba that was used to treat septic shock, this is where somebody has bacteria circulating through the body, and they're in shock. You know, so this is potentially life threatening, um, that drug was approved, but it was found that it was not as effective as the extract on So again, it's the combination of three ingredient sets of ingredients. That makes kinko by Lobo, what it is, um, yeah, I'll give another example. Another herbal Agent hypericum perforatum. I St. John's wort is used to treat depression. And it's been about equally effective to some of the conventional antidepressants. Again, it's unclear what the active ingredient is. One of the putative ones, is called hyper foreign. This is a weird molecule, it's very two dimensional, most molecules are 3d, this is in just a flat plane. When this is isolated, it is highly unstable. It needs to be kept under liquid nitrogen to stay together. However, when you just go through a normal extraction of the plant, and hyperforin is in it, it stays stable. The plant knows how to keep it together, so to speak. So there's an if I may say in any wisdom, I should mention at this point, that throughout human history, plants have been our medicine and remain so for many people around the world, particularly indigenous groups. It's only in the last 75 years that synthetic chemistry has come to the fore as a provider of our medicine. Sometimes that's good, and sometimes it's not. Right.

Nick Jikomes 28:34

Interesting fact. Yeah, so the plant might make a host of compounds, either because there's maybe interactive effects, which we can get into. But But in this last case, it might purely just be to stabilize the the one active compound that's there, because it'll literally just break down in the face of the elements.

Ethan Russo 28:54

Sure, exactly. Another example traditional Chinese medicine. Typically, traditional Chinese medicine is formed from recipes, not one agent, but it might be 10 or more. And typically, if you investigate it, you'll find that maybe three of the 10 ingredients are directly directly related to the condition you're trying to treat. And then some of the others are to counteract side effects the first three and some others, maybe for stability or taste, or otherwise make it a more acceptable medicine. cannabis is like traditional Chinese medicine and one plant because of its combination of ingredients. So the entourage effect refers to the idea that you may have a solo s does sort of active main active ingredient. And then you have these other things which seemingly don't do a lot on their own. But when they're present on they To boost the overall effect on this is called synergy. synergy is the idea that one plus one equals four rather than two synergy can be in the form of boosting of a specific therapeutic approach like treating pain, but it also can be reduction of side effects. So there are many examples for cannabis that support the idea of the entourage effect and synergy. On we can go through those that feel like

Nick Jikomes 30:33

yeah, let's let's get to that. Are there any examples of this in what we would call you know, traditional pharmaceutical medicine where you have a main one soloists domain active ingredient, plus something else to boost it or stabilize it?

Ethan Russo 30:49

Sure. Um, okay, let's use the example and treating Parkinson disease on among other things, Parkinson disease manifests on a deficit of dopamine in the brain. Now, there is a very common drugs Sanomat, but it's a combination drug of two, two things. One is L dopa, which is a precursor to dopamine. But normally when this is given, it's an activated out in the body before it can collect in the brain. So it has to be provided with a second component called carbidopa, which inhibits the breakdown of the L dopa so it can get turned into dopamine in the brain and supplement what's missing.

Nick Jikomes 31:41

It's kinda like IO Oscar or something.

Ethan Russo 31:43

Sure, yeah, that's another example. So there, you've got on the real psychedelic component is dimethyltryptamine. But you can't absorb it. orally, it's inactivated, before it gets to the brain. So it has to be given with harm harming and harmelin alkaloids, Mo inhibitors that prevent its breakdown, it gets to the brain and becomes active.

Nick Jikomes 32:16

That's that's actually a almost a perfect analogy in, you know, the, the western approach, you have this treatment for Parkinson's, and it's literally an active drug plus another drug that prevents its breakdown so it can actually get to the brain. And in the Amazon, you know, that's, that is what I asked it is it's an active drug that will get broken down, except in the presence of this other drug that allows it to get to the brain. So, so this common tutorial approach. I mean, it's it's common, it's been used throughout human history. Before we get to the entourage effect, per se, can you maybe talk about the cannabis plant and its natural history? What Why is this plant producing cannabinoids and terpenes and what are terpenes? Exactly?

Ethan Russo 32:59

Sure. Well, the plan isn't making these cannabinoids to get us Hi. So as much as we'd like to anthropomorphize, the plant is 30 million years old. The endocannabinoid system is 600 million years old humans are under a million years old. So that's the order of things. It's just the happy accident of nature that this has provided recreation and medicine for people. So we're making use of that. Why does the plant expand all this metabolic energy to make all this stuff? Well, it's for ecological reasons. On cannabinoids, many of them are perform activity in the plant in reducing ultraviolet light damage, preventing predation by insects. And this is also true the terpenoids that cannabinoids and terpenoids are produced in the same part of the plant, the glandular trichomes. These are like clear spheres on top of stocks that are concentrated in the unfertilized female flowering tops. The terpenoids again are provide an ecological defense for the plant and they can prevent fungal infection, they can prevent bacterial infection, they can either repel insects or attract beneficial insects. And these will vary according to the genetics and the environmental conditions. So cannabis, as well as other plants can change the components that are produced the terpenoid entourage, depending on what's eating it, so to speak. And we know that plants can actually through their root systems can send signals to surrounding plants, that they're under attack, and they will increase their production of these defense compounds. So, there is wisdom there. plants don't pick up and walk away when there's a threat they learn to combat this through biochemical warfare.

Nick Jikomes 35:25

Yeah, so they're really almost natural pharmaceutical factories that have evolved to produce specific combinations because they actually do things in combination. Right? So talking about cannabis and the entourage effect, and terpenes. So we've already talked about CBD and THC. There's this interactive effect with THC and CBD. We have a pharmacological basis for that one because THC is this partial agonist or activator of CB one? CBD is this negative allosteric modulator. So there's there's a literal interaction at a particular site. They do other things as well. Are there any known pharmacological interactions between any of the cannabinoids and the cannabis? terpenes?

Ethan Russo 36:09

Oh, sure, many, you know, I can provide a lot of examples. Ghana's easiest to talk in terms of what they do with THC. So I've already mentioned THC on its own is dysphoric. People feel very scattered, can't think can't function as well as they would if they were not under the influence. How do we make that better? Well, the terpenoid effects are specific. Let's give some examples. limonene is one of the terpenes that we'd like to see more of in cannabis. It's not around so much these days. But limonene has a marked anti depressant effect and brightens the mood associated with THC?

Nick Jikomes 37:06

Is that is that coming to us from clinical work in humans or animal studies, or both?

Ethan Russo 37:12

Ah, well, combination on a lot of this is human observation, which would be considered anecdotal. There's studies underway formally now at Johns Hopkins University, to look at terpenoid THC interactions. And this would be an randomized controlled trials with humans with strict psychometric testing to demonstrate the results and hopefully shows statistical significance. Um, but these are observations from people who have tried these combinations. And we know what lightning does on its own, both in animals and in humans. It has a marked antidepressant effect. But this seems to be synergized, again, by combination with THC.

Nick Jikomes 38:06

And there's the question, so we'll just we'll stay on limonene as an example. So based on the doses that are used in animal studies to see such effects, and based on the typical concentration of limonene in commercial cannabis flour, say, which is going to be you know, when it's there, it's it's probably not going to exceed point 5% of the dried weight of the of the flower that are examples, but yeah, but but like, I guess the question is, are the terpene concentrations that you would find in a commercial cannabis product high enough for them to be plausible for pharmacological effect,

Ethan Russo 38:43

right? Well, they may be or may not be, but this is part of the reason that I'm always harping about selective breeding for these components. As it stands now for looking at commercial cannabis. The vast majority of what's available is high THC with high mersing, or more recently, CBD with high mersing. But in the latter instance, that's produced this misconception that CBD is the dating. It's not at low or moderate doses. CBD is alerting. There are people in California now that are using CBD instead of coffee in the morning. at extreme doses, it can be sedating. But when when myrcene is combined with THC is predictive of a phenomenon called couch lock, which is basically what it sounds like, people use it. They're immobilized, they can't get up. Now that's fine if you're in pain and need to sleep, but it's not good. If you've got a chronic pain condition. Can we can we

Nick Jikomes 39:50

actually unpack that one because that's one that I hear a lot. Merci makes you sleepy. Mercy is responsible for couch lock. I hear a lot that it is enhances the psychoactivity of THC by affecting blood brain barrier permeability, but I've never been able to find any evidence for those claims.

Ethan Russo 40:07

Okay, again, a kind of thing that hopefully will be proven in these formal studies. And this is an NIH supported study, but it's going to take some couple of years yet to get the results. Here's what we know myrcene in animal testing is the dating. It also is analgesic, which is helpful painkiller, but it is a pain relieving effects are blocked by Naloxone, the same drug that's used to rescue people from opioid overdoses. So it's a narcotic type of effect. That effect again, anecdotally is markedly increased in conjunction with THC. So most modern types of cannabis have a lot of THC and a lot of myrcene and tend to be very sedating. This is quite different to how cannabis was typically a few decades ago. Admittedly, THC amounts were not as high but that really doesn't explain things, the profiles of plants that were quite different to what's happened now in the pursuit of ever higher amounts of THC,

Nick Jikomes 41:25

do we what do we know there so 10 2050 years ago,

Ethan Russo 41:29

these analysis but I can tell you that people my age, will all uniformly attest to this, that cannabis was different than now. Again, even though the average potency of with THC is much higher now than it was then. There were always high potency varieties available on in even in the olden days. You know, it's been hundreds of years that people in India have known how to select cannabis and make sure that it's ganja meaning on unfertilized female flowers, which markedly increases the potency.

Nick Jikomes 42:19

So, staying on the terpenes for a while, so we mentioned myrcene limonene. What are some of the other big ones that would be found in in typical commercial cannabis?

Ethan Russo 42:29

Sure, so an example I like a lot on a very demonstrable effect for people who've tried it. is the combination of THC and alpha pining. Alpha pining sounds familiar because it comes from pine needles in our area of the world, when one wants to feel rejuvenated you take a walk in the woods on coniferous forests. And in the air. The headspace volatiles consists of a lot of alpha pining alpha pining is an acetylcholine esterase inhibitor. It decreases the breakdown of acetylcholine, the memory molecule in the brain. In combination with THC, it will reduce short term memory impairment. That's a notorious side effect of THC. So this is responsible for people losing their train of thought and laughing about it as is typical in movies about cannabis, you know, say Cheech and Chong, that kind of phenomenon.

Nick Jikomes 43:40

And so, so And where does that come from? Is that is that another thing where it's it's anecdotal at this point?

Ethan Russo 43:47

Ah, well, you know, for people who've tried it, the results are pretty uniformly in favor the idea that it happens again, to convince the scientific community. We need double blind randomized control trials. But again, those are going to occur on I'm confident in the results.

Nick Jikomes 44:13

Interesting. What about beta caryophyllene? That's one that I think is interesting. And you hear about quite a bit,

Ethan Russo 44:19

right? So beta carry awfully on is often the most abundant terpenoid that's found in extracts of cannabis, it's a higher molecular weight so it doesn't volatilize quite as easily. It's a fascinating agent. We know that it's been used in other plants, traditionally in South America, such as copaiba balsam as a treatment for inflammation, fibrosis, etc. So it's a well known anti inflammatory agent, but on your Garrett and his group in Switzerland, about 15 years ago demonstrated that it's also a cannabinoid because it is selective as an agonist for the CB two receptor, the non psychoactive receptor that's involved in pain and inflammation, and treatment of fibrosis. So this is a very versatile medical agent on you know, THC works on CB one and CB two, carry offline is selected for CB two. There's a lot of research on CB two agonists right now, synthetic ones, none of them made it to the market. But yet, we have this natural compound that happens to be in cannabis as well as black pepper. That can be very therapeutic, natural, on no real side effects, the speak of reasonable doses, and it should be more utilized.

Nick Jikomes 45:57

So you mentioned black pepper. And that brings me to another series of questions for you. Because there's this myth in the cannabis community, let's say where if you get too high, you inhale black pepper, and that'll help calm you down. And some people attribute that to CBT and carry off lean. Does that make any sense?

Ethan Russo 46:19

Well, I've written about this on paper 10 years ago taming THC, there are various components in black pepper. Also, there are ancient texts that refer to black pepper. And pine nuts. pine nuts, contain alpha pining. These are used as cannabis overdose antidotes in ancient times. So we have a combination of ancient anecdotal evidence, modern anecdotal evidence, we have a lot of animal work that supports these concepts. Now also in need, is the blinded to human data that hopefully will clinch the story. Right.

Nick Jikomes 47:10

But why? Why would I guess in principle, why would a CB two agonist decrease the psycho activity of something if it's coming from CB one activation?

Ethan Russo 47:19

I can't answer fully. But we know that CB two agonist had been used to treat addiction and other compounds as specifically cocaine in animals. And there's every reason to think that carry off linka works similarly.

Nick Jikomes 47:39

Interesting. And a related question here that that actually comes up a lot. I was surprised how much this came up is? Well, on the one hand, there's this question of the route of administration. So are these things purely going to be active through inhalation? Or can they be orally active? And then the related question is, are Are there any foods that contain terpenes? That would, eating them would affect the level of psycho activity?

Ethan Russo 48:09

Quite possibly, yeah. So let's go through things. First, these are going to be most active by inhalation. Now, that doesn't have to be smoking, it's certainly certainly preferable is vaporisation due to less, less pulmonary side effects. I don't recommend smoking anything. They are orally active, but less so on, a lot of these substances can undergo very rapid first pass metabolism in the liver, which will take them out of the running on but it's erroneous to say that they're inactive orally, on another route of administration, unlike the cannabinoids, which really don't effectively penetrate the skin, the terpenoids do on we have human data from years ago showing serum levels of terpenoids within an hour of terpenoids applied to the scan as essential oils on for example, on nasal circulate some again into the brain. So when people have an aroma therapy massage, it's not just the massage that makes them feel good. They may benefit from absorption, I'd even be able to taste some of the components that were in the essential oil mix. Right?

Nick Jikomes 49:39

Interesting. Yeah, and for those who aren't familiar with cannabis or or this type of thing, this is literally the essential oil the plants, this is very oily, greasy compounds that are fat soluble and will in this case, absorb directly through your skin. Right. So okay, we've covered we've covered a lot of stuff. There's still a lot I want to talk about. What about you know, I want to spend some time talking about dose both. Let's focus mostly on the cannabinoids and THC in particular. So there are a lot of highly dose dependent effects for for THC and for cannabis. Can you unpack a little bit of what's going on there in terms of the biology? Why is it that a low dose versus a high dose can have such a different effect?

Ethan Russo 50:26

Well, first we need to introduce the concept of called a bi phasic dose response. cannabinoids are well known for both human experience and animal testing to have possibly opposite effects depending on the extremes of the dosage range. What that means is, you'll observed one effect on at a low dose and possibly an opposite effect at a very high dose, which would be considered toxic. You know, and the same thing can apply to therapeutics. Let me give an example. And this is an entourage example as well. In animals, if we're looking at CBD as a pure compound, a little bit may not treat pain in the animal. When you get to the right dose, it is effective in treating pain. If you go higher, you lose the effect. When the same doses of CBD are used as an extract from cannabis, that curve doesn't go up and down it rather goes up and state keeps going up. In other words is preservation of the pain relieving response becomes linear rather than this by phasic response. So there are also examples of you know too much cannabis can produce nausea. Too much THC. low doses are well known as an antiemetic. One that reduces nausea and vomiting too much can have the opposite effect. And this is why dosing is so critical. The correct dose of a cannabis based medicines, the lowest dose that's going to produce the desired therapeutic effect without producing side effects. And that should be that knowledge should be gained slowly through what we call dose titration. Very basically, on low doses of cannabis with THC would be in the range of 2.5 milligrams or less, that's a threshold dose. Many people will feel it Some will not. five milligrams is a moderate dose, almost everyone will feel it unless they're highly tolerant on 10 milligrams at once for the naive patient is too much 15 milligrams can produce really toxic effects including possibility of delusions, paranoia, etc.

Nick Jikomes 53:04

When you say toxic, you mean mental side effects as opposed to physical, bodily toxins, sure,

Ethan Russo 53:10

but people can get sick as well. And you know, rapid heart rate is also associated with that a panic reaction. So it's a it's not just psychological facts.

Nick Jikomes 53:25

So so for like a cannabis edible because this problem is so pervasive to the uninitiated, the typical dose in a dispensary that you see per edible for THC is 10. That would be the the most common dose that I see out there. 10 milligrams of THC. So you're saying that if you've never tried cannabis before, you've never tried an edible? That is definitely too high?

Ethan Russo 53:46

Yeah, it is. I mean, at most, someone should try a quarter of it. And they need to wait at least three hours. or oral absorption can be quite erratic. It's going to be better if it's taken with some other food but 10 For the uninitiated is too much. Now the problem is, in some places you see edibles so a single brownie could taint contain 100 milligrams of THC, which is a recipe for disaster For the uninitiated. Yeah. I think that that just shouldn't be. You know, people need to be very judicious when using edibles for a couple of reasons. One is you're eating something that may be delicious. Neglecting that the amount you take should be really related to the dose that's available, not how, how great it takes us that's a pitfall. The other thing is you just can't tell for a long while. And there are innumerable instances if somebody tries an animal in an hour they don't feel it. Anything, take the same amount again and then they're way too high. Um, so it's it's a problem.

Nick Jikomes 55:08

So, you know, we've talked about the entourage effect and some of these these potential interactions with different cannabinoids and terpenes. We've talked about the importance of dose, we were just getting into edibles and how you know, there's products available today commercially that contain extraordinary doses. Let's talk a little bit about the consumer experience today. So you walk into a dispensary. And no matter where you are, you can be in any state that has a state legal dispensary system, you walk into dispensary, it's gonna be some, some version of the following. There's gonna be hundreds, if not 1000s of products, there's going to be all kinds of strains, right, you're gonna walk in and you're gonna see all of these different cannabis strains. And the budtender is very likely to tell you that there's two or three types of cannabis strain, there's the indicas and sativas. If they're particularly into cannabis, they might even try and throw some other knowledge at you. So for example, I'm starting to hear budtender say indicas make you sleepy and the reason for that is they have more myrcene sativas make you excited and the reason for that is any number of things that I hear less THC, more THC, some CBD I mean, I hear everything. So what is your general viewpoint on the way that cannabis flower is classified and talked about in the commercial setting today? Nonsense. And can you just kind of unpack maybe the history there? So what is let's let's just tell people what is the notion of an indika and a sativa? Do we know where that comes from? And

Ethan Russo 56:45

don't work comes from but it's been bastardized in modern Park parlance. Okay, let's break it down. Um, Linnaeus designated cannabis is cannabis ativa but he didn't originate the name. It was used for at least 250 years before him by Leonhard fuks, and others. But we're Linnaeus is mid 18th century. So cannabis ativa means cultivated cannabis. 25 years later in France. Lamarck described what he thought was a different species cannabis indico. Now I can show you pictures of the exact plants that are D supposed to supposed to correspond to. So limericks, cannabis indico was bushier. But he had narrow leaflets. Okay. In modern parlance, what people refer to as indika are Afghan type plants, they're short meter or less. They're very broad leaflets, very dark. And they have a particular chemical profile. But the problem in taxonomy, what a thing is called and botany is its ever changing. I like to say if you have 12 Botanical taxonomists, you'll have 25 different opinions. This is a riff on an old Yiddish proverb. But quite truthfully, what we've got now are these descriptions of inductance ativa that have no relation to what the plant looks like, or its biochemical contents. Also, I'm going to pick up the term strain. There are no strains in plants. What we should talk about in relation to cannabis is Kimo rivers chemical varieties. That's what matters in terms of the effects that people are going to get from a particular variety of cannabis. Strain applies to bacteria and viruses. You hear the word a lot now in relation to varying strains of COVID-19. Well, SARS cofi, to the virus itself, co COVID-19 is the disease caused by it? I really think bud tenders and everyone should avoid the terms as a team and manduca. It is better to have a description of what's in the plant. It's cannabinoid profile, its terpenoid profile, also descriptions of what consumers have said in relation to its use. So, um, is it innervating? is it's a dating, does it brighten mood? Is it contemplative? Does it eat sleep? What are the effects that a population of people have noticed that seem to be the common threads?

Nick Jikomes 59:57

And do you think there's so essentially what you just Said correct me if I'm wrong is the the sort of two key things you'd want to know about a product to ascertain what its effects might be or one, its chemical composition, how much THC does it have? What's its terpene profile? And to what have other people said the effects were when they tried the same thing. And that makes a lot of sense. On the one hand, so the chemistry perfectly makes sense that I guess the key issue there is that information is more or less completely unavailable other than the THC percentage and CBD percentage today. Well, that's a political problem. Yeah,

Ethan Russo 1:00:33

no, I really serious about this. This is the kind of thing that should be mandated. When you buy any other product, you go to the supermarket, you've got 1000s of products on the shelves. And it's really simple to pick one up and see. Is it organic? What is the list of ingredients? Is it just stuff that comes from nature? Are there bunch of preservatives and other things that are added? So then the consumer can decide? Now we've got a psychoactive agent sold in stores where you may or may not get good advice about what it's all about. And we've got very limited information. Basically, often you may get how much THC and CBD is in it, I would submit that's wholly inadequate. Do you need to know the cannabinoid profile, the terpenoid? profile? What kind of safety testing as it undergone? is it's been proven to be free from pesticides. How about heavy metal contamination? What about bacterial contamination? Now, the downside is all this stuff costs money, and companies and make these materials they're not going to spend it if the state doesn't mandate it. But we managed to have consumer protection for a whole range of other products, and there's no reason that less stringent standards should apply to cannabis.

Nick Jikomes 1:02:06

How do you think? So let's hypothetically, let's say we fast forward and and we do get these mandates? The you know, it's really intuitive for people to you know, look at consumer packaged goods and and see that, okay, it's been tested for heavy metals. That sounds good. It's been tested for pesticides, that sounds good. The average consumer at this point for cannabis has a probably a good understanding of THC percentage and how that relates to potency, then you start getting into other cannabinoids and terpenes and it starts to get very complicated very quickly. So, you know, in your mind, what would be the ideal way to actually communicate this information to the average consumer with no real scientific background?

Ethan Russo 1:02:51

Sure. Well, again, it's best through consumer education on now that can come from informed a budtender staff. You know, it's like anything else. So there's a bell shaped curve in terms of the advice that people get in that setting, it can be really bad advice, it can be informed advice. People make a big mistake. My son was runner up for best bud tender in Seattle a few years back. His pet peeve was the average person came in and said, Give me the stuff of the highest THC. And he would spend a lot of time and effort to try and explain why they should be disabused of this notion. The better question is, what are you looking for in your experience, and that may not come from the highest THC, it may come from a lower THC with a more nuanced profile of other ingredients. How can this be imparted to patients? Well, there are ways One example is the Filofax report on that mark Lewis on my former colleague developed and it has all the numbers of the cannabinoids and terpenes terpenoids. in it. It's got bar graphs showing how much of each thing but it also has graphic showing on tastes and smells associated with it and most important, what reactions of consumers have been to it? So again, doesn't make you sleepy. Does it wake you up? Does it elevate mood. And this is experiential data from consumers. And I think this kind of thing, it can be presented in one page and it can be explained to people on no reasonable timeframe.

Nick Jikomes 1:04:43

How, how strong Do you think the effect of suggestion is with canopus? Because on the one hand I personally agree with you that the way that terms like intensity are used and applied is You know, basically total nonsense in the industry. On the other hand, when you actually go and look at the consumer reviews, and you know, I've looked at hundreds of 1000s of these, what you tend to find is, people say that the indicators are sleepier. And so for my money, what's happening is, you know, there's a huge dose dependent effect. There's a wide range of potential products out there with different ingredients that we don't know what they are. So you walk into a dispensary someone says, I want something to make me sleepy, the bud tenders gonna say, try and indico because indicas make you sleepy because we just believe that, and then you just go home and consume it until you fall asleep. And then you write a review saying it did in fact make you sleepy. So there's this sort of loop that somehow needs to get broken.

Ethan Russo 1:05:43

Yeah, yeah, that's valid. Um, people can be really suggestible under the influence of cannabis. If you want to sell the Brooklyn Bridge to somebody. That may be one way to do it. Yeah, I again, people can be steered in the direction of having an opinion that conforms to what they were told on. Yeah, it's definitely Yeah, it's one reason that formal randomized controlled studies have anything that psychoactive effects the mind are very difficult. Just to give a parallel example. Most studies of anti depressant, show the mean effective, it's about a third of studies that actually show efficacy. Now the FDA has a role that you can do any number of studies, you often have to show two or three that show the benefit. It may shock people to know how many studies of standard anti depressants were done to get a few that worked,

Nick Jikomes 1:06:49

meaning meaning they did a bunch of studies. Some of them didn't show an effect, but you simply don't submit those to the formal processes. They have to be submitted. They don't don't get published or don't get published. Yeah.

Ethan Russo 1:07:03

So there's a difference. Yeah, they're technically, companies aren't allowed to withhold the data from the FDA.

Nick Jikomes 1:07:12

But effectively, if they're not published, no one else ever sees it.

Ethan Russo 1:07:16

That's true, unless they, you know, make a FOIA submission, Freedom of Information Act.

Nick Jikomes 1:07:25

One of the things that I think is really interesting to talk about, and we've sort of touched on it a little bit, is the power of suggestion and the placebo effect. Can you actually, you know, as a neurologist, can you actually unpack explicitly for people? What is the placebo effect? And exactly how powerful is it?

Ethan Russo 1:07:45

Well, it's very powerful. It's gotten to the point that it's getting extremely difficult to do to show the efficacy of a drug is compared to placebo. It's see if we can explain this. Now this particularly applies to drugs to treat pain. And anything that's psychoactive antidepressants, anti anxiety agents. It is the case, okay, let's use cannabis in particular, for better or worse. This has a reputation of being miraculous works for everything works, great works for everybody. And going into a clinical trial, when people are have the potential to be on a miracle drug tour not, they're always going to hope that that's what they receive and expect that that's what they're going to receive. And it's reflected in the results. Even in a 5050 split, you're going to get a majority of people who think that they're on the drug, and those are going to preferentially be the people that improve. So even drugs that we know work, so to speak, may not be able to show salient differences from placebo. And this effect has gotten worse over time. On the past few decades. It's getting really difficult to show that a good drug words, when you say the effect is getting worse. Are you saying that the actual placebo effects themselves are

Nick Jikomes 1:09:24

stronger today than they used to be? That's exactly right. What what would even be the basis for that? That's kind of creepy.

Ethan Russo 1:09:34

Well, yeah, but it's absolutely true. There are publications on this. Um, again, it's the belief of people Plus, it depends on study design. Let me give an example. We've got to study of pain. We're working on drug x versus placebo. And in the design of the study, people come in, they get a free visit with The herbalist, they get a free massage, and they go into the study and you want to show them that drug x is better than placebo, well, it isn't going to work. People are going to really like going and getting the free massage and consultation with an herbalist or physical therapist, that's ancillary benefits are going to produce a greater placebo effect. So properly done a study may be okay, Mrs. Jones, we've tried a variety of medicines that haven't worked, we have a study that we can offer you. Now, to be really honest, we can't say whether this is going to work or not work, it may or may not. And then in the study, you give half the people placebo and half drug why you don't have massages on the visits. You may have friendly staff, but they can't You can't let people talk to each other in the waiting room. It's got to be very circumscribed and controlled. So that there aren't undue influences that can increase placebo effect and make it harder to demonstrate what may or may not be really true about the drug. So it's very complex phenomenon. You know, how it's mediating the brain, different theories. Some of it may relate to the endocannabinoid system. There also have been theories about relating to endorphins, endogenous opioids in the body. But it is a very real phenomenon that's become extremely problematic in drug development.

Nick Jikomes 1:11:47

Interesting. So it's it is really a pervasive problem. And I didn't know it was actually getting more difficult with time. Yes, it is. Interesting. So one of the things that I think was very interesting at the beginning that I wanted to circle back to is you're describing your background, trained and practiced as a neurologist, so brain physician for a long time, and you got into cannabis and herbal medicine. It sounded like by way of a trip you took down to the Amazon. So what, what happened there?

Ethan Russo 1:12:20

Well, a lot of things. But you know, the interest began before that, when I was a teenager, I was a follower of yield Gibbons, the guy that did the Grape Nuts commercials. Basically, he was a forger and collected plants that could be used to treat various ailments. I used as jewelweed impatiens species, to treat Poison Ivy, it was really effective. So I knew from a young age, there was more than just pharmaceutical medicine. Anyway, yeah, this happened because seven years in practice circa 1990, I got a little bit depressed because I was giving increasingly toxic drugs to my patients with less and less benefit, and thinking of alternatives. But what happened in the rain forest? Well, in the course of two and a half months, we identified 500 different herbal agents that were used by the munchie Ganga tribe, to treat various illnesses quite effectively. Many of these were psychoactive, some were iOS gamelogs were used and on divination and ceremonies. I had the opportunity to test some of these. Among the things that we thought would be psychoactive, we had about an 80% hit rate on serotonin receptor activity, so it wasn't just imaginary, and there wasn't a placebo effect on the theory

Nick Jikomes 1:14:02

actually, you're actually testing some of the stuff out.

Ethan Russo 1:14:05

We did subsequently, we didn't get too far with the studies for lack of funding was same old story. Um, but um, yeah, I've clearly fell in love with ethnobotany the study of medicinal plant usage by indigenous people, which remains fascinating. But again, may have been a tangent at the time but I got into cannabis found it fascinating and 25 years later, here we are.

Nick Jikomes 1:14:39

Yeah, so what? What are you working on today related to cannabis?

Ethan Russo 1:14:44

Lots of stuff. With credo science, we're looking at cannabis in the endocannabinoid system to try and find solutions to a number of different problems. So we've got a variety of provisional patent This are related to products that were developed, developing. A couple are diagnostics related to the endocannabinoid system. But we're also looking at therapeutic applications that other people haven't tapped yet. Also industrial applications from cannabis, which is an area that really hasn't been begun to scratch the surface of what can be done. And again, we have a formulation services to try and create safer and better cannabis based medicines.

Nick Jikomes 1:15:38

Interesting. So in terms of Endocannabinoid biology, so we talked about how, you know, there's there's some chemical diversity in terms of what's in some of these products out there, there is dose dependent effects. So the dose is really going to matter a lot for what you expect, or what you feel from a cannabis product. And then there's the endocannabinoid system itself. Can you talk a little bit about how how much the endocannabinoid system actually varies from person to person? Is that going to be a key factor and what what kind of innovation is going on there to figure out the the genetics of this?

Ethan Russo 1:16:09

Sure, well, it's a difficult thing to study particularly in people but yeah, it varies tremendously. We we talked earlier about the concept of Endocannabinoid tone. So that would be ascertained based on the number and density of the cannabinoid receptors, which is something we can easily study on living patient. It also has to do with the amounts of the endogenous cannabinoids and it also has to do with the activity of the enzymes that make them and break them down. But I've developed a concept which has gained a lot of traction on the literature called clinical Endocannabinoid deficiency and then the idea that certain pathological processes are related to deficiency of the endocannabinoid system, most notably migraine, irritable bowel syndrome and Fibromyalgia on Right,

Nick Jikomes 1:17:13

so the idea is that conditions like that are correlated with endogenous cannabinoid levels that are lower than typical.

Ethan Russo 1:17:22

Yes, that's the theory. And it's borne out to some extent, to give one very concrete example, in migraine that was shown that there was a very marked decrement in the amount of Ananda mind in the cerebral spinal fluid that surrounds the spinal cord in the brain. And this is a very high level of statistical significance. That clearly implies if not proving that there's an Endocannabinoid deficiency associated with migraine.

Nick Jikomes 1:17:54

I've seen there are some products out there I've seen where you do like a 23andme style saliva test. So you spit in the tube, you send it in the sequence genes related to your endocannabinoid system, you know, and liver enzymes that that have to do with THC metabolism, cb one receptor stuff is do you think that those products are on the right track? Is that stuff going to help people actually, you know, zoom in on how exactly they might respond to a cannabis product?

Ethan Russo 1:18:25

Yeah, absolutely. Full disclosure, I'm a scientific advisor to endo Canna health, which is one of the companies that does such testing on Yeah, I've seen the results and not they seem to shed a lot of light on people's tendency to have certain problems. a concrete example would be the person whose genetic profile suggests that they're susceptible anxiety would do better on avoiding high THC products and may do better with higher CBD products. And experientially, this seems to be borne out. Right. So I do think it's one of the future approaches. For people who are really invested on having full information, this can be quite helpful.

Nick Jikomes 1:19:17

So so in some future state, you know, a patient might have this 23andme style test that says you're less sensitive or more sensitive to THC, or some other compound. And then on the flip side, you have some kind of marketplace where the products are available, but they actually have the, the information one would want to act on that knowledge, which would be the chemistry and and related information rather than what we have today.

Ethan Russo 1:19:48

Yeah, ideally, that would be the safest and most scientific approach.

Nick Jikomes 1:19:54

Interesting. And in terms of, well, I mean, we've talked a lot about THC and CBD I think we touched on CBG a little bit. You're starting I'm starting to hear more and more on the commercial side about minor cannabinoids. And, you know, a lot of it is it's tough, I think for the average person to disentangle the facts from the hype. So can we go through some of the the major minor cannabinoids and what we actually know about them. So CBG, thcv CBN, I think are the big three

Ethan Russo 1:20:22

here. Okay, let's start with CBG. So Connect material is sort of the precursor to CBD and THC. Normally, the plant doesn't stop there. It goes on to the others. It's a high throughput system. But there are varieties of cannabis available now that are rich and CBG, especially in the Northwest. It's sort of a regional specialty. CPG is a really interesting age. And it seems to have strong anti anxiety properties without being sedating, or addictive. So it's quite distinct from say, the benzodiazepines, Valium, etc. that are commonly used to treat such disorders. Additionally, it saw works on a receptor called trip m eight trpm eight, which makes it a candidate for treatment of prostate cancer. So, those are just a couple of things that we know it does. And you know, it hasn't gotten the attention that it deserves, I feel

Nick Jikomes 1:21:30

and did you say anything about psycho activity? Well, it's anti anxiety. So it's psychoactive, but it's non intoxicating. Exactly, but we should emphasize that distinction. So So THC is intoxicating, and psychoactive CBD and CBG are psychoactive because they impact anxiety, but they're not intoxicating, because they won't get you high.

Ethan Russo 1:21:51

Exactly. Sure. Okay, next THC big. Yeah, so THC V is like THC, but with a three carbon sidechain instead of five. So it's called a pentyl cannabinoid. It is found in small amounts in cannabis varieties from Southern Africa, but usually very small amounts. thcv can be selectively bred and it's very interesting profile. At low concentrations. It is a neutral antagonist of the CB one receptor, so it reduces hunger. It's been shown in some animal and human studies to reduce factors associated with metabolic syndrome, you know, the precursor to development of type two diabetes. Additionally, it's anticonvulsant. I works on neuropathic pain. So really interesting agent that it could be a useful dietary agent, because it doesn't have the side effects that were associated with drugs like Ryan moon and bat. s are 141716 A, which is briefly on the market in Europe got yanked. It works differently. It's what's called an inverse agonist that actually lowers Endocannabinoid tone and made people anxious and depressed and in a few instances, even suicidal thcv won't do that. So pretends to be much safer. CBM is Canaveral that's the non enzymatic oxidative breakdown product of THC. So if you have cannabis that's been sitting around in the sun for a couple of years, it THC will turn into CBN. Now the good things about it are much more stable. It's a quarter of the potency quarter of the psychoactivity of THC. Now, it's really advocated on the street as a great agent for sleep. Um, but it's not any better for sleep than THC is really it's sort of in a gray area now where a lot of companies are using it because they think it's not expressly forbidden under the hemp act. But, you know, like all the other cannabinoids, it's schedule one if you ask the DEA or the FDA, so it's okay until it isn't and there could be a clamp down if the feds ever were so inclined. Um, but I you know, I would tend to say that CBN is not magical compared to anything else. But again, it may have a safety factor being a quarter of the potency of THC. So CBN

Nick Jikomes 1:24:56

is in toxic it can actually get you off Yeah, again given enough of that, but gotcha. So that rounds out most of the minor cannabinoids that you hear about, what's your perspective? You know, given your background on the most appropriate legal status for cannabis, legalization, decriminalization a different schedule, what what do you think is the best regulation approach from a from a consumer health standpoint,

Ethan Russo 1:25:28

nothing makes sense except the scheduling. On it doesn't fit in on the schedules on. I should remind people historically in 1970, when the Controlled Substances Act was was formulated, cannabis was put in schedule one is a forbidden drug that was dangerous addictive with no recognized medical use only as a placeholder, subject to the results from the Schaefer commission that scientifically studied the issue. They came out saying that cannabis should be decriminalized, and that it should be available medically. But that was ignored and vetoed by President Nixon. Another thing that we have to thank him for. And it's 50 years later now, and it still hasn't changed. So the schedule one status is a historical aberration not based on science. Right. So that's what I have to say about that. I'm down scheduling the schedule to isn't going to solve anything, it might make research a little bit easier. But schedules two through five are designed really for FDA approved drugs. And then having controls about the prescriptions and how often they can be refilled etc, really does not fit. I would like to see cannabis regulated on a way that would be similar to alcohol, but perhaps even more stringent again, so that the consumer has access to biochemical profiles, and all the safety profiles that were previously discussed. Pesticides, heavy metals, microbiological essays, etc. I also think that people should have the right to grow their own model, the likelihood that people are going to get into trouble that way as a relatively minor, someone who's going to take the care to do it. Um, I, it's a plant. It's not a pernicious plant. It's not innately evil. Evil is a function of human behavior, not of plants. Yeah, that's my viewpoint on the situation.

Nick Jikomes 1:28:05

Interesting. Do you consume cannabis at all yourself?

Ethan Russo 1:28:09

Well, that's the question you're not supposed to ask. But it's 2021 21, or the answer. For years has been the following. Yes, I smoked cannabis in college. Unlike some, I inhaled deeply, frequently and with malice aforethought. But that was a long time ago. Truthfully, people would be shocked. I think that most people think that I'm high all the time. I use cannabis rarely, I guess the context would not be considered recreational. When there's a medical problem that requires that y'all try things. But it's a rare event.

Nick Jikomes 1:29:00

Right. Interesting. So what research wise, what do you think some of the biggest unanswered questions are slash? What what some of the more interesting research that you know is going on are happening soon?

Ethan Russo 1:29:15

Ah, hard one. I can't give away trade secrets here. But let me talk about

Nick Jikomes 1:29:20

why in the, in the academic world.

Ethan Russo 1:29:23

Sure. unmet needs on terms of what cannabis is good for are really varied. But clearly psychiatric areas, anxiety, depression, schizophrenia, they need more attention. Also the whole area of Obstetrics and Gynecology. Back in the 19th century cannabis was used extensively for such problems, but it's been sort of a forbidden area. paternalistic society is thought that women are too weak or at risk to consider cannabis based medicines and it's nonsense. When there's a problem you use what is work and what's, what works and what's proven safe. And the same should apply to cannabis based products.

Nick Jikomes 1:30:11

Interesting. What about Is there any research going on related to the entourage effect where people are testing combinations of compounds in humans?

Ethan Russo 1:30:20

Sure. I mentioned the studies underway at Johns Hopkins and there are a lot of lab studies either pure like bench science or animal work to look at this, but we already have very salient examples. I mentioned the study of CBD and the change of the by phasic dose response to a linear response in clinical medicine on a study done prior decade there was a high THC extract Sativex with THC and CBD extracts and placebo that was looked at for cancer pain. And on the high THC extract and placebo didn't differentiate. But with just the addition of CBD as Sativex, there was a statistically significant improvement in the people experienced 30% decrease in pain over the course of a couple of weeks. So it's a demonstration of synergy or entourage in humans, um, you know, so you know that there are data out there, the more on the way on again, my physician colleagues are going to require your standard randomized controlled trials to be compelling, but they're on the way.

Nick Jikomes 1:31:53

Interesting. I don't want to take too much more of your time. We are coming up close to two hours here. Are there any other areas do you think we didn't dive into or any final thoughts that you would leave for people that are interested in medical cannabis?

Ethan Russo 1:32:08

Uh, well, it's a very deep field. And one of the things that attracted me to it is combined some multiple disciplines. I've had to learn some botany, biochemistry, pharmacology. Yeah, so there's always something for everybody's have a scientific inclination. So I'd encourage people to delve in educate yourself.

Nick Jikomes 1:32:35

Awesome. Well, Dr. Ethan Russo, thank you for your time. And I look forward to talking to you again at some point. Thank you.

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