Victoria Maizes: Hi, Andy

Dr. Andrew Weil: I'm Victoria

Victoria Maizes: Today, our guest is Dr. Ethan Russo, who is one of the world's leading researchers on cannabis.

Dr. Andrew Weil: Yeah, I've known him from some time to go through some of his ethno-botanical work. And, I think he's one of the most knowledgeable people about cannabis therapeutics.

Victoria Maizes: And am I correct that perhaps your first research project was on cannabis?

Dr. Andrew Weil: I did the first human double-blind experiments with cannabis. That was way back in, uh, 1968.

Victoria Maizes: But then you let Dr. Russo take it over.

Dr. Andrew Weil: Absolutely.

Victoria Maizes: All right, let's welcome him.

 

Intro Music

Victoria Maizes: Ethan Russo is a board certified neurologist, psychopharmacology researcher and author. He's the founder and CEO of Credo Science. He graduated from the University of Massachusetts Medical School and then completed residencies in pediatric and in child and adult neurology. He was a clinical neurologist for 20 years where he often saw people who had chronic pain.

He's the past president of the International Cannabinoid Research Society and former chair of the international Association for Cannabinoid Medicines. He's authored many books, too many to list right now, but they include the Handbook of Psychotropic Herbs and The Last Sorcerer, Echoes of the Rain Forest.

Ethan, welcome to our podcast.

Ethan Russo: Well, thank you for having me.

Victoria Maizes: Of note medical marijuana is now legal in 33 United States. And also in the district of Columbia. Andy, I want to start with you. Why do you think that cannabis has been demonized in the United States in our culture and actually in medicine?

Dr. Andrew Weil: Well, I think the fear and hatred of that plant in our culture, which is so irrational and completely incontinent with the chemical and pharmacological realities of the plant, can only be explained by cannabis’ associations rather than cannabis itself. It has always been associated with deviant subcultures with outsiders, with people that the dominant culture has considered threatening.

The knowledge that cannabis wasn't intoxicant, it's psychoactive drugs traveled independently from knowledge of the uses of the plant as fiber source medicine, food, and there were many cultures in Europe, for example, that grew hemp for fiber, but really didn't know it as a psychosis.

And the, the knowledge of it as an intoxicant came to North America. By way of African slaves who first brought it to Brazil and then migrated North and that established itself in the jazz culture around New Orleans which provoked the first, you know, cultural reactions to the plant and the 1920s. Later was associated with Mexican migrant workers in South and Southwest.

And then in the sixties, it became strongly associated with the countercultural movement with hippies and political radicals. I think it has always been these associations with, um, minorities with deviant subcultures that really has provoked the kind of reality action that eventually led to criminalization of it and has kept it out of a medical use for so long.

Victoria Maizes:  And yet it's an incredibly useful medicine. Ethan, I'm wondering if you can speak to why you believe cannabis is so very promising.

Ethan Russo: Well first you know, people should understand stand that cannabis was a mainstream medicine, even the United States, between about 1850 and 1940.

Victoria Maizes:  90 years.

Ethan Russo:  Yeah. So a father of modern medicine, Sir William Moseler as late as 1915 said that it was the best treatment for migraine. And it was also widely used in obstetrics and gynecology, even in children. And there really were no problems associated with it. So given that foundation we have to fast forward to the discovery of the endocannabinoid system.

So we have within our body something called the ECS, the endocannabinoid system, which means that we have innate chemicals that resemble the activity of THC. In fact, the endocannabinoid system is the major homeostatic regulator of human physiology. Animal physiology, in fact, so it has a modulating effect on every physiological function, but particularly in the brain, this helps to explain the versatility we see for cannabis-based medicines and treating a variety of conditions that are otherwise intractable, where conventional medicine, if you will has been poorly productive of benefit to patients.

Victoria Maizes: Tell us about some of the most promising areas that it's been used for care of patients.

Ethan Russo: Well, it's widely acknowledged that cannabinoids and THC in particular, have a role in treating chronic pain, not so much in acute pain. So if you have a tooth ache or had a tooth extraction, it's not what to use, but in chronic conditions, particularly those with neuropathic pain the cannabinoids really shine in that context.

It's been known for decades that the cannabinoids have a strong role in treating nausea and vomiting associated with chemotherapy. That's well established and synthetic THC is Marinol was approved for that use in the US in 1985. Although it never gained much traction because THC alone is a pretty lousy drug, poorly tolerated and more likely to produce side effects than cannabis itself.

Beyond that, are there myriad of conditions. We have approval in 30 countries outside the US of cannabis-based medicines. Specifically Sativex or Nabiximols for treating spasticity associated with multiple sclerosis. And more recently in the US FDA approval of epidialects, which is a 97% pure cannabidiol preparation CBD for treatment of intractable, epilepsy associated with Dravet syndrome, Lennox, Gastaut syndrome, and more recently for tuberous sclerosis beyond that we believe that cannabis will have a great deal to offer in treatment a variety of degenerative diseases, particularly those involving the central nervous system and should have a great role in treatment of Alzheimer's disease because of its ability to treat symptoms, agitation, sleep loss, et cetera, but also the prospect, if not proven yet, that it could be neuroprotective and perhaps slowed down or arrest degeneration and the, those diseases.

Victoria Maizes: Now that's really an incredible statement because of course as someone who grew up in the seventies and eighties, all I heard was that if you smoked dope, you were going to destroy your brain. And now you're telling me it's neuroprotective.

Ethan Russo: Well, what you heard was really never true. I will not say that it's harmless. Everyone realizes that cannabis can have side effects when done excess. Uh, but for the most part, it's one of the safest drugs in the armamentarium and the problems that are noted with it are easily avoidable through judicious dosing and administration.

Dr. Andrew Weil: Yeah, I have a question Ethan, a practical question. The chemistry of cannabis is so complex and the pharmacology also complex and a lot yet to be known and there were so many different preparations of it available now.

I'm really at a loss. When patients ask me how to use cannabis or what products they should use. I don't know. It's I don't really don't know how to advise people. There are many people advocating the use of CBD for various conditions. There are some people who say that CBD by itself without THC does very little, except in the epilepsy conditions that you mentioned. So I find it very difficult to give patients advice.

Ethan Russo: You know what? Let's break that down a little bit. Couple of years ago, uh, I realized that there had been yet to appear a peer review journal publication on dosing and administration of cannabis-based medicines so with a colleague, Caroline McCollum, and I, we wrote this article that was in the European Journal of Internal Medicine on people could get that, at a website, we set up Ethanrusso.org on it goes through the evidence base information drawn from a randomized controlled trials, as well as our personal experience in dosing, THC and dosing CBD, uh, etc. Um, so there's a lot of detail there, but to address a couple of the things that you wrote we can make certain basic statements in whatever form two and a half milligrams of THC is going to be a threshold dose. Most people will feel it. Some will not five milligrams as a middling dose. And 10 milligrams is going to be too much, uh, at once, except for people who, uh, have developed some tolerance to it. And that's an important point. People can get accustomed to any amount of THC, because, um, there is a tachyphylaxis a loss of effect as far as the psychoactivity of THC.

If the doses are slowly brought up over time, through a slow titration, but in general, I find for most occasions that people do not have to exceed 15 to 30 milligrams of THC total in a day for any condition possible exception of attempts to primarily treat cancer. Those seem to require a high doses of cannabinoids. For cannabidiol, which is a very versatile substance, um, much less potent. And so the numbers need to be higher and it is true to say that low dose of CBD and pure form may not be too active. I like to say that there's almost nothing that CBD does that wouldn't be enhanced by having at least a trace amount of THC or board and that’s the experience the most clinicians who would do a lot of this work in pure form.

We're finding that very high doses might be necessary. So a few hundred milligrams to treat anxiety and in the range of 1500 milligrams or more of CBD in pure form to treat a serious condition such as intractable epilepsy. And for schizophrenia, it's in the range of 800 to a thousand milligrams a day, obviously that is accompanied by a great expense and burden for patients on, I think that the more whole extracts of the plant have a great deal, more to offer in terms of economy as well as improved therapeutic index, meaning that more bang for the buck, lower milligrams and fewer side effects.

Dr. Andrew Weil: Can you explain the two types of cannabinoid receptors and there are different functions of the body?

Ethan Russo: Sure. Yeah. Great and important question. So CB1 is the more familiar it is the psychoactive receptor and has a major role in the brain in modulating on neurotransmitter function. So what it does actually reduce the release of certain neurotransmitters, which sounds ominous, but from a therapeutic standpoint, if there's an excess of glutamate, a stimulatory neurotransmitter, this will be a driver to neuropathic pain.

Additionally, it is so stimulatory that after head injury, it can actually kill the cells through what's called excitotoxicity where the cells are just burned out and then succumb.

Dr. Andrew Weil: Is there possibility also that that may be a long-term a pathway to degenerative conditions like ALS

Ethan Russo: Absolutely that's a factor there. So when we have medicines like THC that are going to reduce the release or CBD, which does so indirectly this can be very therapeutic in a wide variety of central nervous system disorders the endocannabinoid system and CB1 in particular is really at the root of pain in the brain, uh, whether you're going to vomit or seizure threshold, regulation of emotion, addiction potential.

It really is at the root of everything because it is the most common protein coupled receptor in the brain, exceeding those, the receptor density for all of the neurotransmitters combined. Um, and it's also out in the body, in the spinal cord, in the gut, our regulates propulsion through the gut.

Also secretion of fluids. CB2 to in contrast is mainly out in the body, but can be in the brain under conditions of inflammation. And it is mainly immunomodulatory. So it's going to work on immune function and again is anti-inflammatory and pain reliever.

Dr. Andrew Weil: So most people are not using pure THC or pure CBD, either using whole plant products and extracts. What kind of advice do you give those people? How did they select strains? What route of administration do you recommend?

Ethan Russo: You know, well, it is a morass out there and it's very dependent on geography. If someone lives on the West coast they may have a lot of choices. Um, other places that's much less the case.

One of the major problems is a lack of regulation in the industry. I tell patients and physicians that every preparation of whatever source should be accompanied by a recent certificate of analysis, because for an interested, not just in how much THC and CBD is in the material, but also the terpenoid content, which is going to have a major modulatory influence on the effects of the preparation.

So I shared your difficulty in trying to make recommendations to people is very dependent on where they live and what's available. You know, but with a certificate of analysis and knowing what the patient might be trying to treat, I feel like we can give more specific advice. The industry has been very poorly regulated in that respect and so it is extremely burdensome for a patient to try and figure this out on their own

Victoria Maizes: Cannabis has many different chemical compounds you've spoken to CBD and THC. And now just a little bit to the terpenoids what's the role of the other 300 plus chemical constituents?

Ethan Russo: Well, each one is, uh, has its own particular pharmacology. We know a good bit about the pharmacology of perhaps 12 of the cannabinoids that the plant makes, but there are at least 150 closely related molecules that come out of the plant. It's really incredible. I could give a few examples of the minor cannabinoids. So called, I think the next big thing is cannabigerol.

So this is sort of the parent compound normally in the plant, it doesn't stop there. It goes on to these other substances, but, particularly in Oregon and other parts of the West coast, we're now seeing the advent of more cannabigerol products, I think it's extremely promising. It is psychoactive, but without being intoxicating, and I’ll make that same distinction in relation to CBD. So what CBG does is have a really strong anti-anxiety effect without being sedative or addictive. So this is quite distinct from your benzodiazepines or the drugs normally used to treat anxiety. Beyond that it's a strong antibiotic. It works on methicillin resistant staphylococcus aureus MRSA. Beyond that works on something called the TRMP8 receptor and surely has application to treatment of prostate cancer, which is extremely common in our society. So these are just a few examples.

There also is renewed interest in the so-called acid cannabinoids. These are the forms of the cannabinoid in the fresh plant, before they're heated. So tetrahydrocannabinolic acid, has a couple of very interesting mechanisms of action. It works on tumor necrosis factor alpha, which would make it applicable to treatment of a variety of autoimmune conditions, particularly inflammatory bowel diseases, but also MS or rheumatoid arthritis.

On another activity is on the Ppar gamma receptor, a nuclear receptor, uh, that affects gene transcription and there should make it applicable in weight loss, diabetes type two, and treatment of cancer among others. And I could go on and on. As for the terpenoids there are some 200 that'd be described in cannabis so far, none unique to cannabis.

But these again, have a major modulatory effect THC in particular. So, just look at the most common ones. Um, myrcene is the predominant terpene and in cannabis. And in combination with THC it's responsible for that narcotic couch-lock effect. So they, the there's sort of a synergy in the sedation aspect, which is not what people commonly need, unless they're trying to get to sleep. Better would be to have alpha-pinene which counteracts the short-term memory impairment engendered by THC. In which is a very pronounced mood elevator, antidepressant, and then caryophyllene which is fascinating because it's both a terpenoid and a cannabinoid. It works on the CB2 receptor, the non-psychoactive receptor where THC also works so it can produce anti-inflammatory and analgesic pain, relieving effects, uh, without intoxication. So those are a few examples.

Victoria Maizes: Andy as a botanist, is this spectacular range of effects that cannabis has typical of most plants? Or would you say that this really stands alone?

Dr. Andrew Weil: I think it's, it's exceptional. We see, I think with all plants that have physiological activity, that there is a complex of compounds responsible for the effects. It's not just, they're not just due to a single active principle, but with cannabis, this is really an exceptional array of a molecule families of molecules. I think it is unique in that regard.

Victoria Maizes: And so many of the conditions that we really struggle to take good care of patients with, it seems like there's this potential. I want to point to one in particular, you were a guest at our mental health conference a year ago, and, um, you brought to my attention to a study that had been done in Canada.

This is a really interesting study where they looked at a registry of people who had licensure to use medical marijuana and ask them about their use. And it turned out that people were able to use, um, the products to help manage their anxiety. And they actually were able to go off of some of their benzodiazepine or antidepressant. And I'm wondering if you could speak a little bit more to that study.

Ethan Russo: Sure again, because of its versatility. We find a situation that when people begin to use cannabis medicinally, they're often able to reduce dosage or taper off of a variety of medicines. Most notable would be the opioids. So it has a strong opioid sparing effect.

But, uh, a analogous benefit has been seen on benzodiazepines. Some of the antidepressants on these are mainly from observational studies. Most of the randomized controlled trials have had a requirement that people keep stable on their existing regimen. So this is not an effect that necessarily been confirmed, uh, in most of the randomized control trials.

But I certainly believe it has that potential, uh, because in real life experience we've seen the same thing, especially with prescription products such as on Nabiximols and epidialoges.

Dr. Andrew Weil: In addition to all of these natural constituents of cannabis I'm sure there are now people working in various labs and pharmaceutical companies to develop analogs of the cannabinoids and other constituents. So what do you see as the potential there for developing new medications?

Ethan Russo: Oh, I think that some will get to market. There've been a couple of examples. Marinol is a synthetic THC. It’s had very little market influence. Uh, we also have Nabilone, which is a semi-synthetic analog of THC. Again, not with a lot of traction.

My strong bias, I think you'll share, is that nature does it better. That we need the full panoply of, uh, what the plant offers as opposed to isolated, single agents. Um, now the model of pharmaceutical development in this country, uh, has been to, uh, for some three generations having a target in mind, usually receptor, uh, computer designing a molecule, that's going to fit there with a highest, uh, affinity, uh, specificity and then down the road, maybe they discover it's toxic, but oh, well, um, you know, in this instance, we have co-evolved with cannabis for thousands of years. And although there can be pitfalls and side effects, we're well acquainted with all of the adverse event profile associated with cannabis. And none of it is fatal.

Uh, it should point out what a lot of people know already that, uh, it's not possible to fatally overdose on cannabis. As opposed to the opioids there, very few CB1 receptors in the, uh, respiratory centers in the medullah so, uh, although other things can happen, no one can kill themselves with this drug, fortunately.

Victoria Maizes: Ethan, even the strongest advocates for cannabis may worry about heavy use in teenagers, young adults whose brains are still developing. Can you share what the concern is. And, and if you agree with it.

Ethan Russo: Sure. Well, I think I said this at the conference last year on. Nobody thinks that it's a good thing for kids that come home from school when they're able to do bong hits all afternoon instead of studying or doing sports.

Uh, however that best studies currently showed that even in teenagers heavy use is not associated with permanent damage. I think something that's often lost in this situation is asking why. Why is has this behavior developed? What might this young person be trying to treat that hasn't been addressed, whether it be social anxiety, ADHD, or anything else.

Um, and I really wouldn't be highly critical of studies that failed to address the why. So I think that due caution is required. However, we shouldn't be unduly worried about permanent damage from this because, various studies have shown that almost any cognitive effects of even the heaviest cannabis use will dissipate within 30 days

Dr. Andrew Weil: Given the tremendous potential for therapeutic use. What do you think it will take to get it out of Schedule 1. How do you see that unfolding?

Ethan Russo: We need more enlightened politicians. There is, uh, the umpteenth legal cases going before the Supreme Court. And if they, uh, I just filed an Amicus curiae brief with colleagues, uh, on that. It’s possible something could happen there, but I, I think we need a political solution. Unfortunately this is one of those situations where the public gets it. Uh, recognition of the medicinal benefits of cannabis is about a 90% proposition. Almost anywhere you go in the US but the politicians are not similarly on board with it. So that needs to change.

Victoria Maizes: Andy I want you to reflect on what, uh, Ethan just shared. Cause you wrote a book called long time ago from Chocolate to Morphine about why people might be attracted to mind altering substances. So, do you think it's always a sign of a problem in the young person's life? Or do you think this is just part of what we do is developing humans.

Dr. Andrew Weil: Well, in my first book, the Natural Mind, the thesis was that human beings have an innate drive to alter consciousness. And I think that makes evolutionary sense because I think these altered states potentially are doorways into fuller use of the nervous system and experiences that may be very positive. Substances are one way of satisfying that drive. There are many others. I've written about those, everything. Yeah. From, you know, meditation, whirling, I mean an infinite list. And the basic point is that the experiences people seek are latent within the nervous system. And when drugs are used to get to them. They act as triggers or releases and people in cannabis is one of the best examples of this that people have to learn to get high on cannabis. They have to learn to associate the relatively subtle effects of the drug with a state of consciousness that they're looking for. So I think that's my basic answer.

There are lots of other reasons why people get attracted to the use of substances. A major one is, is that, is they’re illegality. And that, especially for young people, I think is a strong attraction. And then countries, you know, probably the Netherlands was the first country to do this when they decriminalized cannabis, they said their attention was to make it boring.

And it seems to have work that use went down in the Dutch population. They had a lot of people coming in from other countries, Germany, especially to use. But, you know, I think that we often fail to recognize how making things prohibitive and illegal makes them so much more attractive to certain segments of the population. Especially young people.

Ethan Russo: Yeah, here, here. It's that old adolescent rebellion. I would just go on from that, to say that a youth rates in states that have decriminalized or made it medically available have actually gone down. So there's a lesson you have to remove the cache and it will have less appeal. You know, if, if dad needs it, uh, to treat his arthritis, it isn’t so cool.

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Victoria Maizes: Neither of you advocate smoking cannabis. What, how would you recommend it be taken?

Ethan Russo: Well, you know, if, if someone really has an acute need, let's say that someone's having an aura of a migraine and they've got to get it on board fast. They're not going to be able to take anything orally because the nausea and vomiting, then vaporization is a great alternative.

However, for the vast majority of people using cannabis medicinally, they have chronic conditions with a need for ongoing dosing. Under those conditions I really favor tinctures or oral preparations. People get by with two or three doses a day, there'll be fewer peaks and valleys of activity.

So less chance of intoxication with inappropriate dose. Yeah, that, that would be my, my response.

Dr. Andrew Weil: You know, I was very excited when I saw the appearance of Sativex which was one of the products that Ethan advised the company in the UK on that was a metered dose oral spray and it looks like a medical preparation. And I think for physicians in this country to embrace cannabis, they need to have products that look like medical drugs. They're familiar with not like recreational drugs. Uh, so that's, I think a stumbling block at the moment that the define good medical preparations that could be administered, say orally or by oral mucosa.

Victoria Maizes:  And what about topical?

Ethan Russo: Well, that's a complicated one. Cannabis is great for the skin. Uh, so in treating inflammation, itch, any disorder of that type, the real controversy comes in about absorption and what else you can treat. So the terpenoids, if they're in the preparation, get through the skin great. But the cannabinoids hardly do at all. So I know innumerable people that swear by certain preparations to rub on their joints, but they say something funny and that is that they get instant relief or within minutes. And there's no way that a sufficient amount is getting in or into the joint to do that.

So you really have to look at the preparation. Maybe it's got menthol or other agents in them that are affecting the c-pain fibers in the skin. There was a recent trial of a topical preparation to treat epilepsy, which to me was a total laugher because there was no way that it could work you cannot treat a systemic illness, uh, by applying any amount of cannabis on the skin. Again, great for the skin. Not good for internal conditions. Um, and I would just add, uh, for the people using it on their joints. If they get relief and like it, hey, I think that's fine, but they shouldn't fool themselves about what's actually going on.

Victoria Maizes: Andy, have you seen people who are addicted to cannabis and what do you advise?

Dr. Andrew Weil: I've seen people who are dependent on cannabis, but, uh, I think they're complex reasons for that. And if they're separated from the drug, they don't have anything that of the classical signs or symptoms that we associate with addiction. So I think people can become dependent on it. But, it is not a difficult one to break.

Victoria Maizes: Ethan, you are one of the leading cannabis researchers, and I'm wondering if you can share with our audience what you're excited about… what's coming next...

Ethan Russo: Well, As touched on earlier. I really think there's going to be a tremendous role for cannabis-based preparations and treating neurodegenerative diseases. I think that's must happen. We have an aging population. We're going to have a huge public health burden of people with Alzheimer's as well as other degenerative diseases, such as Parkinson's that one's going to be a tough nut to crack.

But I think that the promise particularly in Alzheimer's disease is very realjust in management alone. And again, if we could hit the Holy Grail of slowing down of the progression of the disease or starting people early, who are at risk genetically, I think it would be a major advance.

Victoria Maizes: Well, as I said earlier, I'm not what one might have expected 20, 25 years ago that we would be pointing people towards cannabis as a way of preventing dementia.

Thank you so very much for being our guest on this podcast and for your work.

Ethan Russo: It was an honor.

Dr. Andrew Weil:  Thank you, Ethan so much.