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Dr. Ethan Russo: CBD & Clinical Endocannabinoid Deficiency

ethan russo endocannabinoid deficiency
By on June 21, 2016

Dr. Ethan Russo, neurologist and medical scientist, discusses CBD, clinical endocannabinoid deficiency, and various ways to target the endocannabinoid system for therapeutic benefit. 

Transcript

Project CBD: Today we’re talking with Dr. Ethan Russo. Dr. Russo, a board certified neurologist, is the medical research director at Phytecs, a biotechnology company that specializes in developing different ways of targeting the endocannabinoid system for therapeutic benefit. Dr. Russo was formerly the senior medical advisor to GW Pharmaceuticals and a widely published author in many scientific journals, as well as a contributor and editor of several books. He has also been a faculty member at the University of Washington, a guest teacher at Harvard Medical School, and other academic institutions. Welcome to Cannabis Conversations.

Russo: Thank you for having me.

Project CBD: Ethan, you’ve been way ahead of the curve with respect to cannabidiol, years before most people in the medical marijuana community had ever heard of it, you were emphasizing its significance. Tell us briefly, what is the significance of CBD?

Russo: Well I think we need a little background first to indicate that cannabidiol has always been part of the capabilities of cannabis. Its just that it’s been pushed into the background through selective breeding, basically another byproduct of prohibition where the emphasis has been on maximum psychoactivity to the exclusion, for the most part, of medicinal benefits that might go beyond that. But, clearly, this is a substance that has a lot to offer on many levels.

Firstly, it synergizes with THC, so it complements the ability of THC to treat pain while in its own right it’s an excellent anti-inflammatory without the liabilities that we say get from non-steroidal anti-inflammatory drugs with their tendencies to produce serious side effects like ulcers, heart attacks, and strokes, these just aren’t a liability with cannabidiol.

So cannabidiol, on the one hand, can counteract some of the less desirable effects of THC such as this tendency to produce anxiety and rapid heart rate. But at the same time, cannabidiol on its own has many properties that THC doesn’t – as an anti-anxiety agent, as an anti-psychotic, and doing all this without producing intoxication, if you will, that can happen with too much THC. So this is just a few of the things.

Project CBD: You mentioned CBD in the context of it being combined with THC; you also mention it as an isolate. And GW Pharmaceuticals, when you were involved with the company, has done extensive clinical trials focusing on CBD in combination with THC for Sativex. It’s been approved in a couple of dozen countries as a sublingual spray. But also GW has been focusing more recently on Epidiolex, which is more like a single molecule formula. I realize there are some other things in there, but it’s mainly CBD.

Russo: That’s true.

Project CBD: So what are the advantages and disadvantages of both ways of looking at it, both as an isolate or as a whole plant mixture?

Russo: So in Sativex, basically it’s a 1:1 mixture of THC and CBD, plus some other terpenoid components. That turned out to be the best approach for treating a large variety of symptoms such as spasticity in MS, some pain conditions, particularly neuropathic pain, and worked out quite well. In the early days, the company looked at different ratios and different modes of administration and the oral mucosa spray with Sativex with this 1:1 mixture turned out to be a good balance of efficacy and safety, meaning fewer side effects.

On the other hand, cannabidiol alone, again, would be very good in treating a variety of other conditions. One is epilepsy. CBD as an anticonvulsant has a broad spectrum of activity. In other words, it works on many different kinds of seizures and has the possibility, again, of doing this without any of the liability that THC might produce, both in terms of side effects but also legal constraints. So that’s a big advantage. Additionally, as an anti-psychotic, say to treat schizophrenia, there’s already been a Phase 2 clinical trial with Epidiolex, in essence, with good success apparently. That hasn’t been published yet. But the preliminary results were announced online.

Project CBD: So I’ve heard it described that CBD is like THC without the psychoactivity. Is that accurate? Or is that sort of a blunt description that really doesn’t get at what’s going on here? Are there other conditions that really CBD seems more suitable than THC?

Russo: More the latter. It is really distinct. Something I haven’t mentioned is that in its own right cannabidiol is an endocannabinoid modulator, in other words, when given chronically it actually increases the gain of system, which is, at its core, a homeostatic regulator. To explain that: homeostasis is a state of balance. Many diseases interfere with a balance in a given system and if we can bring that balance back to where it should be there’ll be improvement in the overall condition. This is one reason that cannabidiol is such a versatile medicine because so many disorders operate on that kind of level. So, if there’s too much activity in a system homeostasis requires that it be brought back down. If there’s too little, it’s got to come up. And that’s what cannabidiol can do as a promoter of endocannabinoid tone, we call it.

Project CBD: Well usually when we think of a drug, it goes in one direction or the other. But you’re suggesting that CBD really has a bi-directional effect. It can balance either excess or deficiency. Can you explain how that works? Or would that require a kind of in-depth scientific …

Russo: It would but, looking at the endocannabinoid system, it is sort of a buffer. So CBD can be thought of as a buffer as well – a buffer is something that will work both ways as need be. So, for example, in the endocannabinoid system one of its main roles in the brain is to regulate neurotransmitter function and again, if there’s too much of one kind of neurotransmitter it will bring it down, if there’s too little it will bring it up. Without diagrams, that’s probably as well as we’re going to do this evening.

Project CBD: Now does THC do something similar, but in a different way?

Russo: Yes. Okay, we can think of THC as acting directly on the cannabinoid receptors. In contrast, CBD is quite distinct. It doesn’t tend to bind directly, what’s called the orthosteric site where THC binds. Rather, it binds on what’s called an allosteric site, another site on the receptor, and it so it alters the binding of both THC and the endogenous cannabinoids, the endocannabinoids. So, cannabidiol is what’s called the negative allosteric modulator, which is a fancy way of saying that when THC is present it interferes with its activity – which is a good thing in terms of wanting too much psychoactivity and again limiting side effects like anxiety or rapid heart rate that can be a problem if someone has too much THC.

Project CBD: So the idea that CBD is a negative allosteric modulator of the cannabinoid receptor, that would suggest – if it’s impeding or reducing the signaling of a particular receptor – that it might be helpful for diseases that are an expression of an excess, because you want then a limit, and the opposite would be if you had some kind of allosteric modulator, unlike CBD, that would have a enhancing effect on a receptor that would then perhaps be helpful for disease of deficiency of the endocannabinoid system. Now you’ve written a very important paper, I think it was published back in 2001, on clinical endocannabinoid deficiency, maybe you can explain the thesis of that?

Russo: It was a concept I introduced then, I had a larger review paper in 2004, and just this year 2016, I submitted further review that’s currently under consideration for publication. Basically it occurred to me that many diseases affect neurotransmitter levels. A couple of examples: We know one of the primary problems in Alzheimer’s disease or other dementias is a lack of Acetylcholine, the memory molecule in the brain; similarly in Parkinson’s disease there’s not enough dopamine and you try to replace that with a medicine with a medicine call L-Dopa. So what would a deficiency of endocannabinoid function look like? Well, we already knew that. If you don’t have enough endocannabinoids you have pain where there shouldn’t be pain. You would be sick, meaning nauseated. You would have a lowered seizure threshold. And just a whole litany of other problems. It occurred to me that a number of very common diseases seem to fit a pattern that would be consistent with an endocannabinoid deficiency, specially these are migraine, irritable bowel syndrome, and fibromyalgia. They have some things in common. They’re all hyper-algesic syndromes, meaning that there’s seems to be pain out of proportion to what should be going on, in other words you can look at the tissues they look okay, but there’s biochemically something that’s driving the pain.

Additionally, they occur in the same individuals. If someone has a chronic problem with migraine there’s a high likelihood they’re going to have fibromyalgia at some point in their life; similarly, with the irritable bowel syndrome. Previously there wasn’t a lot of genetic linkage, but we’re still looking for evidence of that and there seems to be a possibility that there’s some linkages there. But again, the theory as it started out was that they would have in common an endocannabinoid deficiency. Subsequently to the review paper in 2004, there’s been a great deal of work done both clinically and experimentally that supports the concept. I’ll just give one example: Some years ago in Italy a group Sarchielli, et al, measured the anandamide levels in the cerebrospinal fluid. They did lumbar punctures, spinal taps –

Project CBD: Anandamide being one of the endocannabinoids.

Russo: Exactly. They showed in people with migraine that the levels were vastly lower than in normal people that didn’t have migraine headaches. So this was the first strong objective proof, if you will, behind the theory. There have been other examples that have tried to document the new paper.

Project CBD: Given just the notion of measuring of the levels of one’s own endocannabinoids, if there was a technology that was relatively inexpensive and accessible that would seem like a very, very valuable diagnostic. Is there such a thing in the works as far as you know?

Russo: Well, in development – we’re not there yet. There are direct measurements, hopefully we’d have a technology that didn’t require an invasive procedure like a lumbar puncture to figure these things out. There are also physiological scans like PET scans and to a lesser extent functional MRI scans that could look at that, but we’re still in early stages of trying to harness the kind of technology that would give us these answers particularly without resorting to more invasive techniques.

Project CBD: Phytecs, the company that you’re working with now, as far as I know has been involved with developing techniques, possibly drugs or herbs or combinations thereof (maybe other techniques, you’ll have to fill us in) that target the endocannabinoid system in a way to restore balance if it’s deficiencies as you’ve just described of migraines and other things – presumably that would somehow enhance the endocannabinoid functioning in the body. Or if it was an excess disease, perhaps something like obesity you’d want to bring it down. Tell us a little bit about what’s in the works with Phytecs? Is the focus just on cannabis or are they looking beyond cannabis to other herbs or other techniques.

Russo: Cannabis is certainly in the mix. We’re interested in developing more focused chemovars that would be chemical varieties of cannabis that would work better on certain diseases that maybe haven’t had as much attention heretofore. But yes, you’re right, we’re also interested in non-drug approaches. This would include herbal approaches that would affect the endocannabinoid system with agents that aren’t intoxicating. Additionally, it would include lifestyle and dietary approaches. And there’s a large body of evidence now to show that diet can positively influence the endocannabinoid system and its balance.

Project CBD: Presumably bad diet, negatively influenced.

Russo: I’m afraid that’s true too.

Project CBD: So, when we talk about the endocannabinoid system, at least when I was first hearing that term several years ago, a kind of simplistic notion was that there’s these compounds in cannabis, they bind to these receptors, and that’s what it’s all about. But when you talk about other herbs, are you suggesting that there are other herbs, other plants, which can also interact directly – or maybe indirectly – with the endocannabinoid system? What would be some examples?

Russo: There’s an example we need to learn a little bit more about, a thing called the New Zealand Liverwort. It’s recently been shown to have a cannabinoid agent that works at CB1, the same receptor where THC binds. I’m afraid the paper isn’t out yet. I’ve just had a tantalizing hint from our colleague Jurg Gertsch about this. A couple of years ago there was an agent called yangonin that was isolated from kava, the south sea beverage, that also works on the CB1 receptor, and it could certainly have something to do with the relaxing properties of that drink. So this is just two examples.

Project CBD: And what about the compounds from the cannabis plant? Do they only bind to the cannabinoid receptors or are there other interactions going on that we might not be thinking about?

Russo: Sure. Let me give a couple of examples: again, CBD is what’s called an agonist, a stimulator of serotonin 1A receptor. This is something that I had hypothesized and with colleagues of the University of Montana back about 2005 we described this. And it turns out to be an important mechanism of a lot of the activity of cannabidiol, seemingly independent of the cannabinoid receptors. Another example is, another component of cannabis that’s chemically wasn’t thought to be cannabinoid turns out to be, that is the sesquiterpenoid called beta-caryophellene.

Project CBD: When you say terpenoid or sesquiterpenoid, what do you mean by that?

Russo: Well, this is a 15-carbon molecule, it’s quite distinct in its appearance from the cannabinoids we think of normally in cannabis, but as it turns out this is a strong selective agonist at the CB2 receptor.

Project CBD: That’s more in the periphery compared to CB1 tends to be more in the center?

Russo: This is thought of, this is a non-psychoactive receptor. It is more important in inflammatory mechanisms and also in pain. So the advantage of an agent that would act on CB2 would be reducing inflammation, reducing pain, but without psychoactive side effects. Now as it turns out this caryophellene is very selective there. It’s a very safe agent. This, for example, is in black pepper. It’s called GRAS by the government – not that kind of grass – rather GRAS, Generally Recognized As Safe as a food additive. So this is something with the government’s seal of approval. It’s in our diet. But more of this would certainly have a positive influence on health, particularly for people with arthritis or other kinds of chronic pain. And again, without any liability in terms of having unwanted side effects.

Project CBD: So beta-caryophellene, this sesquiterpene that you refer to, this is actually present in some cannabis strains and therefore would have presumably an additive effect combined with the synergy with the cannabinoids like CBD and THC could enhance the painkilling or anti-inflammatory effect.

Russo: Yes, that certainly would be the case. It’s going to be present to some degree in almost all cannabis strains. However, if you have, say in a dispensary the ability to have a good assay for the cannabinoid content and we’re able to select for one that was high in caryophellene we would expect that to be much better at treating pain and inflammation.

Project CBD: So if you have a situation where the cannabinoids like CBD and THC from the plant are binding not only to the cannabinoid receptors but other receptors, and then we have other herbs – you mentioned kava, there’s others as well – that are interacting with the cannabinoid receptors, what does this mean in terms of our conception of what the endocannabinoid system is? I remember years ago when I was fumbling around as a non-scientist trying to get a handle on some of these concepts, the idea was I think maybe somewhat narrow: you have compounds in the plant, they bind with these receptors, great, and good things happen. Is that too narrow a conception when we say the endocannabinoid system in that classic way, do we need to expand our idea of it?

Russo: Well it’s a great question because it highlights the problem that we have. First and foremost, we need to better understand the role of the endocannabinoids in our lives and our health status. That’s been ignored, possibly because of its name – having cannabis in the name of this pejorative connation has impeded education, even in medical school. Basically, it hardly exists. Let’s consider this. There are more cannabinoid receptors in the brain than there are for all of the neurotransmitters put together. That being true – and it is – recognizing that fact, why would one ignore this system? Why isn’t this being taught? Our public needs to know about this and how lifestyle and diet affect this system, and how it could be brought to bear to improve their life condition.

Project CBD: We want to thank you Dr. Ethan Russo for bringing this type of information to our attention. You’ve been a pioneer in this area and it’s been greatly helpful to all of us. Thank you.

Russo: My pleasure.

Copyright, Project CBD. May not be reprinted without permission.

Audio-visual category: 

Kristin Nevedal: Cannabis Farming and Pesticides

kristin nevedal marijuana pesticides
By on April 11, 2016

This video features Kristin Nevedal, Director of American's For Safe Access Patient Focused Certification Program, who gives insight on pesticide use in cannabis cultivation. She explains the current landscape of pesticides regulation, pest management, and the need for further research. Thank you to Care By Design for helping to sponsor this video series.

Transcript

Project CBD: Today we’re talking to Kristin Nevedal, the director of Americans for Safe Access Patient Focused Certification program. Kristin is one of the co-founders of the Emerald Growers Association, now known as the California Growers Association. And also, I want to get this exactly right, you’re the chairperson of the American Herbal Products Association Cannabis Committee’s Cultivation Working group.

Kristin Nevedal: That is correct.

Project CBD: For cannabis cultivators pest management is a crucial issue. We’ve had reports out of Colorado recently, and other states, grappling with the fact that they’re finding high residue levels of pesticides in the plant matter from the cannabis growers. How extensive a problem is this actually?

Nevedal: You know, I think it’s kind of hard to gauge how extensive of a problem it is, and I think really the issue is a lack of education on this topic, frankly. So, currently all pesticides in the United States are subject to tolerance thresholds, which is what determines the appropriate spray ratios. And so, what I mean by that is: Can the pesticide be used on an ornamental crop only or is it approved for use on a crop that’s produced for human consumption? And at what rates can you use it on a crop produced for human consumption? This is why we see on pesticide labels different spray protocols for say strawberries versus a squash or an ear of corn. But that has not been established for cannabis. So what we currently have are cannabis farmers who are utilizing pesticides based on how they work on other crops or successes that they might be hearing or reading about on forums. And really, the only legal pesticide products out there are those that are deemed so safe by the Environmental Protection Agency that they don’t require a tolerance to be set. They’re part of the tolerance exempt list.

Project CBD: So when you say “tolerance exempt,” what do you actually mean? And who sets the standards, who regulates pesticides? Is this a federal issue? Is this a state issue?

Nevedal: It’s a little bit of both. The Environmental Protection Agency sets pesticide standards and tolerances nationally, right. And then each state has the ability to take that list or those – say, an intolerance exempt product, the EPA will create a federal list and then each state has the ability to, say, narrow that list down. It can’t make broader exemptions to what the EPA regulates. So, in California the Department of Pesticide Regulations has reviewed the Environmental Protection Agency’s tolerance exempt list, and they’ve taken a couple of products off of it, such as sulfur. So, federally the EPA would consider that a tolerance exempt product. However, the Department of Pesticide Regulation in California doesn’t see it the same way. They see it as having more risk than what the Environmental Protection Agency sees.

Project CBD: Has there been, then, standards set for cannabis cultivators by the state of California? I know they’re trying to do this in Oregon and Washington, Colorado as well.

Nevedal: Yeah, I mean there aren’t currently. What the Department of Pesticide Regulation in California has determined or stated is that only the products that qualify as tolerance exempt products should be appropriate for use on cannabis. So, anything not – it’s interesting because on labels we have signal words, right, and they’re arranged in five different categories. So, when a cannabis product doesn’t have a signal word on it, then we know it’s tolerance exempt. Signal words are, something that might say ‘warning’ or ‘caution’ or ‘danger.’ But in tolerance exempt products, there’s no signal word on it, which is supposed to tell the user that that product is safe for all crops produced for human consumption. And that the spray periods in that crop’s life cycle don’t need to be considered necessarily. So those are the products that cultivators should be sticking with, are those tolerance exempt products.

Project CBD: So a product like Eagle 20 or Avid, which I know that sometimes cannabis growers are utilizing at different phases of the grow cycle, is this – these should be avoided.

Nevedal: Always. Always. So these are pretty toxic pesticide products. In California, both Eagle 20 and Avid, are restricted pesticide products, so they do require a applicators license in order to legally obtain and utilize commercially. So, they are – they’re illegal. No matter how you slice it or look at it, both of those products are illegal for use on cannabis. And that’s true in all states.

Project CBD: So, if a pesticide is considered tolerance exempt does that mean that a farmer, it’s okay for that person to utilize that product at any point in the plant’s life cycle?

Nevedal: That’s a tricky one, because there’s so much that we don’t know, because none of these experiments have been done with cannabis. But, let’s take a product like Bacillus Subtilis, for example, which is what we see in Serenade, which is an over-the-counter tolerance exempt product. Because cannabis, once it starts to produce flowers, the pesticide product will kind of hide in between the stem and that new flower production, and it’s a bacteria-based pesticide product – it’s alive, that’s how it works, it eats up the mildew spores, that’s what the bacteria does. So if you’re spraying that product late, once the flowers are developing and you don’t have sunlight coming into contact with that product, that live bacteria is allowed to proliferate and then you’re likely going to fail a microbiological exam.

Project CBD: So ordinarily the sunlight would break down this type of pesticide. And do the pesticides ever become systemic, not just simply stay on the leaf or whatever, that they actually get in the plant itself so that if one extracts oil, for example, essential oil of the cannabis plant, are you also extracting the pesticide?

Nevedal: It depends on the pesticide product. So tolerance exempt pesticides don’t tend to be systemic. They tend to work on the surface of the plant. But, if you have that residue on the surface of the plant, there is – it’s likely that you could concentrate it through an extraction process. And again, some of that is unknown without having these experiments from the EPA. There’s just a lot that we don’t know.

Nevedal: The very best time to handle the risk associated with disease and pest on this crop is going to be early on in the vegetative state of the plant’s life. And the goal here is to never have the disease show up. So it you’re not acting preventatively, and I don’t mean just with pesticides, I mean preventatively as far as how are you treating your soil, is your soil alive, is it full of microbes, is it full of beneficial bacteria, what kind of precautions are you taking with your clothing, are you walking into a contaminated site and then walking through your garden? Are, you’re bringing that disease with you on your clothes, on your shoes? So, we really as cultivators need to be very mindful about how to not bring the disease home -- and then, how to use very safe products and treatments to make sure that we’re preventing its onset. The entire reason why we have disease outbreaks is because, as cultivators, we’ve created a very friendly environment for that disease. So we have to mind our environmental controls, we have to mind all points of contamination, whether that’s soil, plant matter we’re bringing in, clothing, compost. So it’s really about the preventative components. That’s what’s going to result in success.

Project CBD: And that would underscore the importance of this integrated pest management concept, which entails more than just simply the pesticides one would use, whether they’re natural or safer, to deal with bugs or whatever is going on with the plants.

Nevedal: Right. I mean, if we’re in an environment outdoors or in a greenhouse, what kinds of plants are around our ventilation, around our garden, and even focusing on planting plants such as lavender, yarrows, that are going to bring in beneficials will really help to balance our environment. You know, one of my favorite things has been to, say, release praying mantises. They are vicious little buggers and they eat all sorts of pests, and they will stay in your garden and feast year after year after year.

Project CBD: In essence, you’re kind of augmenting what the plants already do, because plants release terpenes that will attract certain kinds of animals or insects that will then attack their predators or that will repel predators and so forth. So you’re basically working with the essence or the energy of the plant and augmenting what it needs.

Nevedal: Absolutely – and finding that environmental balance. You know, if we’re say in a row cover and we notice that we have some spider mites starting, just take the cover off that row cover and you’re going to see these beneficials come in, eat up your spider mites, and not ever have to treat. It can really be that simple. But it takes a very watchful eye. And you have to really garden year-round; think about what kinds of pests. Like right now is a great time to be spraying beneficial Nematodes.

Project CBD: “Now” being, we’re talking, middle of the winter in Northern California.

Nevedal: Yes, absolutely, because cucumber beetles are going to hatch out as soon as it starts to get warm, right, thrips are larvaeing in the soil right now. So if we are mindful and we’re thinking about issues maybe we experienced last year, we can – over the course of the winter when we’re dormant – we can treat for those issues with beneficials. So, it’s really kind of changing the way you look at pesticides and making a plan to act very preventatively.

Project CBD: Thank you Kristin Nevedal. That’s good advice. I appreciate you joining us today on Cannabis Conversations.

Nevedal: Thank you so much for having me.

Copyright, Project CBD. May not be reprinted without permission.

 

Audio-visual category: 

Jahan Marcu: Cannabis Lab Testing & Safety Protocols

By on March 16, 2016

In this video Jahan Marcu, lead auditor for ASA's Patient-Focused Certification program, discusses lab testing, safety protocols, adverse events reporting, and regulatory standards for the cannabis industry. Thank you to Care By Design for helping to sponsor this video series. 

Transcript:

Project CBD: We’re speaking with Jahan Marcu. Jahan is the scientific advisor to Project CBD. He’s received his PhD from Temple University where he did his dissertation on the structure and activity of cannabinoid receptors. He’s also been involved in some very important scientific papers documenting the anti-cancer activity of compounds in cannabis. He is currently the chief scientist for Americans for Safe Access and the chief auditor for the Patient Focused Certification program of Americans for Safe Access. We’ll be talking about that in a little bit. He’s also served on various committees of trade associations and science organizations, including the American Chemical Society, the International Association for Cannabis as Medicine, and the American Herbal Products Association. Thank you for being with us, Jahan.

I wanted to ask you initially about cannabis and safety protocols. I mean, for those who aren’t wearing “reefer madness” blinders, I think there’s a wide recognition that cannabis is a safe substance. Frances Young, a former DEA administrative chief law officer actually referred to it in a legal document as cannabis being safer than many foods, many common foods that we eat. If it’s so safe, why is it important that in the industry today here should be regulations and standards for safety?

Jahan Marcu: It’s a good question. I think the most basic answer is that those are the rules. In this country, if you sell products that people are going to consume they need to be tested for safety. Those are the simple rules of what it boils down to.

Project CBD: So what does that mean in terms of setting standards of safety protocols? What is a “standard” in this case?

Marcu: Standards usually begin as a best practice. A group such as the American Herbal Products Association (or AHPA) several years ago started these working committees where members of industry, various stakeholders, laboratory operators, patient advocates got together and discussed standards. What makes a good manufacturer? What makes a good cultivator? What makes a good dispensary? What makes a good laboratory (probably the most important aspect of medical cannabis standards)?

And so these best practices get adopted. And as we’ve seen with the AHPA standards, they have been adopted by 11 states, along with the American Herbal Pharmacopoeia standards. And so, would you call the same legislation being adopted over and over again, those are standards. And, they set standards such as how much metal and lead you’re allowed to have in your products. Or, how much fungus or pesticide you’re allowed. Similar standards that what you’d expect when you buy a salad at a grocery store or you buy a pack of vitamin C or some sort of plant extract from anywhere – you’d expect a certain level of safety – and that it was intended for human consumption. It wasn’t intended to feed animals. It wasn’t intended to make a shirt out of it or put some sort of oil in your car. It was intended for human consumption.

I think, also there’s a confusion, too, in what “quality” means to some people. Quality – it refers to purity. And we have to remember that quality is also a term that’s used to describe things like motor oil and poison. And there are high quality of everything. But we have to understand what we mean when we say purity consistency. And, as medical cannabis products are rolling out and people are using them, a lot of medical cannabis users are looking for something that’s going to repeat, it’s going to be consistent. And that’s where we will see the new studies coming through.

You know, there are 6,000-plus rare diseases that exist, where there’s no treatment for them. And if we ever hope to develop treatments for them, we better have standardized medicine that can be used for long-term investigations. And those only come from having standards. That’s just one avenue of what standards can do for an industry, is to help create long-term clinical trials such as the ones that aren’t currently available.

Project CBD: So with cannabis though we’re dealing with a substance, an herb, that is federally illegal. So how do you establish standards that are going to be applicable nationally when it’s only in certain states that cannabis is legal as a medicine and just a few states where it’s legal for adult use. What are the challenges in terms of developing standards and implementing them in this context?

Marcu: That’s a great question. So the reason the American Herbal Products Association and other standards groups have gotten involved, is because they are not controlled by the DEA. You’re allowed to create – it’s not the first time ever that a substance from a plant has been discovered and made into a legal medicine. It’s happened, for instance you might remember there’s a plant called the Poppy plant, and opium and morphine and these things and we discovered another endogenous system by investigating that plant. And there have been rules and standards for that. But there’s really, what’s interesting is that some organizations are prevented from issuing standards. So the USP (United States Pharmacopeia) is not a government organization, but when it issues monographs it gives pharmacists certain abilities. For instance, it allows them to compound with a substance. Well, the USP may not be able to release a formal monograph until cannabis is rescheduled because they would be out of compliance with their DEA standards. However, a group like the American Herbal Pharmacopeia doesn’t have to worry about DEA compliance. A group like AOAC (Official Methods of Analysis) or other groups that are developing analytical standards do not have to work directly with the DEA. They might come to them for help with forensic testing and other issues, but we’re going to see standards – we would hope that the USP would come up with a standard to be adopted by all states and everything would be great and solved over night. But the reality is, it’s going to be a slow process. The monograph and AHPA standards provide a foundation for the industry for consistency.

Project CBD: By AHPA, you’re referring to American Herbal Products Association. Maybe tell us a little bit about the monograph that you were actually involved, with others, in composing.

Marcu: The American Herbal Pharmacopeia has put out about 28 monographs, I believe, on various plants. This is standards for identifying it, and cultivating it, and producing it to meet botanical medicine standards, as well as guides on dosing and administration. And the reason, you know most people can readily identify cannabis, but there are a lot of plants that look like it, like the Japanese Maple for instance and several other members of the Cannabaceae family, all have a very similar leaf structure. So, just a conceptual example: you need a standard method for how you identify it, both by looking at it and by doing chemical analysis. And that’s in the monograph. The monograph has testing standards, testing limits such as residual solvents, identified methods for identifying pesticides, fungal, bacteria limits, and these – while some people criticize any regulatory document – I think you have to remember that there was probably close to 100 people involved in writing this, and there’s an old saying that if 100 people say that this is the way to do it, they might be on to something. Especially since the people that worked on it came from all different disciplines and they were all experts. For instance, this monograph was undertaken by Ethan Russo, Mahmoud ElSohly, Raphael Mechoulam, Appendino, and the list gets a little more esoteric, but we’re talking about people who have worked with the FDA, people who have worked with the USDA, reviewing, editing, all contributing to the creation of this document.

Project CBD: You’re talking about some of the leading lights in the scientific community.

Marcu: Yeah, including one of the final reviewers of the monograph which contains information about individual cannabinoids and their effects, is currently the most published pharmacologist in the world – Vincenzo Di Marzo. He has over 500 publications on endocannabinoids and cannabinoids alone.

Project CBD: Let’s talk a little about “testing.” It’s going to come down to the reliability of the lab that’s doing the testing. And you, through your work with the Patient Focused Certification program of Americans for Safe Access, you’ve been involved in auditing these labs and so forth. What do you see out there in terms of the labs that are servicing the cannabis community in terms of consistency? Is there a long way to go? Are we doing a good job in that respect? What do you find in your work when you are auditing these labs?

Marcu: Some of the labs are absolutely ready to be regulated. Some of the labs also have inspections from state agencies. Like Washington state, they already have some inspectors coming in, the Fire Department, and such. However, I think the biggest challenge for some operators in general is just getting their staff ready for a regulatory inspection. It’s different than interacting with law enforcement. It’s different than interacting perhaps with other municipalities. So I think being ready for an auditor to show up at your place and go through your books, I think it’s a new concept for some people.

Project CBD: Well it implies a certain level of professionalism that may not have been there at the beginning of the whole experience with labs servicing the cannabis industry.

Marcu: I think what first has to happen is the labs need to get on board with “best practices.” Some labs have done a great job in observing this. Other labs, for instance, want to create their own standards and they don’t realize that – you know the monograph was a 19-year project, it involved several phases. Standards aren’t going to be created overnight. I mean, it’s going to take a long time, five to10 years for any organization to even release method 1 right now. And so, I think in order for things to be scientifically valid, things to be consistent, laboratories have to get on board with agreeing on some set of standards. You know, it’s a historical moment. Once – you know this is a scientific problem right now that is in the process of being solved by medical cannabis laboratories, but it represents policy, regulation, breakthroughs in analytical chemistry, and it’s even anthropological. And this is a historic moment right now. We’re going to look back on this later and be really surprised with how far our labs have gone with testing cannabis and what they can do.

Project CBD: There’s an ISO-certified lab. What does ISO stand for? And is that a kind of a certification that should – it’s kind of top of the line? Or is that sort of your base level that has to be there for a lab to be operating well? How does that criteria fit in, because that’s an international thing?

Marcu: Yeah, ISO is an international standards. The ATOA is an organization that trains a lot of those assessors who go in and look at ISO to see if a place is ISO compliant. And they have different regulations. There’s ISO17025, is for analytical laboratories. But they have also general management systems. Like ISO9000, which a hotel can be or a police station, you know, for managing their paperwork a certain way. And it’s important. It includes, for instance, ISO requires there to be for a lab, to be validated methods being used, that staff – but, however, it doesn’t necessarily cover training or tell you whether or not your operation is legally operating within its jurisdiction for cannabis. So, there are a lot of standards out there. Some are better than others. Some address more than others. And some have a different scope. For instance, for Patient Focused Certification we also look at method validation. Having an ISO compliance or being accredited will definitely help you pass a PFC audit, because it will make the review of the data methodology much easier. You’ll have updated Standard Operating Procedures. But I also look at training records, look at licensing, look at zoning, look at how you dispose of your waste. We look at methods that aren’t validated but you’re also using on site. We kind of look at everything. We also look at batch tracking and adverse events reporting, making sure that you know who extracted what and what did it go into and where did it go, so that if there’s an issue, the product can be tracked or recalled.

Project CBD: You mention issues. Let’s talk about some of the issues, because one of the jobs of a lab, you would think, would be to report adverse findings, adverse events, when they come upon them. Project CBD has caught a lot of flack when we reported that in certain CBD-rich products there were solvent residues that shouldn’t have been there. How do you relate to this adverse event reporting? Is that something the industry should be embracing? Should we be shunning that? I mean, it doesn’t necessarily cast an industry in the best light, and yet...

Marcu: I would gently disagree. I think that any operation that engages in a recall plan is engaging in product safety. Any company that is following up on adverse events claim and making a determination about whether or not that product should be recalled or an advisory should be issued, or perhaps labeling should be changed. These are public health issues. And I think it’s important that we not chastise companies for engaging in this recall. Let me give you – and also labs are not the gatekeepers of adverse events. It is the producers of these products, the distributors of these products, are the ones who should be having an adverse events program. And we have to keep – we should praise those companies that engage in this. Because they’re not always wrong. Their products are not always tainted. While there are recalls happening, it seems like every week we hear about them in Colorado.

What’s not publicized very heavily or discussed are the products that are released after they’re deemed clear, because the lab wasn’t using a validated method and condemned these products when they were safe. But it’s best to see this program working. It brings a lot more legitimacy, a lot more of a scientific foundation to what we’re doing when – you know, adverse events should not be shied away from. There should be an open discussion about them. There should be a national repository where operators in this industry can review them and look into them. The community needs to be its own FDA, in this regard, and for many other things. For the most part, states right now do not have the capacity to act like an FDA for the industry. OSHA (Occupational Safety and Health Administration) has enough issues, work safety inspections – but they will get around to the cannabis industry sooner or later. And I think we have to be prepared. We have to be our own FDA. We have to be vigilant. And we’ve seen a lot of other products come off the market due to a lack of pharmaco-vigilance, keeping track of adverse events and addressing them. And a lot of times people will say, well you know it’s adverse events. We can’t really prove that cannabis caused it, just that the products were there at the scene. And I think that that’s even something that needs to be reviewed and tracked as well.

Project CBD: You mention the FDA. I remember Dr. Tod Mikuriya referred to the FDA as the “Fully Discredited Administration.” What role, if any, should the FDA be playing in this situation? Because they’ve recently issued letters, pretty much a slap-down of CBD hemp oil companies for mislabeling or making false claims and so forth. Does the Food and Drug Administration, the federal Food and Drug Administration, have a role to play that’s valid in this context?

Marcu: They are playing a role. Right now. As you said, with these FDA letters. They’re looking at labeling of products. They are not the DEA, though. They don’t have officers that come and arrest you, per se, but they do have officers or representatives who will show up to your laboratory and manufacturing site and fine you for every little thing: lack of approved standard operating procedures, a lack of secure hardware and software, uncalibrated equipment. There are 483 Violations. So right now we’re just hearing about labeling violations, and I think that soon they might actually show up to facilities – in our lifetime definitely – and issue citations. And I think this is what they do if sometimes they’re laboratories they’ll show up with a van and fine you per day until you fix the corrective actions or go out of business.

Project CBD: There’s another kind of adverse event at play here, and that, irrespective of the quality of the product that a person might consume, there are a certain percentage of people that may have a bad experience and that perhaps shouldn’t be exposing themselves to cannabis. I think the number that’s typically bandied about by federal agencies is like 9 percent will develop cannabis abuse. I think that’s way high in terms of the number. But what about that very small percentage of people who are being exposed to something that might prove difficult to them? How does that play out in terms of the concerns that you address?

Marcu: So the research that that is based upon is very difficult, because it contains no standardized products. These are interviews with people where they derive this information. And that 9 percent figure of the number of people who develop cannabis use disorder or dependence, more than half of those, more than 50 percent of that number is generated from court-ordered drug treatment due to possession or something like that. So the number may be around 5 percent or less. We may eventually find out. But studies with cannabis medicine, such as FDA-approved Marinol, which is an oral THC dissolved in sesame oil, and Sativex, the hash oil extract that’s dissolved in ethanol – those have been studied very intensively and they both have extremely low abuse potential. They have virtually no black market value. And these are standardized preparations. If you were to measure, let’s say let’s talk about pain, and you were to measure say every patient in a study and say, if you had a 12-week study involving five patients, that would be 60 weeks, if you added up all the patient years you’d have about 6,000 patient years of data from patients using Sativex and Marinol, and other standardized preparations of cannabis to look at pain. And they have looked at adverse event profiling. They’ve looked at withdrawal. They’ve looked at abuse potential. And it’s very low with standardized preparations. When you don’t know what you’re getting, when the dose can be high, low, medium, the active constituents can vary from day-to-day, I think that that is the biggest issue right now when it comes to adverse events, is that the predictability and guidance on how to use these products.

Project CBD: Well Marinol and Sativex you mention. Marinol is actually an approved pharmaceutical one can access -- it’s a pure THC product -- with a doctor’s prescription. Sativex is actually in Phase 3 clinical trials now for cancer pain in the United States. It’s an approved medication in many different countries. Essentially it’s a 1:1 CBD:THC tincture. Well, the obvious benefits for standardizing these medicines are significant, that one can take something that they know what it is, and be assured that they can repeat that if it’s helping them. But I think there’s another edge to these kinds of medications that are approved on a federal level, it raises the question what will happen to the medical experiment that’s been unfolding at the grassroots in California and other states that have medical marijuana laws. What will the fate of the medical marijuana – the great laboratory experiment in democracy that’s been unfolding in medical marijuana states? In light of the move toward legalizing for adult use recreationally, if you can gaze into the crystal ball and see what do you think is going to happen in the future with respect to medical marijuana, as opposed to big pharma utilizing individual cannabinoids as medicine?

Marcu: I think the first thing that has to happen is rescheduling. And rescheduling of cannabis, even to Schedule 2, will not give the pharmaceutical companies a big incentive to get involved. I think we’re really far away from the total pharmaceuticalization of cannabis. But what perhaps rescheduling would do to cannabis is allow laboratories to access the standards they need. Allow groups like the AOAC, and other analytical standards groups, to develop certified reference standards for inter-laboratory tests across state lines. Schedule 2 DEA licenses are much easier to get then Schedule 1 licenses. I think we would only strengthen the industry. We’d only strengthen the safety of cannabis patients if cannabis was Schedule 2, and laboratories, manufacturers, were actually able to engage in more thorough quality control without being unfairly handicapped by Schedule 1 status.

Project CBD: Do you think Schedule 2 goes far enough in the end?

Marcu: It’s a good step. I think it’s far enough to make waves internationally. And I think what we will experience is not that a single country will change the law, but that it will happen at the international level. I think we’re on the precipice of having some really interesting discussions around the UNODC table or around the various United Nations groups that discuss drugs and psychoactive substances.

Project CBD I think this has been an interesting discussion. I thank you for your participation, Jahan Marcu. Good luck.

Marcu: Thank you.

Copyright, Project CBD. May not be reprinted without permission.

Audio-visual category: 

Robert Clarke: Cannabis Botany & Evolution

Robert Clarke Botánica y Evolución del Cannabis
By on February 17, 2016

In this video Rob Clarke, co-author of Cannabis: Evolution and Ethnobotany, discusses CBD-rich drug plants, disappearing landrace strains, and the future of cannabis farming in the United States.

Transcript

Project CBD: Today we’re talking to Robert Clarke, noted writer and scholar, also director of the BioAgronomics Group. It’s an international consulting firm that services the cannabis industry. Rob is the author of quite a few very interesting books, including Marijuana Botany and, most recently, co-author of Cannabis: Evolution and Ethnobotany, a tome that represents really his life’s work involving extensive travel around the world visiting various hemp cultures, cannabis cultures. Rob, what got you into this?

Robert Clarke: Well, I guess it was going to University of California in Santa Cruz in the formative years. Yeah, it seemed an appropriate way to graduate from university – something I was interested in so I wrote an undergraduate dissertation about cannabis. And it’s been my path ever since.

Project CBD: Well, I remember back in the day, back in the 1960s, late 1960s, when one spoke about cannabis one heard phrases like “Acapulco Gold,” “Panama Red,” yet when I go into a medical marijuana dispensary these days in California, I don’t see those strains. What happened to those great old landrace strains?

Clarke: Yeah, those would be like you say, what we call those landraces. Those were varieties maintained by local farmers in concert with the natural selective pressures of the local environment. And usually selected for a particular end use, whether it was for marijuana or for hemp seeds or hemp fiber. And those were really what the original marijuana varieties were: the imported Colombian and Mexican and Thai of the past. They were the varieties that farmers grew for themselves. Then they became items of trade. And there was never really enough of those to fill the expanding market. So, pretty soon people grew whatever they could get a hold of. They brought seeds from the USA back to production areas like Mexico or Colombia. And, then those landraces began to disappear. There weren’t farmers carefully taking care of them every year, maintaining them. There wasn’t such a selection for quality plants any more. We’ve just basically lost these over the years.

Project CBD:  And, in terms of the genetic explosion, if you will, starting back in the mid-1970s when people in the States, particularly in northern California, started to breed with these different seeds from different parts of the world – these different landrace strains. These became sort of the building blocks for many of the strains that people enjoy today.

Clarke: Absolutely, absolutely. Those genes are still there from those landraces. It’s just not possible to go back and find them in situ any more, living where they used to, in those particular assortments of genes that made that landrace. But those genes are – as you say – they were the basic building blocks, they were hybridized Colombians with Mexicans with Thais, with Indians, Jamaicans, all what we think of today as the narrow-leafed drug varieties. The true indica, the indica from India, where all these originated, whether they ended up in Mexico or not, all these varieties started in the Indian subcontinent. And, this hybridization caused this hybrid vigor, as we would call it. These were isolated gene pools that came together only after people crossed them, marijuana growers in the States and Europe as well, crossed them and made these hybrid varieties that created situations where the best traits of both parents could be expressed. So you’d have large flowers from one parent and early maturation and good resin content from another one, potency from another one. You’ve come together with these poly-hybrid sinsemilla varieties that we have today. They have lots and lots of ancestors, if you will, lots of parents and grandparents and great-grandparents.

Project CBD: It would seem that in the process of gaining these hybrids maybe we’re also losing something, if the original landrace qualities, the actual plants themselves are being disrupted by the very diversity they helped bring about.

Clarke: Sure. Sure, we’ve become very narrow in what we’ve selected. We’ve wanted plants that had a lot of aroma, a lot of potency, matured early, and gave high yields. A lot of the landraces really didn’t give us that. That’s why we’ve gone on and adopted these hybrid varieties as being our standard these days. But, if you look at – despite all the variety we see between a Kush and a Cookie or whatever, this was really looking at variety amongst a very tiny part of the whole cannabis gene pool. It’s leaving out all the hemp varieties. It’s leaving out a lot of the wild varieties or escaped varieties that are there, unselected types. And we can’t really go back and find the original building blocks any more. So we’re kind of stuck. I mean, the genes are there but they’ve assorted into what’s become popular today. And it’s hard to go back and find an original Colombian to get gene combinations from that plant that we’ve suppressed, that we’ve selected against for the last 30 years.

Project CBD: You’ve been involved in assisting a project that entails genetic tracking of strains, the Phylos Project. I believe it’s based in Oregon. Maybe you could tell us a little bit about that. What is that all about, why are you interested in that?

Clarke: This is a project based out of Portland, Oregon. Phylos Bioscience is the name of the company. And the project is the Phylos Bioscience Cannabis Evolution Project. The idea here is to characterize genetically, to look at the genome of cannabis, the entire genome, but to look at different examples. We have, for instance, all the dispensary samples, over 1,000, that have been analyzed so far. And they produce – you can look at it as a cluster of data, three-dimensional cluster of data, everything is a bit related to everything else, because of the situation I just explained with the mixing of the basic building blocks.

But to resolve this and to show what’s gone into these modern varieties, we’re trying to also find original Colombians and Mexicans and Jamaicans, and characterize these building blocks genetically so we can see how they’re related to the modern varieties. And it makes an interesting experiment from two angles. One is you can begin to see the evolution of cannabis, but we also are able to use this model to test whether genomic analysis, whether DNA analysis, is really applicable to cannabis. Because we know a lot of the history, we know that Jamaicans and Colombians were combined together to make certain varieties. And if this is not shown by the data we’re developing, then we have to re-investigate the applicability of whether this data is really fit for studying cannabis.

It’s a very complex plant. It’s unlike most plants, it’s out-crossing. There are male and female plants. So it’s impossible to – nearly impossible – to self an individual for a trait that’s favorable. If you do this, you can do it artificially but it’s not the natural situation. And it’s also wind-pollinated. So that unless you isolate plants to keep them from being pollinated by other ones in the neighborhood, then the pollen blows around in the wind, so one parent, one plant can be a parent to many, many offspring with very many mates. So this is also making for diversity constantly in cannabis. And we, as breeders, fight this diversity by trying to narrow it down to a variety that breeds relatively true. But this is a difficult path. It’s easy to make cannabis seeds, but it’s not an easy plant to breed in a structured way that leads to plant improvement, leads to better varieties.

Project CBD:  And why is that you have these challenges with breeding? How does the history of the plant itself relate to that?

Clarke: It’s basically its natural history – just that it wants to be an out-crosser, it’s always striving for variety in its own survival mechanism, if you will. And we’re trying to narrow that variety so that a cultivar will have certain traits. It will mature in a certain number of weeks, have a certain aroma, and a certain cannabinoid content. It’s always a battle between having enough diversity that the plant is genetically healthy and not terribly inbred, but inbred enough so that it’s not just a dog’s breakfast of different types in one population.

Project CBD:  It’s an interesting point you make, about how studying the genetics of the plant could shed light on that very process of gene sequencing the plant. Usually it’s sort of the other way around, it’s the gene sequencing that’s going to shed light on the plant. It’s an interesting reversal. But, let’s assume that there’s a correspondence there, it turns out what folks like Mowgli Holmes and the Phylos Project, John Page up in British Colombia, the fellow out in Colorado, and Kevin McKernan out there in Boston doing this very interesting work with gene sequencing the plant. Let’s say, the method is validated. So what are the likely implications of that for the cannabis industry, for example? I mean, it’s a burgeoning industry and it’s all basically based on this plant, at least in theory.

Clarke: Right, and people have put a lot of energy into developing what they call varieties, or at least asexually reproducing a cutting, you know making a clonal propagation. And, once you start to be able to identify plants, to fingerprint them if you will (though it’s not a totally appropriate term), but to identify them in a physical way, then you have the ability to protect them. The initial knee-jerk response is, well if I can identify these gene sequences that identify my variety that I’m trying to keep for my monetary gain, then – like patenting any product or any process – you would begin to think about restricting other people from using your intellectual property, your variety. That’s one way to look at it. And that’s the way patent applications and processes basically work.

The situation with cannabis is a little bit different because everybody, pretty much everybody, has given seeds or given cuttings of their favorite plants to their friends. Well the minute they do that they’ve put their creation into public domain. It’s like handing out your manuscript to your book without having copyrighted it. That would be analogous. So it is part of the public domain. And, what that means is that most of the cannabis that’s out there now belongs to everybody. It doesn’t belong to any one person. And if someone has something they haven’t released, they’ve kept it proprietary, then it can belong to just them. And when, and if, there’s a system in America to protect these plants, they could be protected. But, it makes a lot more sense rather than fighting to keep other people from using something you have, to just admit that we all have access to all these things and they belong to the public domain, and they can’t really be sequestered and used by one party.

It would be what’s being termed “defensive” intellectual property rights protection. You’re not on the offense to try to keep other people excluding their use or license the use of your variety. You’re just saying that it’s everybody’s and no one person can take it and profit from it. And that seems, in the current state of the way things are, to be a more logical way to approach the situation.

Project CBD:  Although you have a lot of money moving into the cannabis industry now, where I think IP is considered as one in terms of an offensive approach. This idea of defensive IP (intellectual property) is very interesting and as you say maybe more appropriate for the realities of how the cannabis narrative has unfolded in our culture. Then you have this, still the prohibition hanging over everybody’s head. So where do you see the future of this going? What are the implications here?

Clarke:  It seems to me that we already have models for where cannabis is probably going. We have a boutique wine industry. We have the craft beer industry. People can make their own beer and wine, but very few people bother to do that. They go buy a beer or wine of the price range and quality and varietal characteristics they’re looking for. I don’t see that that would be any different with cannabis. But, like beer and wine, most people drink mass-produced beers and wines. They don’t want to afford the better ones. They’re perfectly happy with drinking whatever they’re drinking, smoking whatever they’re smoking. And I assume that based on convenience and things that a lot of the cannabis industry will be, you know will be the convenience industry – drop by an outlet where whatever it ends up being, a liquor store or a cannabis store or a Speedy Mart or whatever, and picking up whatever product you like, whether it be edible or vape or whatever.

It’s harder really to picture what the regulatory climate is going to be for this whole thing. It’s difficult to perceive what the Food and Drug Administration is going to do with a food-drug or a drug-food, “medibles” as they’re presently called. This is just a nightmare scenario for me. It’s that, medicines were the gateway to getting adult social use of cannabis legalized is – fine that’s the path it’s taken – but as soon as legitimate established medical factions, companies, enter into this the whole terrain is going to change. You can’t say something is a medicine unless you can prove it’s a medicine. And, we just don’t have the science in most of these cases to back up what people feel in their hearts is correct. And probably they are right. We have good anecdotal evidence. But we need hard science. On many, many levels with cannabis, we’re assuming a lot more than we actually know.

Project CBD:  So it doesn’t quite fit in the slot if it can be a food or a drug, it doesn’t fit in with the Food and Drug Administration. It has to be “or” not “and.”

Clarke: And it’s really a health care product. I mean, why make claims. It’s a health care product. If I decide that red wine is good for my heart – which there’s plenty of evidence that red wine is good for human hearts – that’s fine. But I can’t put a label on a bottle of red wine that says “this is heart healthy wine.” That’s where the line is drawn. And we make lots and lots of claims that would not be allowed for any health care product.

So a lot of the aim with our consulting group is to try to help people “pre-comply.” It’s easy enough to see on a federal level many rules that people are going to have to comply with, many hoops they’re going to have to jump through – with any product that is a food or a health care product, or anything of this nature. So it’s not so hard to imagine the obvious hoops you have to jump through. What we have to hope for, and also try to enter in as much as we can as a user group and those responsible for our own futures, that we don’t allow cannabis to be over-regulated.

It’s not any more dangerous, as it’s turning out, then many other food and drug products. So why, why should we be subject to more hassles than other groups. There’s no such thing as “zero tolerance” for rat poop in peanut butter. You’re allowed to have a tiny bit of rat poop in peanut butter – not enough to make people ill – but you can’t say that you can’t have any rat poop in peanut butter. That’s impossible to achieve. So we don’t want goals with cannabis regulation that would make it impossible to achieve.

Project CBD:  It seems that, in terms of a prohibitionist framework, those that define, or try to define what that plant is, are very comfortable calling it a drug plant in a prohibitionist context – calling it a drug plant in a medical context it’s begrudging. In the framework that you present in Cannabis: Evolution and Ethnobotany you speak about drug plants and non-drug plants, the latter being hemp. You don’t speak so much about indica and sativa and the way that it’s folklorically discussed in our own community. Why not? What’s the drawback, why not speak in those terms that people tend to be familiar with? You know, they think indicas, or a certain, make you more tired, and sativas energetic. What’s the shortcoming with that kind of way of discussing things?

Clarke: Well, I think it’s fine to have these characterizations. And people – what we’re talking about here is the study of classifying organisms, or classifying anything, it’s taxonomy. Every culture has a different way of doing taxonomy. Every tribal group that names the plants they use for food and medicines have created their own taxonomy, in their own language. And often those are descriptive. And those words, through the descriptions, relate one plant species to another that because of their similar uses maybe they’re grouped together by this description. They might not be related in terms of their leaves and flowers and growth habit particularly, but based on their usage.

So people have to realize that taxonomy is a very fluid thing. And, of course, it’s valuable to name things because then we have a common system. And when you say you’re talking about cannabis sativa, I know you’re talking about the same plant that I am, not some other cannabis or some other drug plant or some other fiber plant. It’s all very valuable. But, we’ve ended up through sort of a process of elimination, we’ve ended up with calling the two different groups general classes of drug cannabis, it seems to me are either sativa or indica. Well, first of all, they’re all hybrids between two different groups, whatever you want to call them.

We ended up with sativas and indicas as the names because up until relatively recently most taxonomists have concurred that all variation of cannabis is part of one species, cannabis sativa. Then when Afghan cannabis came along that was markedly different, that was called indica. And basically to differentiate it from what already existed which was called sativa, and it was a drug variety and there were reasons to think that it was another species. That’s where the two species debate really began is when Afghan cannabis came on the scene, late ’70s. But before that people had only seen drug cannabis that came from India, no matter where on the planet it popped up, it had originated in India. And Afghan cannabis was limited just to Afghanistan and parts of Pakistan until the late ’70s.

Project CBD:  And did it look substantially different, these two?

Clarke: It does look substantially different. It’s a different general growth habit. It’s shorter, more compact, broader leaflets –

Project CBD:  The Afghani?

Clarke: The Afghan. And darker green color, shinier, and unique aromas. And it matured quite a bit earlier then the semi-tropical –

Project CBD: But they’re both drug plants in the sense that if you use them they get you high.

Clarke: Psychoactive drug plants. They both contain THC. The narrow-leaf drug varieties, what people call sativa. The true indicas (indica means from India), and what Lamarck named cannabis indica, that’s what he meant. He meant the narrow-leafed drug varieties from India. And they’re just entirely different from the Afghan varieties, which when they were brought into California, revolutionized the whole sensimilla industry: made plants that were higher yielding, easier to manipulate and manage because they were shorter, and they matured earlier. And they had unique aromas and flavors that people initially quite liked. They’re also very high in CBD. All the hashish varieties have quite a lot of CBD in them as well as THC. On average, maybe about the same amount of CBD as THC. And we’ve basically bred the CBD out of these varieties in our modern sensimilla.

Project CBD:  And yet, today there’s a lot of discussion about CBD derived from industrial hemp, as if this is – and because of the somewhat arbitrary definition of hemp as being below 0.3 percent THC, that makes it a hemp plant, there is this idea that somehow the CBD-dominant plants are not cannabis, they’re hemp. And, yet when you step back and look at it, a CBD plant with 10, 15 percent, maybe 20 percent CBD by dry weight like with ACDC in California – while it doesn’t get you high necessarily, it’s still a drug plant. So does it make sense to call that hemp when it’s got all that cannabinoid in there, it just happens to be not mainly THC. Isn’t it all just drug plants, as you’d say?

Clarke: To me it is. And, their backgrounds are the same too. ACDC and Harlequin and these things, as far as I know – and I’m pretty sure we’ll see in the genetic analyses – they don’t have a hemp heritage. They don’t have European cannabis sativa in them or they don’t have Chinese cannabis indica subspecies chinensis, that’s what the broad-leafed drug varieties or hemp varieties. It’s a different hemp, the Asian hemp. But these are not in the high-CBD varieties. I would suspect that the CBD in those comes from Afghanistan. And they are, they were bred as psychoactive drug varieties. It just so happens that they didn’t get – the baby didn’t get thrown out with the bathwater in this particular case.

When analysis began on a public available level a few years ago, people went back and looked at their different varieties and went wow, this one has CBD in it. Far out! They had no idea. No idea at all. And those were psychoactive drug varieties before they realized that they could use them for something else. So of course they’re drug plants. They were bred for drugs. They were selected for high THC. They happened, also, to be high CBD plants, some of them – very few of them. And that’s what we have today is these high CBD drug producing plants, but the end product is drugs. They’re not hemp plants. We’re not eating the seeds or wearing the fibers. So yeah, you have to call them drug plants, non-psychoactive drug plants.

Project CBD:  To me, that makes a lot more sense. The way that we talk about CBD derived from hemp, what are we really talking about here? If it’s a plant that has 8, 10, 15, 20 percent cannabinoids, whether they be CBD or THC like you’re saying, is a drug plant. That’s what it is. A hemp plant grown for fiber or for the [seed] oil, that’s a different kind of thing. And yet, it’s been blurred, I think, partly because of this green rush toward establishing a foothold in the brave new world of legalized cannabis, such as it is. But, anyway, this has been very interesting. You know your work, going back to Marijuana Botany in the early ’80s, has really been -- it’s really mentored a whole generation of farmers who I think these days are in for some interesting changes. Maybe you could comment on what you see in the future for the farmers who have carried the ball in places like the Emerald Triangle doing this kind of breeding, this outlaw farming. What do you think the future holds?

Clarke:  I think the future for some of these people will be really bright. But they’re the kind of people who land on their feet no matter what. The vast majority of people, I think, are going to be left behind. And, that’s just because we’ve operated in a prohibition setting. You know, the price of cannabis is artificially very high, and that’s because it’s been prohibited. It’s not particularly difficult to grow. It’s easier for the average person to grow now then it ever was. And, people who’ve been involved with this business, especially in California, live in agriculturally marginal areas. They were fine areas for back-to-the-land movements because land was discarded and cheap, left behind by the logging industry. You see where the bottomlands, they’re occupied by wineries that have been here for 100 years or more. That’s where the good land was in northern California. And the back-to-the-landers ended up with the rest. They’ve made an incredible go of it. In a way, unfortunately, cannabis has become a key part of the economic picture in places like northern California. And this can’t persist. There’s going to be way too many regulations for most people to deal with. It’s just simply not going to be worth the trouble. And there will be people who stick with it. They’ll be the boutique growers. But, you know what, a lot of them are probably going to move to some part of the state that’s got better weather, if they’re really serious about it. And it’s sad, but true. It’s the economic settling out of this picture. There’s going to be bigger producers, just like there is for everything. So, yeah. I hope everybody adapts as best they can.

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Dr. Bonni Goldstein: Cannabis Therapeutics

Dr. Bonnie Goldstein speaking on cannabis and epilepsy
By on February 02, 2016

Dr. Bonni Goldstein discusses using cannabis medicine in her practice for patients with intractable epilepsy, cancer, autism, and mental health conditions.

Transcript

Project CBD: I’m here with Dr. Bonni Goldstein from Los Angeles. Please introduce yourself, Bonni.

Dr. Goldstein: My name is Bonnie Goldstein. I’m a physician and I am the medical director at Canna-Centers, a group of medical practices throughout California that educate patients on the use of cannabis therapy. And I also do some medical consulting for Ghost Group, the parent company that owns Weedmaps.

Project CBD: So we have heard a lot over the years, in terms of the “reefer madness” context, about marijuana being the “assassin of youth.” But in your practice, as a pediatrician, you’ve seen different results. Maybe you can tell us about that.

Dr. Goldstein: That’s true, Martin. So, remember, healthy kids are not coming to a doctor for help with cannabis. It’s the children that are sick. And, in my practice I’m seeing the sickest of the sick. I’m seeing children who have intractable epilepsy, that means they’re not responding to any treatment that’s available. And there’s some aggressive treatments – brain surgery, special diets that are very difficult to keep, lots of different medications that have toxic side effects. I’m also seeing children with autism. And we know, really there is no medicine for autism. There’s therapy, which can be very helpful, but there’s only two approved medications, and both of them are anti-psychotics, not great for children (many bad side effects). As well as children with cancer. And also I’m seeing some children with severe psychiatric disease where current conventional medication hasn’t helped.

What we have to remember is that the endocannabinoid system, the part of the brain that’s required for many physiologic processes throughout the body, this system helps with homeostasis. It keeps the brain in balance. And, in certain patients – people with illness – that system is the core of the problem. In most healthy children, their endocannabinoid system is functioning and actually adding cannabis to that endocannibinoid system may actually interfere with developing brains. So I don’t encourage teenagers – and I’m the mom of a teenage boy – to use cannabis until their endocannabinoid system is “finished developing the brain.” But in children who are sick, these are special cases. These are children who sometimes are not finding the answers. Years go by, and when you lose years of a child’s life, you’re losing development, quality of life – the burden of illness is tremendous, not only for the child but for the whole family.

Project CBD: So what have you seen in terms of your practice that has surprised you?

Dr. Goldstein: Well, with the group of patients with intractable epilepsy, the average number of medications that the children who come to me – by the time they get to me – they have usually tried 12 medications that have failed them. They often have developmental delay. They often have significant other problems, pulmonary problems, GI problems, immune function problems, which all can be interrelated with the endocannabinoid system. They also aren’t living what I would call a “normal” life. They’re not going to school. They’re not able to go to school. The school doesn’t want to have them there if they are having lots of seizures and so on. So, what I’m seeing is, when we add CBD-rich medicine – so basically an oil that the children take under the tongue or they swallow it or it goes through a G-tube – what we’re seeing is that number of seizures is reduced. Many parents report frequency down, severity down, duration down. And interestingly, they say, where my child had a seizure before and it would take all day to recover, my child just bounces back. And then we can get up and go do things. So that was very interesting to see that the positive response, not only in less seizures and so on, but even when they still continue to have seizures they’re not as disruptive. So that was an interesting thing to see.

Project CBD: When you talk about the CBD oil, what are you actually referring to?

Dr. Goldstein: So I’m talking about oils that come from a plant that has the genetics to grow high CBD and low THC. And what we’re talking about is a ratio. Some of my patients respond to a ratio that’s 25 parts CBD to 1 part THC. Some of my patients respond to a 10:1. Every individual responds differently to medicines, as we know from all medicines, but especially with cannabis medicines. CBD oils, remember, contain not only CBD but whole plant, and so there’s THC, there’s other cannabinoids, there’s also terpenoids which are the essential oils – all of these interplay to give the beneficial effects. You know, we talk about CBD only in dosing CBD, but really it’s the whole plant that’s very important because it’s all of these compounds that work synergistically to give the effects.

There’s one particular compound called beta-caryophyllene which is a terpenoid, which has been shown to be anti-inflammatory. And I really believe that that’s one of the compounds that’s very important for a child who has seizures. One of the interesting things that I’ve seen is that neuro-inflammation is documented in a lot of research in a brain that has active seizures going on, yet most of my patients come in and nobody’s doing anything to treat the inflammation. And I really believe that the reason – one of the reasons that CBD is so helpful, not only because CBD, cannabidiol the compound, itself actually works to help balance some of the messages being transmitted in the brain and lessen the firing that causes the seizures, but also the anti-inflammatory effect. One of the other parts is the neuroprotective effect of cannabidiol. And remember, in a developing brain seizures are damaging. And so, having that neuroprotective property is extraordinarily important.

Project CBD: What would be some of the cases that you’ve dealt with that have had the kind of outcome you had hoped for when using the CBD-rich oil? What would be an example?

Dr. Goldstein: Well, I have this beautiful little girl that comes to see me. She was adopted by this fantastic mom and dad, and it appears that there was some event while she was still in the womb that they’re likening to a stroke. And so when she was born there was a lot of complications. And she started having seizures right away. And, it appears that as she developed through the first year of life a portion of her brain didn’t develop properly. You can see it on a scanning test. So, she had a lot of seizures. She’s small for her age. And, she wasn’t responding to any medications. And her parents came to see me and they had heard about CBD on TV, and then they did their research and they came to see me. So we started her on CBD oil, and my protocol is to start low dose based on weight and to titrate up which is very typical in the pediatric population.

And, I’ll never forget this, because I was on vacation when the mom texted me, but prior to this particular text, pretty much every week they checked in with me as I had asked them to. And so, the next week we go up on the dose, and the week later we go up on the dose – no negative side effects, but they haven’t really seen any reduction of seizures. And this is a little girl that’s having about 40 seizures a day. One particular week I get the text on Friday morning, and the text says: Well we went up on the dose on Friday a week ago, and on Monday we only had 20 seizures instead of 40. On Tuesday, we had only 13 seizures instead of 40. And on Wednesday, we only had nine. And yesterday, we had four. And so far today, nothing. That child is currently seizure free on CBD oil. She’s been weaned off her anti-seizure medications. And she’s making some developmental progression, doing things that nobody thought that she could do. She’s a happy child. And the parents are thrilled.

Project CBD: And what other kinds of cases, in terms of the pediatric patients you’ve been dealing with? You talk about seizures, epilepsy, the autism spectrum which could include seizures as a symptom, what other kinds of cases have you been dealing with?

Dr. Goldstein: So, I’ve seen a fair amount of teenagers who are struggling with various psychiatric disease, things like bipolar disease, severe anxiety, depression. Most of them who come to me have tried pharmaceuticals and have not done well on them. Not to say that you can’t do well them, it’s just that’s the population I see. Many of them are teenagers, so they tried cannabis with their buddies and then came home and said, either the parents noticed, my child’s not anxious today, my child’s being pleasant today. And then the parent confronts and says what’s going on? And the child will often say, well you know, mom guess what I did with my friends. Or the parents read about it and they say maybe this is an answer to our problem that we have.

So again, going back to the developing brain, in those patients you know they may have found, you know that kind of smoking pot with their buddies really helped, but we have to remember too that that may be the answer but again, in a developing brain, I think combining CBD with THC is probably the better bet. The combination is probably going to be something that will benefit them more and hopefully they can find a balance. I’ve had very good success. I had one young man who’s 15 years old, who struggled with severe anxiety to the point where, before they came to see me, the patient’s father said maybe you could make a list of what bothers you and we can bring it to Dr. Goldstein’s office. It was three pages long. He worried about everything at school, everything with sports, everything with girls, everything with everything. This poor kid had so much on his mind that he couldn’t function. It really, you know, just overwhelming anxiety including social anxiety. I taught the family about CBD oil. They were interested in trying a high-CBD to THC ratio. And two weeks after starting the oil, I got a text from the dad and he said that he had received a text from his son, which is very unusual, and his son said: I’m having a good day, I’m really happy, dad. And, I had talked to the father maybe a week later, and he was in tears. He was just blown away by the fact that there was a solution and they didn’t have to take all the various drugs that they didn’t really want their son to be on.

Project CBD: So when you’re dealing with a patient like this, how do you determine dosage and ratio? Are there criteria you go by? Is it a case-by-case thing? It’s just on the basis on your experience you’re drawing from? Is there a lot of experimentation typically that’s involved?

Dr. Goldstein: Well, the interesting thing with cannabis – and I find this easy because I tell all my patients this – you start low and you titrate up to effect. If I guess a dose, I could be way off. I really can’t guess that you’re going to get 50 mg and this guy over here gets 10. There is a clinical sense that when you start taking care of a lot of people doing this, you get a sense of where they may end up. But since everybody’s endocannabinoid system is different and different sensitivities, and remember there’s other factors involved – what’s their metabolism, does it last longer in their body, right, meaning because some people metabolize very quickly and some people metabolize very slowly. I’ve had patients who tell me that they will get a full day’s effect from one morning dose. I have other patients that have to dose multiple times during the day, maybe a lower dose multiple times. So, some of it’s the clinical experience. Some of it’s learning from my colleagues, what they’re doing as well.

But in general, starting low and titrating up. With children who are non-verbal, we pretty much, you just have to observe and you have to trust the parents to observe. I have yet to meet a family or a parent who doesn’t want the best for their child. They’re in my office because they’re seeking a solution. When it doesn’t work, I know about it. I trust the parents to tell me. They may have missed two seizures because they ran off to the bathroom or they’re cooking dinner, but in general, when your child is doing things that they have never done before – when they’re smiling, when they’re learning – I currently have a little girl who is doing very well on cannabis oil and the mom just sent me a video of her first time she ever said “mama.” And she’s around 9-years-old. So, we know her brain is doing well on this oil. We can tell. She hasn’t been able to do that before. And that’s probably because she’s on much less medication and she’s not having seizures all the time that are interfering with development.

So the dosing is really, you know it’s a little bit of a – it’s not like dosing that we know with pharmaceuticals. It’s different. Cannabis is a different compound. Remember it’s not one molecule; it’s a whole bunch of different molecules. Really, I think one of the very important things is that we really can’t harm people with cannabis. Of course, someone who uses a dose of THC that alters them and they shouldn’t be driving, sure they can get hurt. But that’s not what I’m doing in my practice. We’re giving measured doses of CBD oil to children, again starting based on weight, low dose, titrating up, looking for that child’s – what I call the sweet spot. And sometimes less is better than more. Sometimes we hit a point, we say, ‘Oh no we did much better at a lower dose,’ and we back down. And so there’s a lot of dose management going on, but because the tolerance is so good there’s no negative side effects really. I’ve even had the experience of three particular patients over the last few years that measured wrong on the syringe and overdosed their children. The child had a very nice nap! Slept all night, and really there was no negative – other than the parents worrying – there was no downside.

Project CBD: That’s important information for parents to hear, particularly for parents who may not be able to get a consultation with you directly. Let’s face it, there’s not many physicians that are doing this kind of work. I can probably count them on one hand really, who are doing this kind of cutting-edge work with oils, cannabis oils. And yet, there are so many families that are in need of this kind of therapeutic information. What could you tell a family or parents of a child who can’t get into see you – you have a waiting list or they’re in another part of the country. Can you give advice that’s more than just, ‘Okay this won’t hurt if you overdose’? What can you tell people in this situation, because there are so many people in this situation?

Dr. Goldstein: Well, it is hard, because you want to have the whole picture beforehand. I was trained very well as a doctor. I feel that my training was excellent. And I think the nuances of somebody’s illness is important to kind of gather up before you proceed forward. I have had a few patients that came in who were actually doing well without side effects on a medication. The parents came for my opinion. And at the time, I made the decision to hold off on treatment just to see where we end up. Because, you know, sometimes with children with seizures, they do stop. And they may not have another seizure, ever. It’s a very strange phenomenon but it happens. And so, if you’re four months away from being taken off your medication, I don’t want to rock the boat and cause a seizure because of the drug interactions.

So sometimes getting the whole story is really needed beforehand, it’s hard to just throw doses out there. For any physician – you know, I don’t want to be irresponsible and say, ‘Oh do this and do that.’ But, I think gathering as much research as you can gather, talking with people about – you know people who are in the business of either making the oils or who are helping patients with the oils – there’s a lot of people out there who know a lot. I think one of the big things is that my colleagues in the medical community need to start seeing this as an option, and they need to learn about it, and have it in their amamentarium of medicine. It is a medicine.

Lee: Why isn’t that happening more with doctors? Why aren’t there more doctors jumping on board? Because certainly there’s a buzz about medical marijuana in the culture, and there’s a general respect that something’s going on here among the population. Where are the physicians in all of this?

Dr. Goldstein: Right. Well it’s interesting and I think there’s lots of answers to that, so bear with me here. The first thing is, when you’re in medical school you’re taught that cannabis is a drug of abuse. When we’re children we’re taught that cannabis is a drug of abuse. And then it’s reinforced when you go to medical school. There’s a billing diagnosis for cannabis abuse. And there are some people who do abuse it, usually they are not the very sick, it’s usually someone who may be self-medicating but you know I have found in my practice that somebody comes in sometimes and says I think I have a problem with it. We talk about it. I educate them about their receptors and how by overdoing it the receptor number goes down and then you don’t get a good response – so sometimes an educational intervention, because it’s not so highly addictive, does the trick. So, one, is the cannabis is a drug of abuse. Any drug can be a drug of abuse. And we’ve seen that of course with the opiate, prescription opiate death increase in this country.

I think the second thing is that when California passed – when we as voters passed the law here in California [in 1996] – the medical board and the environment was negative toward doctors who recommended this, and some doctors actually were brought up on charges with the medical board and had to defend themselves. That’s scary. If your livelihood is based on the fact that you have a medical license, you really don’t want to risk all those years of practice and your livelihood to step out on a limb in that kind of environment. The people who did that were very special pioneers. There’s no question. They’re the ones who we can thank now in 2015 that were able to do this.

And then I think, in general, it’s that the lack of education about the endocannabinoid system, the lack of understanding about cannabidiol. I still, to this day, get people who come to see me, parents of children who say when I told my doctor we were going to look for medical cannabis treatment, they asked me if I was going to blow smoke in the child’s face. And that’s, you know to me, is one of the most ignorant statements because I just feel that if you’re a physician you need to look at the science, you need to look – just the same way you would learn the preparations of a medications that came out on the market that was, that you thought was beneficial – you need to take the time and learn.

Project CBD: People hear about medical cannabis, and then they hear about this “CBD,” and it’s almost like a fairy tale. You know, they hear these miraculous outcomes of children who are seizing 100 times a day, and then they stop seizing. Give us a perspective here. Is this a magic bullet? Is it, you know, once in a million that you get this kind of response? Based on your practice – and I understand you’re dealing with really tough cases, people come to you when nothing else has worked, and people come with a sense of hope, and that’s important, that’s therapeutic in and of itself that they can be hopeful. But give us a perspective. You don’t want to raise false hopes either in talking about these things. Give us a realistic sense of what the potentials are here.

Dr. Goldstein: Sure. So realistically, there’s a lot of variables to get to the point where “somebody’s a success story.” There are children who respond immediately and beautifully and do well – and that is not the usual case, but I have seen it, where literally within two days of starting CBD oil, life as they knew it is not the new normal. So that happens. But for most cases, it’s over time because remember inflammation doesn’t go down overnight; getting off other medications is not something that you do overnight. I have patients who’ve been weaning medications for two years.

If you remember in the CNN documentary showing little Charlotte, there’s the video of her laying on the floor having seizures, but then it cuts to her riding a bike. And I think that it’s a nice side-by-side comparison, but that didn’t happen overnight for Charlotte. It took time for her to get there. And so, I tell my patients that you know it’s not magic fairy dust. It is medicine and you have to take it, and we have to find the dose, and we may have to wean other medications, but that if you’re willing to give it a shot you kind of have to be on board for at least three to six months if not longer, if we’re seeing good results. I have had some patients who, you know, tried numerous different CBD preparations and it took them until the third one to actually see a result. And if you talk to adult patients who are using cannabis for other treatments, they’ll tell you oh that strain works for migraines, but this strain doesn’t. Well, the same may be true – and I see it – with children who are sick. One strain may work better than the other and there are a few different CBD strains that patients can try. Finding something affordable – because remember, it’s out of pocket. Finding something consistent that you can get over and over again, something tested, that’s a lot of the difficulty. So, you know it’s not an easy answer. It’s not a miracle. But when you look back at what some of these families have been through with 10 years and 15 different medications, that’s what they’ve been doing all along.

Project CBD: Well it is not only important that people can access the good medicine, but they also need good health counseling. And we’re very, very fortunate Dr. Bonni Goldstein that you are part of this community and have really been leading the way with cutting edge clinical input. Thank you very much.

Dr. Goldstein: Thank you, Martin.

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