martin lee

ICRS 2016: Report from Bukovina

ICRS Bukovina Cannabinoid Science
By on July 05, 2016

In late June, two hundred and ninety-seven delegates from 24 countries attended the 26th annual conference of the International Cannabinoid Research Society (ICRS). This year’s meeting took place in Bukovina, a Polish retreat nestled in the picturesque foothills of the Tatra Mountains.

The four-day science symposium featured 87 oral presentations and a hundred posters covering a wide range of topics germane to cannabinoid science and medicine.

Several reports shed light on potential therapeutic applications of CBD:

  • Brain trauma. Spanish scientists report that CBD administered after a stroke reduces brain damage in animals, restores neurobehavioral performance, and prevents excitotoxicty from dopamine and serotonin release.

  • CBD protects. Combining CBD with hypothermia (cooling) is more effective than hypothermia alone in protecting the brain function of newborn mammals after hypoxia-ischemia.

  • Neuropathic pain. Temple University researchers determined that CBD and THC work synergistically for treating neuropathic pain from spinal cord injuries.

  • Cancer. Italian scientists found that a CBD-rich cannabis extract potentiated the chemotherapeutic effects of standard Big Pharma meds for prostate cancer; another Italian study showed that CBD reduces the viability of white blood cancer cells and induces cell death in multiple myeloma cell lines.

  • CBD for kids. Why do some pediatric epileptics respond remarkably well to CBD and others don’t? Douglas Smith with Medicinal Genomics spoke on genetic factors that influence the efficacy of CBD in catastrophic seizure disorders.

  • Gaba Gaba hey! One of the ways that CBD imparts an anxiolytic or anti-anxiety effect is by enhancing GABA receptor transmission, according to Australian researchers. GABA receptors are directly activated by Benzos such as Clobazam, an anti-epileptic drug. Clinical research has shown that CBD raises Clobazam blood levels in pediatric seizure cases, indicating a drug interaction.

  • CBD lowers blood pressure. Polish scientists showed that CBD relaxes pulmonary and enteric arteries in animal models of hypertension.

  • Gut check. CBD is protective against intestinal permeability in response to pro-inflammatory cytokines (stress hormones) in the colon.

Beyond the manifold actions of CBD, numerous presentations focused on the role of the endocannabinoid system in disease pathology, including Alzheimer’s and other neurological ailments. German investigators reported that activation of the CB2 cannabinoid receptor reverses beta-amyloid-induced memory impairments and neuroinflammation. There was disagreement among scientists as to whether CB2 receptors are expressed in the brain and central nervous system under normal baseline conditions or only under conditions of duress, such as after a stroke.

A collaborative animal model study by researchers at the University of London and the University of Nottingham in the UK underscored the possibility of protecting against vascular aging by targeting the endocannabinoid system -- specifically by inhibiting the FAAH (fatty acid amide hydrolase) enzyme that breaks down anandamide, a key endogenous cannabinoid lipid, which activates the CB1 receptor. Less FAAH means more anandamide, and more anandamide means greater CB1 receptor signaling. But rat FAAH differs from human FAAH, and thus far synthetic FAAH-inhibitors have yet to impress in human trials.

Dale Deutsch, a biochemist and cell biologist at Stony Brook, NY, first identified FAAH as a crucial component of the endocannabionid system in 1993. The 2016 recipient of the ICRS Career Achievement Award, Deutsch discussed his latest studies on endocannabinoid reuptake, transport, and deactivation in a keynote address. His lab has identified specific fatty acid binding proteins (FABPs) that transport anandamide inside the cell where it is delivered to FAAH and deactivated. Deutsch noted that CBD binds to the same FABP transport molecules, and this can impact endocannabinoid signaling. When CBD is present in sufficient amounts it will block anandamide transport and breakdown, resulting in higher endocannabinoid levels. “This may be one mechanism by which CBD works in childhood epilepsy, raising anandamide levels,” Deutsch suggested.

Anandamide is one of two main endocannabinoid compounds that are produced on demand 24/7 to maintain physiological homeostasis. The other principal endocannabinoid, known as 2AG, figures prominently in stress adaptation and resilience. Sachin Patel, winner of the 2016 ICRS Young Investigator Award, and his colleague at Vanderbilt University, Rebecca Bluett, elaborated upon the role of 2AG in regulating stress. “In most cases,” according to Patel, “endocannabinoid signaling via CB1 receptors appears to counteract acute stress responses and the adverse effects of chronic stress exposure, while functional antagonists of this system impair the ability of organisms to appropriately cope with stress.”

Ning Gu, a University of Ottawa scientist, explained that cannabinoid receptor signaling regulates how we regain consciousness as we recover from general anesthesia. Other presentations examined the impact of diet on endocannabinoid tone. Not surprisingly, the typical Western “cafeteria” diet dysregulates the gut-brain axis, which is mediated by the endocannabinoid system.

Dr. John McPartland, coauthor of a seminal paper, “Care and Feeding of the Endocannabinoid System,” talked us through a geological dreamtime expedition that traced the oldest known cannabis pollen samples, dating back 19.6 million years, to the grasslands of the Tibetan Plateau. This unique, ancient botanical diverged from its cannabis/humulus prototype 27.8 million years ago, according to DNA chloroplast sequences.

Scientific research into the cannabis plant led to the discovery of a hitherto unknown biochemical communication system in the human body, the Endocannabinoid System, which plays a crucial role in regulating our physiology, mood, and everyday experience. The knowledge that there are receptors in the brain that respond pharmacologically to cannabis — and the subsequent identification of endogenous cannabinoid compounds in our own bodies that bind to these receptors — has significantly advanced our understanding of human biology, health, and disease. And it also goes a long way toward explaining why cannabis is such a diverse and effective medicine and why it is by far the most popular illicit herb on the planet.

Martin A. Lee is the director of Project CBD and the author of Smoke Signals: A Social History of Marijuana -- Medical, Recreational and Scientific.

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

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. 


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: 

Dr. Dustin Sulak: Cannabis Dosing

dustin sulak cannabis dosing
By on May 23, 2016

Dr. Dustin Sulak, director of Integr8 Health and cofounder of, discusses cannabis dosing regimens, a sensitization protocol for chronic users, and the potential health benefits of THC’s psychoactivity. With cannabis, more isn't always better.


Project CBD: Welcome to another edition of Cannabis Conversations. I’m Martin Lee and today we’re speaking with Dr. Dustin Sulak. Dr. Sulak is a practicing osteopath. He’s the founder and director of Interg8 Health, a cannabis-oriented holistic healing practice based near Portland, Maine. There are also two other locations for the Intergr8 Health network in the New England area. And Dr. Sulak is also co-founder of, a very interesting educational website that’s chock-full of helpful information for patients and physicians. Dr. Sulak, thanks for joining us today.

Sulak: Glad to be here, Martin.

Project CBD: One issue that I think is really a challenge for both patients and physicians when it comes to cannabis therapeutics is the whole issue of dosing and how one begins a correct dosing regimen for their condition and their situation. You’ve done a lot of work in this area – kind of pathbreaking really. How do you determine an appropriate dosage recommendation for a patient?

Sulak: That’s a great question, and I get asked that question a lot. There’s really no way for someone like me, or any practitioner, to meet a patient and learn what’s going on with them and say I know exactly what you need to do in terms of cannabis dosing. It just doesn’t exist because people have such a varied response to the medicine and there’s so many different types of medicines. And from what I’ve seen in my practice, there’s this huge dosing range where some people do well with really low doses, other people do well with really high doses. There’s all the different delivery methods. So instead of trying to figure out exactly what someone should do, what I found works the best is to give someone a starting point, and then give them a methodology, a program for titrating from that starting point to determine what works best for them based on their individual goals.

Project CBD: So what might be an example? If there’s a patient who is cannabis naïve, who comes to you with a certain condition, how do you deal with that? What criteria do you use to develop a dosing regimen?

Sulak: Right. So the first thing I would do with that patient is understand if they have any fears about cannabis, because we see a lot of people that are cannabis naïve – meaning they’ve never tried it before – that are interested in it. They’ve probably known someone that’s gotten good results with it, but they’re also a little scared. So, we know that one’s mindset and one’s setting (their environment) can determine their experience with cannabis, and it can be related to side effects that they may or may not experience, if they’re set up with a positive expectation. So I like to go through and dissuade any myths, or address any fears that they might have, and at the same time figure out what that person’s goals are. So say it’s someone that’s cannabis naïve, maybe someone in their later years that has arthritic pain or low back pain, and so sure, one goal would be to reduce pain, another goal might be to improve sleep, and maybe to improve function. You know, I want to be able to play with my grandkids or I want to still be able to mow the lawn, or something like that. So we set some realistic goals. And then the first thing I would do with that patient is get them started on a dose of cannabis that’s actually sub- therapeutic. I think what works the best for the most people, especially cannabis naïve, is something they can take orally to be absorbed through the mucosa in the mouth. And they can certainly swallow a little bit and absorb some through the GI tract. So, an alcohol-based tincture or an oil, and something that we know the dosage of, we know how many milligrams of CBD, how many milligrams of THC. Typically, I would start with about an equal ratio, a 1:1 ratio for most patients because it’s very effective and very well tolerated. But if that person had a history years ago, say of having a paranoid reaction to cannabis, then I would go much higher on the CBD and lower on the THC, maybe a 4:1 or even an 8:1.

Project CBD: Would there be a situation where you might go higher on the THC and lower on the CBD in this context?

Sulak: Absolutely, Martin. Even the people that come to me that really don’t want a psychoactive experience, you know I encourage them to do that during the day; but for folks in the evening or maybe even just once a week on the weekend, I usually recommend that they do something THC-dominant to get some of that consciousness that cannabis has to offer to help them get a new perspective on their lives, to help them solve their problems creatively, and just to laugh and enjoy themselves. And also, THC-dominant cannabis sometimes just works better for people. Sometimes it works better for pain, better for anxiety, better for spasticity, and is more likely to help with sleep.

Project CBD: So when we talk about high dosing and low dosing of cannabis, what kind of range are we really talking about that you’ve seen in your practice? How low can work? How high might be necessary? What’s the range there?

Sulak: So I’ve been really surprised by what I’ve found. And part of the discovery has been really just listening to patients and they bring in their formulas, we can test them in our lab, which is part of the office. And sometimes we’re really surprised to see that some people do great with just milligrams per day – single milligrams – even as low for an adult as 1-2 milligrams a day total cannabinoids. That’s the very low end of the range that I’m seeing. And it might sound hard to believe. It’s certainly below the psychoactive threshold. But at these tiny doses, over time people find that they’re feeling better, their function is better, their symptoms are reduced. So that’s the low end. The high end for people that have sometimes failed the low and moderate dose approach, also for people that are trying to treat aggressive cancers and other severe conditions, the high end goes up to thousands of milligrams, maybe 2,000 or more per day. So we have 2 milligrams, 2,000 milligrams, and then a whole range in between which can be somewhat predictable but it varies from one individual to the next. 

Project CBD: You mentioned cancer specifically, and you’ve been treating cancer patients presumably. Is it correct to assume that a cancer patient will require a higher dose, almost a priori, or are you also seeing low dose working for cancer patients?

Sulak: We’re certainly seeing low doses working to improve the quality of life in someone with cancer. And that’s always my first goal. You know we’re all going to die and cancer is going to be the cause of death for quite a few of us. So when people come to me with cancer and they’re wanting to use cannabis and wanting to rush into some kind of a super high dose because they’ve heard that’s what works best – unless it’s a very aggressive cancer and the person’s already really well experienced with cannabis, I say let’s take a month or two to work on low dosing, to really improve your quality of life and get you laughing, get you sleeping, get you feeling great. Because if someone feels great, it’s most likely that their immune system is going to be functioning well, their elimination and detoxification will be functioning well, and they can augment the healing force within them that’s already trying to address that cancer. Now during that month or two, we’ll look at a blood marker or a follow-up scan to see is this low-dose approach actually preventing the growth of the cancer. And sometimes it does. But if it’s not, and the person has gone through that low dose, then it’s time to discuss Plan B. And Plan B is usually let’s really crank up this dosage here, either to as much as you can tolerate or as much as you can afford, and let’s do that for a few months and see what the follow up tests show. Is that effective for treating the cancer?

Project CBD: So what if you’re dealing with a person who’s a long-time user of cannabis, who’s coming to you? A chronic user. It doesn’t seem like a low dose would necessarily be appropriate because that person is already using high doses. What have you found in terms of dealing with people in that context?

Sulak: This is really interesting, and it’s been a big part of the work that I’ve done. We’ve had numerous patients that are already using cannabis that come in saying this used to work better for me, how can I adjust my use to get more health benefits? And typically, the answer is to reduce their dose. I found that over time everyone has an optimal dose of cannabis where they don’t build tolerance, they get the most benefits, they get the least side effects. When they exceed that optimal dose, they start to lose the benefits over time. Then they think they need to use more. In order to regain those benefits they use more, and over time the benefits diminish even more. So I developed a 6-day protocol. I call it “the Sensitization Protocol.” And it involves two days of cannabis abstinence and then four days of very careful dose titration. And what happens, people come in, they reduce their dose by at least 50 percent over those six days. So by the end of the program, they’re using less, they’re feeling more benefits, they’re feeling less side effects, they’re saving money; it’s just great for them. And I say 50 percent, but often it’s a lot more. Something I hear quite frequently goes like, “Doc, I was smoking 12 joints a day, now I’m smoking two. And it’s stronger, it feels better, I’m getting more benefit from it.”

Project CBD: It’s a little bit counter-intuitive in a way because you think if something’s not working you want to use more. But we know about the biphasic effect, which would suggest that maybe that’s not the way to approach it. What is the biphasic effect and why is it important for a cannabis clinician and a patient to keep that in mind?

Sulak: Great question. A lot of us think more equals more in our lives. But we know that’s not always the case. And it’s certainly not the case with cannabis, based on what I’ve observed in my patients, and also based on animal and human data from research, shows that – so the biphasic effect refers to a dose response curve. If we were to plot, we give someone a certain dose, what’s their response; we give them a higher dose, do they have a higher response; an even higher dose, they have an even higher response. But then, we give them a higher dose and the response goes down; a higher dose and the response goes down again. So we have this bell-shaped curve. And it’s that optimal dose that I’m talking about which is right in the center, the peak of that curve, and once you go more you’re actually going to get less of a response. That’s what biphasic means.

Project CBD: So what about triphasic? I’ve heard that phrase recently, and I wasn’t really familiar with it. Does that also apply in terms of cannabis therapeutics from what you’ve found?

Sulak: Absolutely. Triphasic or multiphasic, because we see that it can go up and down and up and down. Each direction is a phase, right. So if I start sub-therapeutic and someone gets benefit, that’s one phase. If they go up even higher and they lose benefit, that’s another phase. But then often, when they really crank the dose up high, that benefit will return. Sometimes when it returns, it returns with side effects or the benefits may be a little bit different than they were at the low doses. And there’s probably a phase at ultra-low doses, where people can take such a small amount and get benefit down there as well.

Project CBD: So when you talk about dosing, you’re talking mainly about THC and CBD, the main cannabinoids, are you also dealing with the acid forms, the raw cannabinoids, THCA, CBDA, that actually exist on the plant – it’s only when we heat them that changes. What has been your experience with respect to the THCA and CBDA?

Sulak: I’ve been extremely impressed with the acidic cannabinoids. I used to not believe that they would do what people were saying they would do and a couple of years ago a mother of one of my seizure patients brought in a bottle of CBD that was working to reduce the seizures, and I said great let’s test it. We had just set up our lab. So we looked in that bottle. There was no CBD, there was no THC. It was all THCA, and a very small amount. And since then, I’ve been paying a lot of attention to what THCA and to some extent CBDA can do for people. And what I’m finding is that they’re effective at reducing symptoms, sometimes at a tenth or even a hundredth of the dose that it would require if they were using the neutral, or decarboxylated, cannabinoids THC and CBD.

Project CBD: And that also applies not just to the seizure patients, you also find benefits with THCA, maybe CBDA, for other conditions?

Sulak: Absolutely. I’ve seen benefits with migraine headache, benefits with pain benefits, benefits with other inflammatory conditions.

Project CBD: Is there much science that explains what’s going on here? Because we know there’s been research showing how THC acts on the brain, what receptors it connects to, given the fact that THCA is not really psychoactive like THC, do we know how it’s working?

Sulak: There’s a little science, but not much. We know that the acidic cannabinoids will reduce inflammation. And they’ve been shown in a couple animal models of nausea and vomiting to reduce the nausea at doses that are somewhere between 1/100 and 1/10 of the dose that would be required of THC. So that confirms some of my findings with my human patients – that yes, we can actually take 10 percent of their THC dose, give it to them in THCA, and get good results. We don’t believe – scientists don’t believe that the raw cannabinoids, the acidic, especially THCA, have the same mechanism of action of THC. So it’s not binding to the CB1 receptor. Its function may be dependent on the cannabinoid 1 receptor, but it’s not directly acting upon it.

Project CBD: Which sounds a little bit like CBD, maybe, in a way.

Sulak: Perhaps, absolutely. We just don’t know. There’s probably been 99.9% of the research has gone into neutral cannabionids and there’s just a small handful of studies looking at the acidic cannabinoids. We need more.

Project CBD: Let’s talk a moment about The kind of information you’ve been sharing now, is that also available on

Sulak: Absolutely. So is a free educational website. And we created it because we were finding that to practice cannabinoid medicine in a way that was really working for our patients, we needed to provide them with a lot of education. So there’s programs on that solve those educational needs, because not all clinicians have the 45 or 60 minute office visit luxury like we have in our practice. So we have a program for people that are brand new to cannabis and it will walk them through, step-by-step, give them a shopping guide, to really make things simple for them. We have a program for existing users, to reduce their dose using the sensitization protocol and improve the benefit; a program for people that want to switch from inhalation to tincture. So you know, all the different – a program for people that don’t want to get high. Then also we can explain to them why it might be good for them to get high every once in a while. So all the biggest educational needs that we’ve seen in our practice, we’ve put on A really big thing that I’ve had in my practice over the last two years, has been a lot of really informed but very concerned parents wanting to use cannabis to treat their children that typically have severe neurologic conditions. So I have a whole video series on to kind of tell the parents everything they need to know when they’re considering this as an option.

Project CBD: Sounds great. Well thank you for joining us and sharing your experience with dosing and other matters.

Sulak: My pleasure, Martin.

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

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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.


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

Jahan Marcu on marijuana testing and safety
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. 


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 Botany and Evolution of 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.


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.

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

Audio-visual category: 

Kevin McKernan: Sequencing the Cannabis Genome

kevin mckernan cannabis genome
By on January 05, 2016

Kevin McKernan on sequencing the cannabis genome and its implications for the cannabis industry and “personalized medicine.”


Project CBD: We’re speaking with Kevin McKernan, chief scientific officer of Medicinal Genomics, a Massachusetts-based company which a few years ago—I believe in 2011—sequenced the cannabis genome or a particular cannabis strain.

McKernan: Yes, that’s right.

Project CBD: This would seem to have some significant implications for the cannabis industry as a whole. We’d like to explore that with you. Maybe you could explain a little bit about what we mean by “sequencing the cannabis genome”?

McKernan: Sure. So, this was in 2011 and the tools we had to sequence back then were still evolving very, very quickly, but we were able to get a very draft version of this genome sequence. Now what this is, is reading every letter in the genome and really, in any cannabis samples, many know there are two genomes: there’s really the mother and father genome. The plant is known to be diploid. So it’s got 20 chromosomes and one copy of each from mother and father, there are some chloroplasts and mitochondria genome in there as well, but we want to read all of those letters so we can begin to build a map of all of the genetics that might predict cannabinoid expression, terpene expression, maybe even flavonoid expression. As it moves into hemp, maybe some of the genes that are governing either seed size and oil and fiber.

So to read the entire genome, it’s about 1 billion bases long, it’s a billion letters of genetic code. In the process, with the technology we have, we probably only got about 400-500 megabases of really nicely aligned sequence. Now that seems like it, you’ve only gotten about half of the genome. That’s probably true. There’s a lot of repetitive nature in plant genomes. They have copies of things that are identical scattered throughout them. And those end up when you sequence them, it’s kind of like putting together a big jigsaw puzzle. Those are like all the pieces that look the same. And sometimes you don’t know exactly where they go. And so they get—they’re in the sequence but they get kind of left as ambiguous when you put all this data together. But we do have is a really nice scaffolds of some of the genes everyone is very attentive to, like THC synthase is one that is of real interest, really nice sequence coverage of those, CBDA synthase and some of the genes that are governing cannabinoids.

Project CBD: When you say “synthase” you’re talking about the kind of the precursor gene for what will become CBD or the gene that encodes the enzyme that creates CBDA and THCA?

McKernan: Yeah, so it’s an enzyme involved that the DNA codes for protein, and that protein folds into little enzymes that folds the precursor molecule into either THC—and there’s another gene called CBDA synthase, and the “A” is for the acid form because it makes THCA and CBDA before it, in the plant form. That’s taking a Cannabigerol precursor, and if you look at Cannabigerol, it’s like a ring structure and it’s got a long tail on it that it kinds of folds and wraps into two more cyclical groups that either makes THC, or one more cyclical group can make CBD. And there’s two different genes responsible for folding that precursor two different ways, and they’re actually in competition for the precursor.

So we believe, and many others before us have actually done this work to demonstrate that DNA variants in those genes have some predictive capacity on how much THC it’s going to make. So, there’s been some publications showing mutations in key areas of the gene—and this is known as a FADA-binding domain, a very technical term for a really catalytic core of the enzyme, that folds those molecules. And when there’s DNA variance in there, it does a slower job at it. Sometimes it doesn’t do any job at it. So, we believe—this is kind of a [rheostat] of how much THC is produced depending on where these variants are in the gene. And if we can get a better picture of this, we can begin to predict these chemotypes of the plant at a seedling stage without having to fully grow them out.

Now, the environment is always going to play a role in this dance as well, but we’re just trying to get a really firm picture of the genetics so that we can have some understanding of the capacity of the plant. If we know the plant is going to make all CBD, you might put that in a different grow room, or you might do something different with it, breed it with something else where you’re trying to bring CBD in. But if you know it’s going to be really strong THC strain that perhaps gives you a different direction to go with it.

Project CBD: You’ve touched on some of the implications of this genetic science for cultivators, for breeders possibly, or for people who are trying to fine-tune particular strains for particular medicinal properties. Let’s get into this a little bit more. How will this really be—this kind of knowledge—other than pure science, how will it be applicable for growers or for the cannabis industry as a whole?

McKernan: So, where we’ve seen this take foothold in other marketplaces is with a process known as “marker assisted selection.” I’m a much bigger fan of that type of breeding than let’s say let’s go monkey around with the genes, when we don’t really understand the whole genome yet. So the genome stuff, I think, is a little bit arrogant right now, and maybe even ever, depending on how much we ever get to know about this genome. But what people do tend to do with the sequence information in breeding is they use the DNA markers to track the traits. And it’s just kind of a measuring tool. Instead of measuring the chemotypes as they grow out—which is a great way, I don’t think that’s ever going to go away. But if you want to measure what chemotypes you might get at the first sign of the leaf, there’s information to be had there that can tell you, okay, here’s the terpene profile we think it’s going to have.  

Now we don’t know the markers that do that today, but this is what they’ve done in other very valuable crops, is that they get an understanding of maybe 100,000 to a million of these different single letter changes in the genomes, and they track those in all the plants. And they use those as sort of a proxy for, okay all of these changes over here tend to track with terpinolene and these ones tend to track with beta-caryophyllene , and these ones tend to track with maybe pinene. And so, we know that those markers are predictive that this plant’s going to be, maybe a myrcene dominant indica, and this one’s going to be a pinene or something that’s more Jack Herer—like with a terpinolene.

So those markers we think at a hole-punch we could distill. You could get a hole-punch of the leaf, all you need is about 30 nanograms of DNA to do this. This is 30 billionths of a gram of DNA that you could get this information from, and it will give you maybe 100,000 to 1 million different data points on the strain. Ultimately, there’ll be databases to help you correlate that all right, this pattern is from a plant that’s on this part of the phylogenic tree and we know that it tends to make these types of terpenes. And we’re going to track those SNIPS, they’re called single-nucleotide polymorphism. So there’s a lingo here what people call them SNIPS. Once we have that, we can then make some more informed decisions about, okay, we have a wonderful plant over here making some cannabigerol and some cannabichromene and we really want to bring in limonene to this, and what do we cross it with to make that happen in the fastest way possible. So we think it becomes just a tool set to help guide breeding. And this process called “marker assisted selection” is simply a fancy term for we’re going to measure this with something other than photography to perhaps guide where we go with the breeding.

Project CBD: So Medicinal Genomics has actually been gene sequencing several different strains, many different samples?

McKernan: We have, yes.

Project CBD: And what have you found in terms of diversity or lack thereof, and how has prohibition affected that?

McKernan: So it’s a fascinating question. There’s certainly signs of there being a genetic bottleneck toward high-THC plants. But at the same time of that having happening, there’s been a tremendous amount of inter-breeding that’s going on, that if you were to compare the variation we might see in the drug type plants, next to those that we see in the plants that have had less prohibition on them, like hemp plants (hemp plants are registered and there’s process in some countries to actually legally grow those), you actually see far more genetic diversity in the drug types, the ones that are underground. And, although they might have more THC in them, there has been perhaps a lot more exchange to find different terpenes or to breed different traits into them. I’ve always found that very fascinating: that the ones that are a little bit more above board and leveraging perhaps the registries and the patent systems actually have less genetic diversity then what we’re finding in the markets that perhaps that are out here.

Project CBD: Let’s talk a little bit about the implications for the medical use of marijuana. Personalized medicine is a buzzword today within the cannabis therapeutics world, and in terms of what that means, I think, on the ground for patients—patients are sort of groping in the dark to find what strain might work best for them, what helps them the most, maybe what ratio of CBD to THC is going to be their entry point into utilizing cannabis medicinally, and that always comes down to well, it’s about that person, how that person is going to relate to a particular strain or the plant in general. But I think what you’re talking about with the science of genetics sort of takes this idea of personalized medicine to a whole different level. So, how—and I know also that Courtagen, your sister company, has been working on the human side of the genome—so how do the two come together and what does this mean for personalizing medicinal cannabis?

McKernan: So I’m really excited about this topic because we—on the flip side of our business we’re sequencing 700-800 patients a month to try and find variants that help dosing patients with different drugs; sometimes it does implicate that you might benefit if you go straight to CBD. The classic case is sodium channel 1 mutations or Dravet syndrome, and they are the class of patients that are responding very well—not just anecdotally on the Internet, but even in the FDA-based trials you can’t deny this, that they’re having a real positive affect from [GW Pharmaceuticals’s] Epidiolex, that they’re testing this on.

Project CBD: You’re speaking about CBD or CBD-rich product, it’s helping these particular children with epilepsy and in terms of Dravets, but there are many different epileptic diseases 

McKernan: We tend to sequence 500 genes for epilepsy patients because it’s a long-tail, and this is really the lesson of personalized medicine. It’s kind of a lesson of the FDA, is that they’re not designed for personalized medicine. They’re designed for one-size-fits-all drugs, that aspirin and things just hit everybody with the same thing. Those are gone. There are no more of those. There are very few of them. And it’s pretty clear now that the reason drugs are failing in the FDA and the reason the costs are going up is that they’re trying to apply this model of blockbuster drugs to shove it through the FDA. What we’re really seeing in cancer and all these fields is that everyone’s genome is, we differ by probably 4 million variants in our own genome. And so what you might describe as chronic pain could be a completely different molecular mechanism if I have chronic pain. And we begin to understand that when we dive in and sequence people’s genomes. Oh yeah, you have chronic pain because you have TRP receptors that are off. And I have chronic pain because I have a TRAP1 variant. And those might require different mechanisms for dosing. It might require different cannabinoids.

And so, I’m very excited about bringing those two fields together because we can see the personalized medicine—there’s only one market in the country that I think has grown faster than personalized medicine, and it’s cannabis. And cannabis is this market that has, what looks to be, about to become, the largest open source set of pharmaceutical drugs that grow to high concentrations in plants that are weeds. I mean this is a total revolution in medicine that’s about to become over-the-counter for physicians; that if we can line up the right patient variants with the right cannabinoid and terpene profiles, the cost of health care is just going to go right down. And we can do—what I would like to call it as, it’s almost like a technological leapfrogging event, right. You see these cases where two different technologies kind of—the two different tsumanis that are coming together and they create a kind of a perfect storm of a wave.

Project CBD: The two different technologies are now the—?

McKernan: I think it’s the personalized medicine insight. Knowing the patient’s genome and then also knowing the entire cannbinoid profile of these plants—and the reason I’m fairly focused and myopic on the cannabinoids is because it’s really not that myopic at all! There’s just a whole portfolio of these things, and they all grow in the best factory you can imagine. There’s certainly a lot of interest in ripping these genes out and putting them into yeast and seeing if you can keep up with the plant.

Project CBD: That’s not your focus.

McKernan: No, I think that’s harder. I think it’s a harder job to do. And the plant’s very good and it grows—we have all this infrastructure to grow this plant. What you do find, in some places the pharmaceutical industry, they want to put their pathways into plants like this because they become medicinal factories for them. And then, you know, we have a science of growing this plant that’s quite mature and produces tons of this stuff. So, I’m actually quite optimistic about that side of the equation being done just perfectly today. But to bring the two together, you do see these destructions happen in other markets that I’m always very attentive to, that you see things like new batteries that are coming out these days can now drive things on the ground that are gyroscopic scooters now, and cars like Tesla, and then there’s solar panel technologies—and when those things come together, you see third world’s skipping landlines right now. They’re not installing landlines, they’re going right to Nokia cellphones. They’re not going to build central banks because they have cryptocurrencies or M-Pesa like currencies that are happening in Kenya.

The same thing I think is going to happen in medicine with the FDA. The FDA is one form of doing medicine, but it can’t scale with the innovation that’s out there. And the innovation I see really happening in medicine is, at this level, is the level of trying to get cannabinoids to the right patients. And that model is much more democratized, it’s much more individualistic, it’s much more focused on and respectful of each patient being unique. And we’re losing that in the health care system. The health care system is getting very one-size-fits-all.

Project CBD: In a sense what you’re talking about, is kind of eliminating the “crap shoot.” If you’ve got a drug, and you have a person with a certain genetic constitution, and you’re throwing CBD at an epileptic kid, why does it stick with some kids, why does it work so amazingly and why doesn’t it work with others? So you would be able to determine this in advance?

McKernan: We’re starting to see some signals on this. And this isn’t any coordinated effort, necessarily, with FDA or with GW [Pharmaceuticals]. Because we sequence so many patients at Courtagen, we happen to have a lot of patients that are in those trials, and they tell us. And when we take their data and compare the responders to the non-responders, we can see that there’s a pattern. They’re starting to show a pattern of the responders have variants, there are four particular variants that we’ve been showcasing that they have. And interestingly enough, they’re in—one’s in a drug metabolism gene known as a CYP2C9 gene, it’s a gene involved in the metabolism of CBD. The other three genes that are showing some predictive power here are sodium channel genes that we know anandamide interacts with. So there’s a thesis here that kind of makes sense. And the reason it’s important is, in some of those patients, CBD isn’t their molecule. They get 2-400 percent, smaller, 15 percent of the kids get worse. When seizure patients, like Dravet patients get worse, it’s extensively worse. It’s like they get intubated. They end up in the ER. Sometimes they get Status Epilepticus. And often times you hear anecdotally, some of those parents switch into THC or THCA, and they get better.

So there’s different mechanisms of causing seizures, and I think as we understand those mechanisms from a genetic level, we get more challenging about which cannabinoids to hand them. We don’t know the answer to how to mix and match that perfectly today. That’s kind of the vision. That’s where we want to go. But I think what we’re going to see over time is that puzzle is going to slowly fill in piece by piece, publication by publication, that these variants, very predictive of success and this class of patients. This class of patients really needs maybe a THCA, which is a completely different molecular pathway.

Project CBD: It’s very exciting. Presumably that could be applicable to other conditions, and not just the epilepsy.

McKernan: I think so. I think chronic pain is one. We’ve published a paper on the chronic pain front. And some of these patients were very responsive to antioxidants. And we all know that some of the best lipid soluble antioxidants in the world are cannabinoids. So these patients didn’t happen to jump on that. But the fact that they were responsive to N-acetyl cysteine, which is more of a—not as much as a lipid soluble antioxidant, so it could be some improvement there. It’s very exciting to us because this variant is in 1-2 percent of the population. It’s in a gene known as TRAP1, that has some implications in cancer, but it’s never really been pinned to chronic pain or chronic fatigue. And so, we refer about 1,000 patients and we summed up all the patients that had chronic pain and chronic fatigue and Bang! A big signal pops out saying TRAP1. And when that gene’s broken the hypothesis is it’s making lots of reactive oxygen species [ROS]. So your body is churning through energy and creating all the side products of energy consumption, but it’s not actually functional. And that’s creating, we think, the pain and the fatigue, it’s that this enzyme is broken, it’s eating up all the ATP [adenosine triphosphate].

So we’re really hopeful that that will translate into maybe making a dent into this opiate problem, right. These people are just getting handed opiates and it’s probably not really addressing the core issue of creating lots of ROS, it’s just dulling the pain that’s coming from. And we’ve seen where that’s gone. It’s just gone into total and complete opiate epidemic right now.

So, we’re hopeful that some of the sequencing will come in and objectify what is the subjective problem for a physician. Patient shows up and says I have pain. Sure you do. Then they have to really monitor how much dosage they give them and whether it becomes chronic, whether they get GI issues with the opiates. But if you had a molecular marker that said no, these are the patients that actually have a broken gene that we know responds with antioxidants, you can suddenly change that conversation to “we should be considering cannabinoids for this.” I’m hopeful that’s going to happen in autism, in mitochondrial disease. We’ll probably see it in Parkinson’s and Alzheimer’s. A whole host of diseases that you can see on the Project CBD website that are playing a role. And they probably all have different molecular mechanisms as to how CBD is benefiting those things.

Project CBD: Well I think Medicinal Genomics is changing the conversation. And that’s great. It’s amazing the work that you’re doing. I appreciate Kevin McKernan for being with us today.

McKernan: Thank you. We’re excited about the field.

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