Cannabis Science

Cannabis as Medicine Has Strong Roots in Science

greg gerdeman opinion piece
By on July 18, 2016

A version of this article was published in South Florida Hospital News and Healthcare Report

The use of cannabis as medicine is not going away. Testimonials from patients, families and physicians continue to fuel a swing in public support for reintroducing cannabis to widespread use in the American medicine cabinet. Regardless of the pace of change in cannabis policy, it is critical that physicians and other allied health workers attend with an open mind to the real world rationales for cannabis used as a medicine, its risks with respect to other widely used medicines, and the ethical question of whether honest medical access to cannabis should be prohibited by law.

Clinicians should also know that an important aspect of the popularity and staying power of medical marijuana is its scientific credibility. Biomedical research has yielded a trove of discovery about the endocannabinoid system (ECS). Endocannabinoids are arachidonic acid-derived lipid signaling molecules that are produced throughout the body, not at all confined to nervous tissue as once imagined, and which mostly act as paracrine signals serving a wide variety of homeostatic functions. These range from the neuroendocrine control over feeding and metabolism, to bone remodeling, to pleiotropic effects on inflammatory immune function, to the more familiar anti-seizure effects, to name but a few. Numerous authoritative books and literature reviews demonstrate the scope of endocannabinoids’ physiological importance to be vastly beyond that of a brief commentary.

This body of research is of course powerfully relevant to cannabis. In some ways it’s ironic that many of the most compelling discoveries about the neuroprotective properties of cannabinoids, for example, have arisen out of funding priorities to study the presumed risk of marijuana. However, the field has expanded well beyond the prerogatives of drug abuse research, as presaged by seminal findings showing the extraordinary abundance of CB1 cannabinoid receptor expression throughout the mammalian brain, and how the endocannabinoids behave as cellular negative feedback signals to dampen excitotoxicity.

The scientific consensus that has arisen from this body of data is exciting. The human ECS can be viewed as an intrinsic system of neuroprotection, a homeostatic defense of the brain and spinal cord to excitotoxicity, seizure, traumatic injury and ischemia. Cannabinoids also defend against many facets of immune responses that exacerbate brain injury, such as microglial activation. Moreover, chronic neuroinflammation is now believed to be central to the etiologies of many age-related neurodegenerative diseases.

Inflammation is a key cause of chronic neuropathic and rheumatic pain, and clinical data increasingly support the use of cannabinoids as a potential therapeutic strategy. The central neural circuitries of pain are also regulated actively by cannabinoids and at multiple levels; indeed the very same can be said for the neural systems of fear, stress and emotional affect.

The scientific literature supporting these broad claims is extensive and of high caliber, and is actively disseminated to the public at various degrees of sophistication. While it is true that only a relatively small fraction of cannabinoid research has been from clinical trials – clearly a consequence of obstructing policies of prohibition – the research continues at a rapid pace to demonstrate mechanistic plausibility for a range of conditions that still surprises me after 20 years in the field.

It is also universally recognized that in modest doses cannabis and its extracts are well tolerated, and that even very high doses will cause distress but not death. Thus it shouldn’t be taken with surprise or cynicism that so many patients have the perception that cannabis does or might help them. The response of the healthcare community should instead be to stay ahead of the educational curve.

It is also time for healthcare professionals to engage in critical evaluation and engaged commentary on the systems of prohibition that force honest patients to become criminals should they try cannabis. Educate yourselves to form an opinion and ethical position on the use of criminal sanctions to deny access to medical marijuana. As for me, I believe that measures like Amendment 2 in Florida are a cautious approach and a moral imperative.

Dr. Gregory L. Gerdeman is Assistant Professor of Biology at Eckerd College in Saint Petersburg and Chief Science Officer for 3 Boys Farm in Ruskin, Florida. He has researched the neuroscience and pharmacology of cannabis and the endocannabinoid system since 1996.

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. 

Transcript

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

Russo: Thank you for having me.

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

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

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

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

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

Russo: That’s true.

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

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

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

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

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

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

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

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

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

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

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

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

Project CBD: Anandamide being one of the endocannabinoids.

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

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

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

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

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

Project CBD: Presumably bad diet, negatively influenced.

Russo: I’m afraid that’s true too.

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

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

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

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

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

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

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

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

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

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

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

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

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

Russo: My pleasure.

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

Audio-visual category: 

Chronic Marijuana Use is About as Bad for Your Health as Not Flossing

chronic marijuana use flossing
By on June 05, 2016
Published in full in the Washington Post.
 

Researchers led by Madeline H. Meier of Arizona State University tracked the marijuana habits of 1,037 New Zealanders from birth to middle age to see what effect those habits have on some common measures of physical health, including lung function, systemic inflammation, cholesterol levels, blood pressure, body weight, blood sugar and dental health.

What they found was surprising: After controlling for other factors known to affect health, especially tobacco use and socioeconomic status, marijuana use had no negative effect on any measure of health, except for dental health. People who smoked more weed had a higher incidence of gum disease.

The cause is something of a mystery . . .

Read full article

Greg Gerdeman, PhD, on Cannabinoid Treatment for Rheumatism

greg gerdeman cannabinoid rheumatism treatment
By on June 05, 2016

Greg Gerdeman, assistant professor of Biology at Eckerd College in St. Petersburg, Florida, recently spoke at the Annual Meeting of the Congress of Clinical Rheumatology. His remarks on cannabinoid treatment for rheumatic diseases can be heard here.

Greg Gerdeman:

“Using cannabis or other sources of cannabinoids for rheumatic diseases shows a lot of preclinical promise because of the importance of the endocannabinoid system in regulating inflammation and the adaptive immune response.

"A lot of the players involved in rheumatic disease like macrophage, infiltration, and the release of pro-inflammatory cytokines, the release of interleukins that are pain sensitizers and help to lead to the chronic inflammatory pain associated with rheumatic diseases -- these inflammatory cytokines are dampened down by CB2 cannabinoid receptors present on lipocytes, present on synovial fibroblast-like cells.

"In general, there is a great deal of preclinical research supporting showing that cannabinoids are generally immunosuppressive, they dampen down inflammation for example in situations of brain injury or stroke but also in the case of rheumatic diseases like rheumatoid arthritis.

"The take-home message for practicing rheumatologists: There needs to be more research. But in my view, that research needs to include research with patient populations who are already using cannabis and are seeking it. And the research structure – physicians and scientists – needs to be able to, need to be less shackled by policy so that they can research this with populations. There needs to be more preclinical research, but I think there needs to be research with patients who are using it so that they can be carefully followed and we can actually track the evidence of use that’s already going on, and in some places, with really good – positive that is – anecdotal reports of outcome from cannabis whether it’s inhaled or topical therapies.

"There’s a lot of legitimate scientific excitement about the use of cannabinoids in rheumatic disease. Doctors should be aware that it’s not going to go away, and they should support a research infrastructure for the best evidence-based medicines in cannabinoids and rheumatic disease.”

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

Is CBD Really Non-Psychoactive?

cb1 receptor cbd non-psychoactive
By on May 17, 2016

CANNABIDIOL AND THE CB1 RECEPTOR

Understanding how cannabidiol (CBD) exerts its myriad effects on human physiology is a work in progress. Thus far, scientists have identified more than 60 different molecular pathways through which CBD operates. It is known, for example, that CBD acts through multiple receptor-independent channels and it also binds to various receptors in the brain, including serotonin 5HT1A (which contributes to CBD’s antidepressant effect), TRPV1 (which contributes to CBD’s anti-psychotic effect), the nuclear receptor PPAR-gamma (regulates gene expression), and the orphan receptor GPR55, among others.

CBD and tetrahydrocannabinol (THC) have similar molecular structures, but CBD does not directly stimulate CB1 and CB2, the canonical cannabinoid receptors, like THC does. THC, marijuana’s principal psychoactive component, makes a person feel high by binding to CB1, the most abundant protein receptor in the brain and central nervous system.

THC fits snugly into a special pocket -- an “orthosteric” binding site -- on the CB1 receptor. The image of lock-and-key is apropos for orthosteric binding: THC, the molecular key, fits into the CB1 receptor lock and turns it on, which triggers a signaling cascade on a cellular level that inhibits the release of other neurotransmitters (thereby protecting the brain from too much excitation). It’s one of the many reasons why THC is such a remarkable therapeutic substance.

CB1’s orthosteric binding site is also the “keyhole” for THC’s endogenous cousins, anandamide (the first endocannabinoid compound discovered in the mammalian brain) and 2AG (our most abundant endocannabinoid). Likened to the brain’s own marijuana, these endogenous cannabinoid compounds fit into the same orthosteric binding pocket as THC and activate some of the same signaling mechanisms.

New data versus old science

Since the CB1 receptor was discovered in 1988, it’s been an article of faith among cannabinoid researchers that CBD, unlike THC, has little binding affinity for CB1. But this notion is based on old science.

New data emerging from the international cannabinoid research community indicates that CBD interacts directly with the CB1 receptor in ways that are therapeutically relevant. But CBD parks at a different docking site on CB1 that is functionally distinct from THC’s orthosteric binding site. CBD attaches to what’s known as an “allosteric” binding site on the CB1 receptor.

When cannabidiol, an allosteric modulator of CB1, docks at the receptor, it does not initiate a signaling cascade. But it does impact how the CB1 receptor responds to stimulation by THC and the endogenous cannabinoids. Allosteric modulation of CB1 changes the conformation (shape) of the receptor, and this can have a dramatic impact on the efficiency of cell signaling.

Every cell membrane has lots of receptors for many types of messenger molecules, which influence the activity of the cell. It’s not uncommon for a receptor to have two distinct binding sites or loci that can be activated by various drugs and endogenous compounds. The orthosteric site is the switch that a drug turns on, whereas an allosteric modulator can either amplify or decrease a receptor’s ability to transmit a signal depending on how the allosteric modulator changes the conformation of the receptor.

To extend the lock-and-key metaphor: If the orthosteric binding site is the lock on a door, then the allosteric binding site, when activated, makes the lock easier or more difficult to open. A “positive allosteric modulator” changes the shape of the receptor in a way that potentiates receptor signaling, while a “negative allosteric modulator” will reduce receptor transmission.

Healing without the high?

Numerous pharmaceuticals target orthosteric binding sites for receptor stimulation. Big Pharma has also brought to market several synthetic allosteric modulators of other receptor systems (Mimpara, Piracetam, and Selzentry, for example). There is serious interest among drug companies in allosteric modulation of the endocannabinoid system. In theory, if not practice, allosteric modulators can prime the system for amplification or inhibition by fine-tuning receptor transmission with amazing subtlety.

Full-on stimulation of CB1 can deliver therapeutic benefits, but THC’s psychoactivity intrinsically limits its medical utility, according to Big Pharma catechism. For the medical constabularies, getting high is by definition an adverse side effect. Allosteric modulation raises the prospect of increasing CB1 receptor activity without causing disconcerting dysphoria or needless euphoria.

Scientists at the University of Aberdeen in Scotland have synthesized a positive allosteric modulator of CB1 to treat pain and neurological disorders. When researchers at Virginia Commonwealth University tested the compound on mice, this experimental drug, known as “ZCZ011,” had no psychoactive effects of its own, but reduced neuropathic and inflammatory pain by boosting the CB1 receptor’s response to anandamide, an endocannabinoid compound.

Research into allosteric modulation of the endocannabinoid system is still in its early phases. Allosteric modulators of CB1 were first discovered in 2005. Ten years would elapse before scientists at Dalhousie University in Halifax, Canada, reported in the British Journal of Pharmacology that cannabidiol is a negative allosteric modulator of CB1 in vitro. This means that CBD lowers the ceiling on the ability of THC and endogenous cannabinoids to stimulate CB1.

The Canadian research team identified the exact molecular niche where CBD parks at the CB1 receptor, a protein which consists of 472 amino acids strung together in a crumpled chain that wraps around the cell membrane seven times. Scientists can mutate CB1 receptors with precision, targeting one amino acid at a time. Data generated by mutational analysis pinpointed positions 98 and 107 on CB1’s amino acid chain as the key docking loci for CBD.

A Dimmer Switch

Negative allosteric modulation of CB1 is conceptually similar to a dimmer switch on a light fixture. CBD alters cognition and improves mood; it creates mood lighting for the brain and dims the ‘strobe light’ triggering seizures. As a negative allosteric modulator of the CB1 receptor, CBD shows particular promise for treating conditions associated with endocannabinoid excess or overactivity (obesity, metabolic disorders, liver disease, cardiovascular issues), whereas a positive allosteric modulator that enhances CB1 receptor signaling could be helpful for diseases linked to endocannabinoid deficits (such as anorexia, migraines, irritable bowel, fibromyalgia, and PTSD).

It should be noted that allosteric modulators typically are unable to alter receptor conformation unless the orthosteric binding site is also stimulated. CBD can modulate CB1 receptor signaling only when THC or another cannabinoid compound is active at the orthosteric binding site. In terms of whole plant cannabis therapeutics, CBD’s efficacy as an allosteric modulator requires the co-presence of THC.

THC and CBD work in tandem; they are the power couple of cannabis therapeutics. Given the intimate synergies between these two plant compounds, how much sense does it make to attribute psychoactivity exclusively to one (THC) and not the other (CBD)? Is it really accurate to say that CBD is a “non-psychoactive” substance?

Researchers have demonstrated that CBD confers antipsychotic, anxiolytic (anxiety-reducing), and antidepressant effects. If CBD can relieve anxiety or depression or psychosis, then obviously cannabidiol is a profound mood-altering substance, even if it doesn’t deliver much by way of euphoria. Perhaps it would be better to say that CBD is “not psychoactive like THC,” rather than repeating the familiar and somewhat misleading refrain that “CBD is not psychoactive.”

The identification of cannabidiol as a negative allosteric modulator that binds directly to the CB1 receptor challenges antiquated assumptions about CBD and sheds new light on its medicinal potential. In turn, as our scientific understanding and therapeutic experience deepens, the description of CBD as non-psychoactive may fall by the wayside.

Jahan Marcu is Chief Science Officer at Americans for Safe Access with 14 years of experience in Cannabis research and regulations. Ali S. Matthews is the pen name of an endocannabinoid researcher currently studying allosteric modulators and the mammalian brain, who wishes to protect the privacy and identity of his federally funded laboratory. 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.

Sources

Abood ME. “Allosteric Modulators: A Side Door.” J Med Chem. 2016 Jan 14;59(1):42-43.

Bogna Ignatowska-Jankowska, et al. “A cannabinoid CB1 receptor positive allosteric modulator reduced neuropathic pain in the mouse with no psychoactive effects.” Neuropsychopharmacology. 2015 July 29.

Elham Khajehli et al. “Biased agonism and biased allosteric modulation at the CB1 receptor.” Molecular Pharmacology. 2015 June 4.

Kukarni PM, et al. “Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s).” J Med Chem. 2015 Nov 3.

Laprairie RB, et al. “Cannabidiol is a negative allosteric modulator of the type 1 cannabinoid receptor.” Br J Pharmacol. 2015 Jul 27.

Straiker A, et al. “Aiming for allosterism: Evaluation of allosteric modulators of CB1 in a neuronal model.” Pharmacological Research 2015 Jul 23.

Greg Gerdeman: Brain Science & the Endocannabinoid System

Greg Gerdeman cannabis science
By on January 20, 2016

Professor Greg Gerdeman on brain science, the neurobiology of stress, and how the discovery of the endocannabinoid system has liberated cannabis from the drug abuse paradigm.

Transcript

Project CBD: We’re speaking with Greg Gerdeman, a neuroscientist and professor of biology at Eckerd College in Florida. Greg Gerdeman is one of the few professors that we know of who actually teaches classes on something called the “endocannabinoid system.” What is the endocannabinoid system? Why do you teach classes on that, and what’s its significance?

Greg Gerdeman: The endocannabinoid system is an area of research that’s been my focus for 20-some years. It was discovered by understanding how cannabis works. So cannabis works at the endocannabinoid system. It’s a broad way to speak about it. But partly what’s so exciting is that as scientists have studied the endocannabinoid system to understand cannabis, we’ve really come to learn a tremendous amount more about how our brains, our bodies work. How we work, not just how cannabis works. So to the education piece, I’m a neuroscientist and now teaching about how the brain works and processes information, how different circuits work in the brain, endocannabinoids are such an integral part of that, that it should be part of neuroscience curriculums, let alone a course in and of itself.

Project CBD: So what do we specifically mean by endocannabinoid system?

Gerdeman: Well, it means, first and foremost I think the receptors by which THC and other cannabinoids act. So, the targets of how cannabis works and an intrinsic set of neuromodulators called endocannabinoids that are released by cells and act at the receptors. So, although the system is distributed throughout the body, I tend to think about the brain and it’s very highly utilized by the brain. And, as an example of how the brain works with endocannabinoids, a given neuron – a cell within the brain receiving thousands of different inputs – will release endocannabinoids, these small signaling molecules, to fine-tune the strength of their own synaptic inputs. So the endocannabinoids are signaling molecules that are created and broken down by enzymes in the body. They act at cell surface receptors that change the activity of cells. And all of this – the signaling molecules, the enzymes that make them and break them down, the receptors that exert the effects of the compounds – are bundled up into what we call the endocannabinoid system.

Project CBD: So when you talk about “endocannabinoids,” you’re talking about molecules that exist in our own brains and bodies.

Gerdeman: Right.

Project CBD: Would it be correct to say they’re marijuana-like molecules? How do they relate to THC and CBD, or other components of the plant, these endocannabinoids in our own body?

Gerdeman: In some ways, it’s fair to say that. And people say it’s like the body’s own marijuana. A structural chemist they might take some objection to that because the structures [of the molecules] don’t look that much alike. But functionally, which is what a physiologist thinks about, the physiology of how anandamide binds to and changes cellular activity binding a cannabinoid receptor is actually quite similar to THC.

Project CBD: Anandamide is an endocannabinoid.

Gerdeman: That’s right. “Endo” is short for endogenous cannabinoid, molecules within our own body. They primarily are represented by anandamide and a compound called 2-AG. There are probably several others. We know there are other endocannabinoid-like molecules that are released in an entourage sort of way. And, regulate in a concerted way a great many cellular functions. It’s quite variable, but it seems to be a system that promotes homeostasis well being, keeping the body within an optimal set range. The endocannabinoids modulate the body in that way.

Lee: So you talk about homeostasis and about other crucial functions that the endocannabinoid system plays in the body; homeostasis balancing physiological systems is one. What other aspects of human physiology and biology is the endocannabinoid system affecting or interacting with?

Gerdeman: Well, it certainly interacts with processes of learning and memory and how we integrate sensory, motor information. In a way, as a physiologist, I can think of that all as homeostasis. Like if you’re hungry and go get cues through your body to seek food, that’s a complex process of homeostasis – the human organism is sensing deficit and seeking to restore balance by eating food. And the endocannabinoid system in fat tissue and the hypothalamus of the brain, in the brain pleasure centers (as they get called) that motivate behavior – they’re all being choreographed, sort of orchestrated by endocannabinoids.

Project CBD: In your own research, I know you’ve done work on exercise and how physical exercise affects the endocannabinoid system or the cannabinoid receptor signaling. What drew you into that research? What did you find essentially?

Gerdeman: Well I got drawn into that because, being a cannabinoid brain guy, I had an interaction with an anthropologist named David Raichlen and we started teaming up because he has a long interest in what drove endurance running behavior as an evolutionary force in human evolution. And, so the question of why do people engage in distance running, anthropologists get caught up on the notion that it’s energy intensive, it has risk of damage to your body, and to make what can be kind of a long story short, we started investigating what others had already seen, that with aerobic exercise, anandamide (not 2-AG), anandamide goes up in the blood in humans. We found it in dogs, another group of animals that have evolved to run distances. And we relate it to sort of the runners joy, the runners high. When you get a sense of wellness, elevated mood, wellbeing, the kinds of things that make exercise a good compliment to just healthy lifestyle and well being, the endocannabinoids are related to this. We think that the anandamide levels that go up with exercise are really important for how running and other forms of exercise helps to maintain a robust, resilient physiology – resilient to stress and disease.

Project CBD: So it’s kind of like a feedback loop. It gives you kind of a pleasure, like the runners high, you’re saying, and that’s related to the endocannabinoids in our body, you specifically mentioned anandamide.

Gerdeman: Anandamide. 2-AG doesn’t seem to go up. And that’s part of the new and emerging complexities of the endocannabinoids – what’s the difference between these two. But in the biology, in studies of the neurobiology of stress, it’s interesting that keeping a solid anandamide tone, having a healthy level of anandamide, at least within certain brain areas, seems to be very important to one’s resilience to stress. And the neurobiology of sensing fear and perceiving fear is related to that anandamide level transiently dropping. This is work by Matt Hill. When an organism senses fear, anandamide levels in the amygdala drop, and that triggers the fight or flight immune response. And it also triggers sort of higher level coding of the fearful experience. Higher anandamide levels – and this could be oversimplified – but higher anandamide levels or a healthy anandamide level seems to be, in some very mechanistically clear ways. This is high-end scientific research, related to resilience, to stress, and overcoming and forgetting stress and stressful cues that provoke anxiety from past trauma, for example.

Project CBD: And what do we mean by “stressful cues” in this instance, because so many different things can act as stressors in the body. Are there only certain kinds of stress, like psychological stress, that the endocannabinoid system will mediate in some ways? Or would that be a plethora of different stressful cues that the endocannabinoid system in some way will be involved in helping the organism cope?

Gerdeman: Well, I think more the latter. Because I look at it as a brain scientist, and the neural circuitry involved in perceiving stress, sensing it, responding to it, communicating to the body to elevate the heart rate, the whole suite of stress sensation, responsing, remembering -- those are complex neural circuits and they regulate themselves on a moment-to-moment basis with endocannabinoids. So the system is involved. Now, as far as real close investigation, real fine investigation of stress, the best evidence is for what in jargon you might call homotypic stress, the kind of repeated day-in, inescapable stress that describes some people’s conditions in life that lead to chronic anxiety.

Project CBD: Stress is understood to underline many different diseases or aberrant medical conditions. In general terms or in broad terms, the advances that have been made in understanding brain science through studying the endocannabinoid system -- what are the implications just in terms of understanding disease and health and how we function? What light does studying the endocannabinoid system, or what light has it shed on these basic challenges that we confront in life, on a day-to-day basis? Because most people aren’t scientists, we don’t think it terms of molecules and these things, it’s just we want to improve our health. What does the endocannabinoid system tell us about that?

Gerdeman: Well, I mean, I think we’ve learned enough to say it’s incredibly promising and fascinating focus to look into. The endocannabinoids are implicated in so many different disease states. And it fits in with the whole area of cannabis as medicine, and botanical cannabis products tweaking or interacting with the system in a way that there’s just so much potential for, you know, pain states and stress states and chronic disease. Part of what fascinates me, as a neuroscientist that looks at how endocannabinoids like allow cells to fine tune their own inputs, I can think of how this relates to motor control, for example. And there’s really high-level research showing that endocannabinoids are related in Huntington’s Disease and Parkinson’s Disease, different kinds of tremor. But these same molecules that interact with these electrical neurocircuits are like controlling tumor growth and are signaling in the gastric, the intestinal cell lining, to regulate healing and scarring. There’s so much we don’t know yet. But it’s fascinating that this system acts at so many different levels that are related to health and wellbeing.

Project CBD: So the implication would be that if cannabis interacts with this very subtle and important physiological system, the endocannabinoid system, that it could be used to improve health, to bring the system back into balance if there are some deficits in our own physiology, that for some reason this particular plant interacts in a very profound and deep way with our own physiology and to understand that relationship somehow the endocannabinoid system in crucial.

Gerdeman: Yeah, like no other. The endocannabinoid system, sort of crystallized by the cannabinoid CB1 and CB2 receptors, the evolution of these genes that appeared at sort of the base of the vertebrae tree of life, they weren’t there before, these receptors. And now you look at human animals and we’ve got this extraordinarily complex brain, extraordinarily adaptive immune system, that really fine tunes itself all the time with endocannabinoids, the endocrine system that works with endocannabinoids, something really works with endocannabinoid signaling. And the cannabis plant interacts with it in such incredibly diverse ways, surprisingly subtle ways. You know the notion that you don’t get more serious side effects from using a medicine that interacts at such an integral level with your neurocircuitry, is pretty amazing. It’s pretty amazing.

Project CBD: Opens up whole new vistas, it seems, to understanding human biology with great implications for medicine.

Gerdeman: It does. And that’s why different avenues of research – I mean, when I got into it, the National Institutes of Health really only funded endocannabinoid research under the National Institute on Drug Abuse. Nobody – if you told people, hey you’re interested in the circuitry of the amygdala and fear, learning, and stress, what do you think about endocannabinoids because they’re all over that circuit, the response among scientists would still be kind of like well I don’t study marijuana! I don’t study drug abuse. They didn’t get yet. But now, I like to say that the scientific discovery of the endocannabinoid system has, in some important ways, liberated cannabis from the drug abuse paradigm that’s been locking it in for so many, several decades here – which in the long span of cannabis as medicine is a short period of time – but it’s been enormous. And the endocannabinoid system has liberated cannabis more into the biomedical health and wellbeing – not just for terminal illness, not just as a last resort – but there’s so much value to researching the endocannabinoids and cannabis-derived botanicals as medicines for wellness and resilience.

Project CBD: Well fortunately there are some scientists such as yourself who are not simply operating within the drug abuse paradigm, but have been really doing cutting-edge research that has advanced our understanding of health and disease. And hopefully that can be used to make a better life. Thank you, Greg Gerdeman for speaking with us at Project CBD.

Gerdeman: Thanks Martin.

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

Audio-visual category: 

Vaporization: CBD & THC Boiling Points

volcano vaporizer boiling points of THC and CBD
By on January 11, 2016

Project CBD received this inquiry from a Canadian citizen:

“I'm wondering the best way to use CBD from flowers. Smoking a high CBD strain (Charlottes Web) still got me stoned despite having very minimal THC. I am thinking about buying a Volcano Digital Vaporizer, but I want to make sure I can effectively get CBD. So, can I vaporize the THC out of cannabis flowers? Can I vaporize at 157°C and let the THC escape and then vaporize between 160°C-180°C to get just the CBD only? Or is that an impossibility and you have to have both THC and CBD together? Much appreciated, thanks for your time!”

Project CBD responds:

"Thank you for contacting Project CBD. Check out the boiling point chart on various cannabinoids and terpenes below. THC boils at a slightly lower temperature than CBD. However, when vaporizing a strain that contains any THC at all, you still may absorb some effects. Here is why:

CBD doesn't have a clear set boiling point. It's more in the 160-180°C range. While THC is listed at 157 Celsius, the fact is that both will sublimate off at a lower temperature. This is similar to the way the snow disappears on a really cold day when the humidity is low and there is sun or wind—the flakes just go directly from solid to gas (water vapor) even though the temperature is seemingly too low for melting.

As great of a product as a Volcano is, it is not perfect. The digital Volcano model provides tolerances at +/- 0.5 degrees Celsius. Nevertheless, beyond that, there are marked temperature gradients in the chamber—one area will be quite hot compared to another, particularly if the herbal material is large or clumped. Thus, you cannot ensure that the herbal material will be exposed to uniform temperatures required for fractionation. Therefore, if there is THC present in the cannabis you are vaporizing, some will likely remain in the vapor even after its boiling point is exceeded.

Separating out cannabinoids from one another is practical only with industrial strength techniques, such as centrifugal partition chromatography. It can't be done in the kitchen, unfortunately. So your best bet would be to try another strain if you do not like the psychoactivity. Cannatonic (ACDC) is one strain that can have an 18:1 CBD/THC profile. Users generally find that they can also develop a tolerance to psychoactivity over time.

I hope this is helpful. Let me know if you have further questions."

Another reader from Poland had a related question on decarboxylation from CBDA to CBD:

"At what temperature I should heat cannabis to decarboxylated CBDA to CBD? 80 degrees Celsius? 120 degrees?"

Project CBD's Response:

"130°C is the boiling point for CBDA, but the boiling point is different than decarboxylation. There are a couple of issues. Decarboxylation happens at different temperatures at different speeds. You lose some of the plant's compounds when you bake cannabis in the oven, for example. It can be done more slowly at 80°C, but takes several hours. Cannabinoids and other compounds in the plant will sublimate off at a lower temperature. We are not sure of the ideal method for you in a home situation, so it will require some experimentation. You could try using a jar placed in water. Heat the water to 80 degrees Celsius for 4 hours, and check on it to ensure the temperature remains the same.

Good luck!"

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

Kevin McKernan: Sequencing the Cannabis Genome

kevin mckernan cannabis genome
By on January 05, 2016

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.

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

Audio-visual category: 

Get High and Lose Weight?

Marijuana for weight loss
By on November 23, 2015

Marijuana Use Associated with Decreased Chance of Developing Metabolic Syndrome

First the bad news: The United States is facing epidemic levels of obesity, diabetes, and cardiovascular disease.

Now the good news if you are a cannabis consumer: According to a recent study published in the American Journal of Medicine, marijuana users are much less likely than non-users to develop metabolic syndrome, which is a significant risk factor for obesity, type II diabetes, and heart disease.

Conducted by scientists at the University of Miami in Florida, this study examined the relationship between cannabis consumption and the individual components of metabolic syndrome, such as high blood pressure, increased abdominal fat, elevated blood sugar, and unhealthy cholesterol levels. 

Nearly 8,500 people from age 20 to 59 provided survey data for the study. Participants were separated into three categories—current marijuana users, past users, and those who had never smoked the herb. Whereas metabolic syndrome afflicts 22 percent of the U.S. adult population, less than 14 percent of current cannabis-using adults in this study had metabolic syndrome.

Among young adults, cannabis consumers are 54 percent less likely than non-consumers to present with metabolic syndrome. Past marijuana use is associated with lower odds of metabolic syndrome among middle-aged adults. And seniors who medicate with cannabis tend to be slimmer and less insulin-resistant than seniors who just say no.

The Munchies Receptor

The results of the study, entitled “Metabolic Syndrome among Marijuana Users in the United States,” may seem counterintuitive given marijuana’s notorious appetite-stimulating effects, jocularly known as “the munchies.” Under the influence of marijuana, flavors seem to jump right out of food. That’s because tetrahydrocannabinol (THC) activates CB1 cannabinoid receptors in the brain that rouse one’s appetite and heighten one’s sense of smell.

The munchies are a scientifically proven phenomenon. THC is a CB1 “agonist” that turns on the appetite receptor and causes it to signal. An “antagonist” will block the receptor and prevent it from signaling. Tetrahydrocannabivarin (THCV), a minor but medically significant component of the cannabis plant, is a neutral CB1 receptor antagonist.

Scientists have also synthesized “inverse agonists” that can activate a cannabinoid receptor and cause it to signal in the opposite manner from how it functions naturally. A CB1 inverse agonist will curb appetite and reduce food intake by binding to CB1 receptors, whereas THC boosts appetite and food intake by binding to CB1.

One could reasonably assume, given what we know about the munchies, that increased use of marijuana will result in greater caloric consumption with consequent adverse metabolic outcomes, including obesity. However, the results of this study and other reports indicate that such is not the case. Indeed, the opposite appears to be true.

In addition to underscoring potential health benefits of herbal cannabis, these findings highlight the discrepancy between human research that links marijuana use to lower rates of obesity compared to preclinical studies involving synthetic isolates in which CB1 antagonism (blocking the munchies receptor) and CB1 inverse agonism (flipping the anti-munchies switch) are shown to prevent obesity.

How is it possible that marijuana consumption, which activates CB1, is associated with preventing obesity in humans, while blocking or reversing the CB1 receptor via a synthetic, single-molecule compound results in weight-loss in animal models and human trials? What can explain this apparent contradiction? It may have something to do with the complementary, yet opposing functions of two different sets of cannabinoid receptors.

CB2 Receptor Activation

Australian scientists recently examined the role of the cannabinoid CB2 receptor “in modulating energy homeostasis and obesity-associated metabolic pathologies.” The CB2 receptors are concentrated in the peripheral nervous system, immune cells, and in metabolically active tissue. The Australian researchers found that CB2 receptor activation by JWH-015, a “selective CB2 receptor agonist,” reduces food intake in mice and prevents the build-up of body fat.

THC, a non-selective, plant-derived agonist, binds to both the CB1 receptor and the CB2 receptor. The fact that THC and other cannabis components (including the aforementioned THCV) activate CB2 receptor signaling may explain why marijuana users are less likely to develop metabolic syndrome than marijuana abstainers. Metabolic syndrome is a generalized, low-grade inflammatory condition, and the THC-sensitive CB2 receptor regulates immune function and inflammation.

CB2 receptor activation—through healthy diet and cannabis-enabled stress reduction—may prove to be a better strategy for preventing and treating metabolic syndrome than the misguided attempt by French pharmaceutical giant Sanofi-Aventis to market Rimonabant, a synthetic CB1 inverse agonist as an appetite suppressant. Promoted as a blockbuster diet drug in 2006, Rimonabant was soon recalled in Europe because of severe side effects, including neurological deficits, depression, and suicide. The anti-munchies pill was never approved for sale in the United States.

Sorry Big Pharma, but when it comes to preventing or mitigating metabolic dysfunction, synthetic isolates are much less effective than whole plant cannabis with its synergistic treasure trove of natural medicinal components that enhance and balance each other’s effects.

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

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

Sources:

  • Englund A, et al. “The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial.” Journal of Psychopharmacology. 2015 Nov 17.
  • Karlsson C et al, “Baseline anandamide levels and body weight impact the weight loss effect of CB1 receptor antagonism in male rats,” Endocrinology, 2015 April.
  • Verty, AN, et al. “Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice. PLoS One. 2015 Nov 20.
  • Vidot DC, Prad G, Hlaing WM, Arheart KL, Messiah SE. “Metabolic Syndrome among Marijuana Users in the United States: An Analysis of National Health and Nutrition Examination Survey Data.” American Journal of Medicine. 2015.
  • Yale University press release, “Mulling the marijuana munchies: How the brain flips the hunger switch,” 18-Feb-2015.

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