endocannabinoid system

Clinical Endocannabinoid Deficiency Reconsidered

endocannabinoid tone russo
By on August 02, 2016

Abstract (Cannabis and Cannabinoid Research) 2016

Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

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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.

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