CBD User's Manual

A Beginner's Guide to Cannabidiol & Cannabis Therapeutics
Beginner's guide to CBD Medicine
By on July 13, 2016

In 2009, a handful of CBD-rich cannabis strains were discovered serendipitously in Northern California, America’s cannabis breadbasket, where certified patients could access medical marijuana legally. Thus began a great laboratory experiment in democracy involving CBD-rich cannabis therapeutics. The advent of whole plant CBD-rich oil as a grassroots therapeutic option has changed the national conversation about cannabis. It’s no longer a question of whether medical marijuana works – today the key question is how to use cannabis for maximum therapeutic benefit. But most health professionals have little experience in this area. So Project CBD has created a CBD User’s Manual for patients that addresses key questions about cannabidiol and cannabis therapeutics.

What is CBD?

Cannabidiol or CBD is a non-intoxicating component of the cannabis plant with enormous therapeutic potential. Although CBD doesn’t make people feel high like THC does, it’s causing quite a buzz among scientists, health professionals, and medical marijuana patients who are using CBD-rich products to treat a wide range of conditions - chronic pain, cancer, Crohn’s, diabetes, rheumatoid arthritis, PTSD, cardiovascular disease, anxiety, antibiotic-resistant infections, multiple sclerosis, schizophrenia, and more. Academic research centers in the United States and elsewhere are currently studying the effects of CBD on these and other ailments. Scientists refer to CBD as a “promiscuous” compound because it confers therapeutic benefits in many different ways while tapping into how we function physiologically and biologically on a deep level. Extensive preclinical research and some clinical studies have shown that CBD has strong anti-oxidant, anti-inflammatory, anticonvulsant, anti-depressant, anti-psychotic, anti-tumoral, and neuroprotective qualities. Cannabidiol can change gene expression and remove beta amyloid plaque, the hallmark of Alzheimer’s, from brain cells.

Which is better CBD or THC? Cannabidiol and THC (The High Causer) are the power couple of cannabis therapeutics; they work best together. CBD and THC interact synergistically to potentiate each other’s curative qualities. CBD enhances THC’s painkilling and anticancer properties, while lessening THC’s psychoactivity. CBD can also mitigate adverse effects caused by too much THC, such as anxiety and rapid heartbeat. When both compounds are present in sufficient amounts in the same cannabis strain or product, CBD will lower the ceiling on the THC high while prolonging its duration. (“Relaxing but not intoxicating” is how one patient described CBD-rich cannabis.) CBD broadens the range of conditions treatable with cannabis, such as liver, cardiovascular and metabolic disorders, which may be less responsive to THC-dominant remedies. CBD and THC both stimulate neurogenesis, the creation of new brain cells, in adult mammals.

What’s the best way to take CBD? The most appropriate delivery system for CBD-rich cannabis is one that provides an optimal dose for a desired duration with few unwanted side effects. CBD-rich cannabis flower varietals for smoking or vaping are available in many medical marijuana dispensaries, but most CBD patients prefer non-inhalable products made with cannabis oil concentrates. Although banned by federal law, measurable doses of potent CBD-rich cannabis remedies are available in many non-smokable forms and can be utilized in various ways. The time of onset and duration of effect vary depending on the method of administration. CBD-rich cannabis oil products can be taken sublingually, orally (as edibles, lozenges, beverages, tinctures, and gel caps), or applied topically. Concentrated cannabis oil extracts can also be heated and inhaled with a vape pen. Inhalation is good for treating acute symptoms that require immediate attention; the effects can be felt within a minute or two and typically last for a couple of hours. The effects of orally administered CBD-rich cannabis oil can last for four hours or more, but the onset of effects is much slower (30-90 minutes) than inhalation.

Read more: Different Types of Cannabis Medicine

Can CBD cure epilepsy? Marijuana has a rich history as a medicine for quelling seizures and convulsions going back thousands of years. In the mid-19th century, the U.S. Pharmacopeia listed cannabis tincture as a treatment for pediatric epilepsy, and subsequent scientific studies have documented the anticonvulsant effects of CBD, THC, and whole plant cannabis. CBD-dominant/low- THC cannabis strains and oil extracts can facilitate dramatic improvement in some children with intractable seizure disorders. Between 10-15 percent of severe childhood epileptics who are given CBD oil products experience a near complete cessation of seizures; most improve (with a decrease but not total elimination of seizures); and some children have worse seizures when they take CBD. Many parents of epileptic children have learned through trial and error that augmenting CBD-rich oil by adding some THC -- or better yet, THCA, the unheated, non-psychoactive form of THC that’s present in raw cannabis flowers and leaves -- helps with seizure control. The take-home message: Low-THC cannabis oil products don’t work for everyone. Patients of all ages need access to a wide spectrum of whole plant cannabis remedies, not just high CBD oil.

Read more: List of studies on CBD & epilepsy

What is the right CBD:THC ratio for me? Cannabis therapeutics is personalized medicine. There is no single ratio or strain or product that’s right for everyone. Optimize your therapeutic use of cannabis by finding the proper combination of CBD and THC that works best for you. A person’s sensitivity to THC is a key factor in determining the appropriate ratio and dosage of CBD-rich medicine. Many people enjoy the cannabis high and can consume reasonable amounts of any cannabis product without feeling too high or dysphoric. Others find THC unpleasant. CBD can lessen or neutralize the intoxicating effects of THC. So a greater ratio of CBD-to- THC means less of a high. In some states with medical marijuana laws, cannabis oil concentrates and other products with varying ratios of CBD:THC are available so users can adjust or minimize psychoactive effects to suit their needs and sensitivities. Those who don’t like THC have the option of healing without the high by using a CBD-rich remedy with only a small amount of THC. But a low THC remedy, while not intoxicating, is not always the most effective treatment option. In essence, the goal is to administer consistent, measurable doses of a CBD-rich remedy that includes as much THC as a person is comfortable with.

Are specific CBD:THC ratios better for different conditions? Some patterns are beginning to emerge. For anxiety, depression, spasms, psychosis, and seizure disorders, many people report they do well starting with a small dose of a CBD-rich remedy with little THC. For cancer, autism, and many other diseases, some say they benefit more from a balanced ratio of CBD and THC. Extensive clinical trials conducted outside the United States have shown that a 1:1 CBD:THC ratio can be effective for neuropathic pain. Some people use cannabis products with different CBD:THC ratios at different times of the day (more CBD for sunlight hours, more THC at night). Almost any cannabis strain or product theoretically could benefit a wide range of autoimmune and inflammatory disorders because THC and other cannabis components activate the CB2 cannabinoid receptor, which regulates immune function. Note: The CBD:THC ratio in not an indication of how much CBD or THC is present in a given cannabis product or strain.

What is the optimal dosage of CBD? An effective dosage can range from as little as a few milligrams of CBD-enriched cannabis oil to a gram or more. Begin with a small dose of high CBD/low THC oil, especially if you have little or no experience with cannabis. Take a few small doses over the course of the day rather than one big dose. Use the same dose and ratio for several days. Observe the effects and if necessary adjust the ratio or amount. Don’t overdo it. Cannabis compounds have biphasic properties, which means that low and high doses of the same substance can produce opposite effects. Small doses of cannabis tend to stimulate; large doses sedate. Too much THC, while not lethal, can amplify anxiety and mood disorders. CBD has no known adverse side effects, but an excessive amount of CBD could be less effective therapeutically than a moderate dose. “Less is more” is often the case with respect to cannabis therapy. 

Read more: Cannabis Dosing Guide

What should one look for when choosing a CBD-rich product? Look for products with clear labels showing the quantity and ratio of CBD and THC per dose, a manufacturing date, and a batch number (for quality control). Select products with quality ingredients: No corn syrup, transfats, GMOs, artificial additives, thinning agents or preservatives. CBD-rich products should be lab tested for consistency and verified as being free of mold, bacteria, pesticides, solvent residues, and other contaminants. Best to avoid products extracted with toxic solvents like BHO, propane, hexane or other hydrocarbons. Opt for products that utilize safer extraction methods such as supercritical CO2 or food-grade ethanol.

Read more: What To Look For In Your Cannabis Medicine

If CBD is so good, won’t pure CBD be even better? Single-molecule CBD will inevitably become a federally approved Big Pharma medicine. Products infused with a crystalline CBD isolate, derived and extensively refined from industrial hemp, are already being marketed by unregulated internet storefronts. But single-molecule CBD is less effective therapeutically than whole plant CBD-rich oil extract. Scientific studies have established that synthetic, single-molecule CBD has a very narrow therapeutic window and requires precise, high doses for efficacy, whereas lower dose, whole-plant, CBD-rich treatment regimens are already showing efficacy for many conditions among patients in medical marijuana states. Whether synthesized in a Big Pharma lab or derived from industrial hemp, single-molecule CBD lacks critical secondary cannabinoids and other medicinal compounds found in high-resin cannabis strains. These compounds interact with CBD and THC to enhance their therapeutic benefits. Scientists call this the “entourage effect.” Numerous cannabis compounds have medicinal attributes, but the therapeutic impact of whole plant cannabis is greater than the sum of its parts.

Read more: Synthetic vs. Whole Plant CBD

Is there a difference between CBD derived from hemp and CBD derived from marijuana? If you live in a state where medical marijuana is legal and available, look for CBD products made from high-resin cannabis (rather than low resin industrial hemp) that are sold in medical marijuana dispensaries. Hemp-derived CBD-infused products of varying quality are also available via dozens of internet storefronts. Compared to whole plant CBD-rich cannabis, industrial hemp is typically low in cannabinoid content. A huge amount of hemp is required to extract a small amount of CBD, thereby raising the risk of contaminants because hemp, a bioaccumulator, draws toxins from the soil. That’s a great feature for restoring a poisoned ecosystem, but it’s not recommended for extracting medicinal oil. Heavily refined CBD paste or terpene-free CBD powder is poor starter material for formulating CBD-rich oil products. The FDA has tested dozens of so-called CBD “hemp oil” products and found that in many cases these products contained little or no CBD. CBD-infused nutraceuticals have not been approved by the FDA as food supplements; nor are these products legal in all 50 U.S. states. By and large, however, interstate CBD commerce is tolerated by federal authorities.

Read more: Sourcing CBD: Marijuana, Industrial Hemp & the Vagaries of Federal Law

Is it safe to inhale hemp CBD oil fumes from a vape pen? Many cannabis- and hemp-derived CBD vape oil products include a thinning agent, which dilutes the oil that is heated and inhaled by vape pen users. Beware of vape pen oil that contains propylene glycol. When overheated, this chemical additive produces formaldehyde, a carcinogen, as a byproduct, according to a 2015 report in the New England Journal of Medicine. Why do so many vape oil products contain this thinning agent? It’s because of the dubious quality of the extracted material from which these unregulated cannabis oil products are made.

Read more: How Safe is Your Vape Pen?

Does CBD have any adverse side effects? What about drug interactions? CBD is a very safe substance, but patients taking other medications should check with their doctor about drug interactions, which are more likely when consuming high doses of single-molecule CBD products. At sufficient dosages, CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds, including THC. Cytochrome P450 enzymes metabolize more than 60 percent of Big Pharma meds. CBD is a more potent inhibitor of cytochrome P450 than the grapefruit compound Bergapten, so ask your doctor if grapefruit interacts with your medication. If grapefruit does, then CBD probably does, too. Patients on a CBD-rich treatment regimen should monitor changes in blood levels of prescription medications and, if need be, adjust dosage.

Read more: CBD-Drug Interactions: Role of Cytochrome P450

Will big pharmaceutical companies control the CBD market when cannabis is legalized for adult use? Only if we let them. Cannabis is a medicinal herb and it should be regulated as an herb, not as a pharmaceutical or a street drug.

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

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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Is CBD Really Non-Psychoactive?

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


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.


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.

Survey: Cannabis Better Than Big Pharma Meds for PTSD

cannabis better for PTSD
By on March 08, 2016
Survey: Cannabis Better Than Big Pharma Meds for PTSD

Between seven and eight percent of people will develop PTSD (Post-Traumatic Stress Disorder) in their lifetime. Among military veterans, the rates are higher.

Care By Design recently surveyed 300 patients on their use of cannabis and other medications to treat PTSD. The survey asked what medications patients had been prescribed for their PTSD-related symptoms and what impact these medications—and cannabis—had on five telltale symptoms of PTSD: anxiety, depression, pain, anger or irritability, and sleep problems.

Among the findings of the survey:

  • Respondents reported that cannabis was the most likely to improve PTSD symptoms and the least likely to make symptoms worse.
  • Veterans reported being prescribed more pharmaceutical medications than civilians. They were also more likely to be prescribed medications that generally worsened their symptoms, including anti-psychotics, narcotic pain meds, and so-called mood stabilizers.
  • The most common medication prescribed for the treatment of PTSD among survey respondents was anti-depressants. Yet, few report these were effective. Only 18% of respondents said their depression got better on anti-depressants. Half reported that their depression got worse on anti-depressants.
  • Roughly half of respondents reported they had been prescribed narcotics for PTSD, and a majority of them reported that their anger and irritability, depression, and sleep problems got worse while they were on narcotics.
  • Half of the respondents reported using CBD-rich cannabis to treat their PTSD symptoms.
  • 80% of respondents reported that they consume less alcohol when using cannabis.

While largely anecdotal and limited in scope, this survey offers hope for PTSD sufferers. A growing body of research suggests that there is a strong connection between the endocannabinoid system and PTSD, and that cannabis therapy may help address the root causes of PTSD, including impaired fear extinction, poor memory consolidation, and chronic stress.

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.

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